Wednesday, 25 July 2018
Herbal Supplements for Prostate Enlargement: Current State of the Evidence
Urology Volume 112, February 2018, Pages 145-150 Urology Prostatic Diseases and Male Voiding Dysfunction Author links open overlay panelRezaNabavizadehaMahdiZangibMichelle M.KimbMaryamYavari BejestanibShahinTabatabaeib a Department of Urology, Emory University, Atlanta, Georgia b Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, MA Received 25 June 2017, Accepted 10 October 2017, Available online 26 October 2017. crossmark-logo https://doi.org/10.1016/j.urology.2017.10.021 Get rights and content Objective To provide a comprehensive review of the current state of herbal supplement market for lower urinary tract symptoms (LUTS) and correlate the ingredients of each product with available scientific evidence. Materials and Methods Twenty-seven products from Amazon.com that were advertised as herbal supplements for LUTS and had listed their active ingredients were selected. Active ingredients were reviewed on Google Scholar. Product price, warranty, and consumer review information were also collected. Results A total of 58 unique active ingredients were identified. The mean number of ingredients was 8.26 (standard deviation 5.25). Whereas 17 (63%) products had an ingredient with a systematic review to support their use, 20 (74%) had an ingredient with conflicting evidence based on systematic reviews. Out of the supplements that contained ingredients supported by literature, all (100%) products simultaneously had other ingredients with no, conflicting, or refuting evidence. There was no (0%) product that contained only scientifically proven ingredients. There is no scientific study to evaluate these supplements as a whole. Conclusion Despite the widespread use of herbal supplements for LUTS, there is scant scientific evidence to support their safety and efficacy. Lack of adequate regulation and government support for research and development are some of the factors that disincentivize researchers to study safety and efficacy of these products. We encourage physicians to warn their patients on the lack of adequate evidence to support the safety and efficacy of many of these supplements. Previous article Next article The use of complementary and alternative medicine (CAM) continues to grow in the United States from $21.2 billion in 1997 to $34 billion in 2007.1, 2 A significant part of this growth in urology has been seen in the treatment of benign prostatic diseases signifying the increased demand for these therapies. Although there is limited scientific evidence to support their efficacy, numerous botanical preparations are available, often produced with herbal extracts that contain additional additives such as minerals, vitamins, or amino acids. Given the large consumption of herbal medicines for benign prostatic enlargement and lower urinary tract symptoms (LUTS), there is a need to further investigate these products for safety and efficacy. Physicians are commonly asked about the efficacy and safety of these herbal supplements, but unfortunately, most physicians do not have sufficient information to provide their patients with adequate facts to persuade them one way or another. The purpose of the study is to provide an extensive review of the current state of herbal supplement market for LUTS relief and correlate the ingredients of each product with available scientific evidence. To our knowledge this is the first study of this kind to critically evaluate these supplements and their individual ingredients. Methods To determine the CAM products available for benign prostatic enlargement, we searched on Amazon.com as the largest online marketplace in the United States using the search term “prostate enlargement.” We selected all products that specifically addressed LUTS. Products that did not list their ingredients were excluded. Listed ingredients were reviewed on Google Scholar to assess the efficacy of each ingredient without limitations on language or publication status. We used the search term “[ingredient name] benign prostatic hyperplasia” to review all scientific evidence available. We categorized the scientific evidence for each ingredient into 3 types of studies: human, animal, and in vitro studies. Human studies were further categorized as systematic reviews, randomized control trials (RCTs), cohort, or case-controlled studies. We also collected product price, warranty, and consumer review information. Google Scholar was used for the literature review because it is easily available to all consumers and indexes the publications beyond the standard journals in PubMed.3 This would certainly lower the bar and may question the quality and credibility of some of these publications. Statistical analysis was conducted using SPSS v.16. As a final step, we used the same search term on Google Shopping to compare our results with a second online market to ensure inclusiveness of our study. Results Forty-one products were advertised as herbal supplements for the treatment of prostate enlargement and claimed to relieve LUTS. Of these, 34 (83%) were produced in the United States, 2 (5%) in Australia, 2 (5%) in Canada, 2 (5%) in India, and 1 (2%) in Spain (Table 1). The median price per month supply was $26.47 (range: $2.63-$319.98). There was no statistically significant correlation between number of effective ingredients and monthly supply cost (P = .80) or consumer satisfaction (P = .20). Less than half of the products (46.3%) had a money-back guarantee. Thirty-six (87%) supplements were reviewed by customers with a mean satisfaction score of 4.38 out of 5 (range: 3.1-5). Consumer reviews were mostly descriptive and not based on any specific methodology. In some instances, we observed that the same review was used for more than 1 supplement. We did not formally study the reviews and cannot comment on the prevalence of unreliable reviews. Table 1. Summary of the 41 supplement products Manufacturing Country United States 34 (83%) Australia 2 (5%) Canada 2 (5%) India 2 (5%) Spain 1 (2%) Price ($) per 1 mo supply 26.47 [2.63-319.98] Money-back guarantee 19 (46%) Satisfaction score (out of 5) 4.38 [3.1-5] Mean number of ingredients (SD) 8.36 (5.25) Commonly used ingredients for the 27 supplements that listed their ingredients Serenoa repens 20 (74%) Zinc 20 (74%) Lycopene 14 (56%) β-Sitosterol 14 (52%) Pygeum africanum 12 (44%) Urtica dioica 12 (44%) SD, standard deviation. Range in brackets. Of the products advertised for prostate enlargement, 14 (17%) did not list ingredients and were excluded from this study. A total of 58 unique active ingredients were identified across the remaining 27 supplements. The mean number of ingredients per supplements was 8.26 (standard deviation 5.25) (Fig. 1). The most commonly used ingredients were Serenoa repens (saw palmetto) (74%), zinc (74%), lycopene (56%), β-sitosterol (52%), Pygeum africanum (44%), and Urtica dioica (stinging nettle) (44%) (Table 1). Table 2 presents the level of evidence associated with each product. Seventeen (63%) products had an ingredient with a systematic review to support its use and 20 products (74%) had an ingredient with conflicting evidence based on systematic reviews (Appendix I and Table 3). Six (14%) products had at least 1 ingredient with an RCT. Twenty-three products (85%) had at least 1 scientifically proven ingredient based on human studies. One product (4%) had ingredients shown to be effective only in animal studies. Out of the supplements that contained ingredients supported by literature, all (100%) products simultaneously had other ingredients with no, conflicting, or refuting evidence. There was no (0%) product that contained only scientifically proven ingredients. Currently there are few studies that have evaluated the potential synergistic or antagonistic effects between 2 or 3 of the most commonly used ingredients. However, in most cases, the herbal supplements are a blend of many different ingredients. We could not find any scientific study to evaluate these herbal supplements as a whole. Figure 1 Download high-res image (86KB)Download full-size image Figure 1. Average number and relative frequency of ingredients based on the level of evidence for the 27 herbal supplements marketed for BPH on Amazon. BPH, benign prostatic hyperplasia. (Color version available online.) Table 2. Twenty-seven products with evidence for efficacy of their ingredients Name of Product Human Studies Animal Studies Molecular/In Vitro Conflicting/No Scientific Evidence Amazing Prostate Formula, Advanced Support for Prostate Health 6 4 0 8 Activa Naturals Prostate Health Supplement 6 4 0 8 Advanced Prostate Health, Bladder Discomfort & Urinary Tract Health Supplement 4 1 0 1 AE-3 Chrysin with DIM & Stinging Nettle Root Extract 1 1 1 1 Cenegenics Prostate Formula 3 1 1 3 DHT Blocker for Hair Growth and Gray 4 2 0 4 EXTRA MEGA PROSTAMAX 4 2 0 4 Hammer—PSA Caps 3 0 0 4 Health Products Distributors, Prosta Plus 3 2 0 8 Maximum Strength prostate 6 4 0 8 Miracle Prostate Health Supplement 0 0 0 1 Natural Factors Saw Palmetto with Lycopene 2 0 0 2 NOW Foods Saw Palmetto 0 0 0 1 NutriMen+ 0 0 0 11 Prairie Naturals Prost-Force 3 2 0 4 Prost-Xtra Plus 2 0 0 3 Prosta Health 1 1 0 4 Prostacet Prostate Support 2 0 0 2 Prostalex Plus 2 0 0 2 ProstaMale 1 0 0 3 Prostamax 1 0 0 3 Prostate control 4 1 0 4 Prostate Essence 2 0 0 8 Prostate Support Natural Formula 6 4 0 8 Prostate-D 1 2 0 2 Rite Aid Saw Palmetto Complex 0 1 0 2 SWISSE ULTIBOOST PROSTATE 4 3 0 6 Table 3. Level of evidence for each ingredient Human Studies Animal Studies Molecular/In Vitro Conflicting or No Scientific Evidence Lycopene (56%) Pumpkin seed (37%) Chrysin (7%) Serenoa repens* (74%) Fo-Ti (12:1 extract) (4%) Beta-sitosterol* (52%) Reishi mushroom (19%) Zinc (74%) Folic acid (4%) Pygeum africanum* (44%) Graviola (15%) Vitamin E (37%) Glycyrrhiza glabra root (4%) Urtica dioica (44%) Shiitake mushroom (15%) Vitamin B6 (30%) Grape seed extract (4%) Selenium (37%) Diindolylmethane (11%) Copper (22%) Guarana extract (4%) Cat claw (19%) Korean ginseng (7%) Green tea (22%) Horny goat weed (4%) Maitake mushroom (15%) Genistein (4%) Broccoli (15%) Isatis tinctoria (4%) Vitamin A/beta carotene (7%) Pomegranate (4%) Red raspberry (15%) Lecithin (4%) Annual ryegrass/Cernilton* (4%) Quercetin (4%) Vitamin D (11%) Magnesium (4%) Turmeric/Curcuma longa (4%) Vitamin C (7%) Manganese (4%) Glutamic acid (7%) Methyl sulfonyl methane (4%) Graminex G63 flower pollen extract (7%) Molybdenum (4%) l-Alanine (7%) Mucuna pruriens (4%) l-Glycine (7%) N-acetyl-l-cysteine (4%) Bioperine (4%) Tongkat ali (4%) Boron (4%) Uva ursi leaf powder (4%) Chromium (4%) Vanadium (4%) Cnidium monnieri (4%) Vitamin B3 (4%) Dehydroepiandrosterone (4%) Xanthoparmelia scabrosa (4%) Parentheses indicate prevalence of ingredient in the 41 products examined. * Systematic review. In the last step we compared the above results obtained from products sold on Amazon with products marketed on Google Shopping. A total of 50 ingredients were identified in the top 20 products that were marketed on Google for prostate enlargement and LUTS. Six ingredients (12%) showed clinical efficacy in human studies (1 systematic review, and 5 RCTs). Four ingredients (8%) showed benefits in animal study models, and no products had ingredients with molecular and in vitro evidence of efficacy. Out of these 50 ingredients, 28 (56%) were similar to the ingredients found in the Amazon products. Of the other ingredients, none had any level of evidence for effectiveness in LUTS. Discussion The results of this study demonstrate a significant online market presence for herbal supplements advertised for management of LUTS. Some of these products are supported by money-back guarantees and strong claims about their efficacy and safety. Besides manufacturers' claims, anecdotal consumer testimonials in the form of online reviews try to enhance product credibility. We used Google Scholar for the literature review because it is easily available to all consumers and indexes the publications beyond the standard journals in PubMed.3 This may reduce quality and credibility of some of these publications. Nevertheless, we intentionally included all sources to amplify the potential claims supporting the evidence of these supplements. The purpose of this study was not to question the credibility and methodology of these publications, which certainly deserve more scrutiny, but to report on the presence or absence of any evidence that evaluated the clinical use of herbal ingredients for LUTS. We found that many of these products contain ingredients that lack sufficient scientific or clinical evidence to support their efficacy. Only a few ingredients had supporting research that included systematic reviews or RCTs. Additionally, the majority of the RCTs and systematic reviews only followed patients for 6-12 months, making it difficult to determine the long-term efficacy and safety of these products as demonstrated in multiple case reports with longer follow-up.4 Proponents of herbal supplements usually claim that lack of evidence for safety and efficacy does not infer risk or inefficacy. We do not disagree with them on this principle. However, it is also true that the lack of safety data does not assume the product is safe. In fact, pharmaceutical medications face rigorous approval process to demonstrate safety and efficacy before sales begin. We believe any manufacturer selling a supplement to consumers who claims an alternative to standard, FDA-approved medication, is responsible for proving validity of their claim. This trend could make some manufactures legally liable for their unfounded claims.5 Although many factors contribute to the lack of research on dietary and herbal supplements, the Dietary Supplement Health and Education Act of 1994 restricting Food and Drug Administration oversight may have been the most important factor in this regard. Herbal supplement manufacturers do not have to fund rigorous, time–consuming, and expensive trials to prove the safety and efficacy of the product before bringing them to the market. This has allowed manufacturers to produce supplements without significant efficacy data and quickly turn profits.6 Other barriers for research include the lack of standardization in the potency of the herbal supplement. Potency varies across batches depending on the source and geographical location of the herbal plant, time of harvest, extraction method used (aqueous, alcoholic, glycerin). This problem is compounded by the variety of ingredients that are used in each product, leading to adulteration risk from undeclared additives.7 Furthermore, the lack of patent protection can also be a deterrent for many of these herbal supplement companies to invest on costly clinical trials. The cumulative effects of the regulatory state lead to little incentive for companies to invest in research to support their safety and efficacy.8 Moreover, another limiting factor for independent investigators is lack of reproducibility. During this study we found that repeating the search with the same query term after only a few weeks yielded a different list of supplements. This seems to be due to introduction of supplements with similar or identical ingredients under new names and termination of the products with low consumer ratings by the same company. The current state of federal regulation makes the aforementioned practice financially attractive and allows these companies an affordable “fresh start.” Despite the lack of convincing evidence for their efficacy and safety, CAM products continue to demonstrate increased consumer demand both in the United States and Europe.9 Utilization estimates are upwards of 50% of all US adults. Overall, 23% reported use based on recommendation by a health professional.9 Supplements are most commonly taken to improve or maintain health and it seems are being used more often in consumers who have lower body mass index, use moderate alcohol, are more likely to exercise, and usually have health insurance.10 Because CAM is often not covered by health insurance, patients who are willing to pay out-of-pocket for these supplements may be more lenient toward their presumptive effectiveness. These consumption patterns give rise to concerns about unsubstantiated health claims provided by herbal supplement manufactures and the potential dangers to patients. Conclusion Despite the widespread use of herbal supplements for LUTS, there is scant scientific evidence to support their safety and efficacy. Lack of adequate regulation and government support for research and development are some of the factors that disincentivize researchers to study the safety and efficacy of these products. We encourage physicians to warn their patients on the lack of adequate evidence to support the safety and efficacy of many of these supplements. Appendix I Summary of Evidence for Ingredients • Serenoa repens S. repens is one of the most commonly used ingredient for benign prostatic hyperplasia (BPH). In a randomized controlled trial (RCT) by Marks et al,11 318 mg of daily S. repens intake was not shown to be significantly better than placebo in controlling BPH symptoms after 6 months of consecutive use. In another RCT by Gerber et al,12S. repens lead to improvement in self-reported urinary symptoms and quality of life; however, it had no measurable effect on urinary flow rate when compared with placebo after 6 months. In a large RCT by Bent et al,13 225 men over the age of 49 years with moderate-to-severe symptoms of BPH were treated with either S. repens extract (160 mg twice a day) or placebo for 1 year. At the end of the study, S. repens did not show any improvement in symptoms or objective measures of BPH. Several systematic reviews have also been conducted with mixed results in terms of efficacy or subjective and objective urinary measures (Wilt et al; Tacklind et al).14, 15 Although there are a few RCTs supporting the use of S. repens for BPH, recent systematic reviews and majority of literature do not show any improvement in objective urinary measures and self-reported symptoms. There are several placebo-controlled RCTs that have reported the following adverse events associated with S. repens16: headache, vertigo, nausea, vomiting, diarrhea, gastrointestinal bleeding, and other gastrointestinal disorders, fatigue, cardiovascular complaints, common cold, and urinary problems. Moreover, a recent study has shown potentially increased risk of bleeding in geriatric population who take S. repens with anticoagulants.17 • Zinc The prostate gland has a high concentration of zinc, and it is occasionally considered as a zinc pool in the body. Moreover, zinc concentration is significantly decreased in prostatitis and prostate cancer. Therefore, it was suggested that dietary zinc might have a role in lowering BPH symptoms (Dunzendorfer et al; Zaichick et al; Wilden and Robinson).18, 19, 20 However, there is no consensus in the literature about the effectiveness of zinc in BPH. Lagiou et al (1999)21 conducted a case-control study which showed that increased dietary zinc was associated with increased risk of BPH. Kristal et al22 found a weak but statistically significant association between zinc and reduced BPH risk. Given the inconsistency in literature and lack of a systematic review, we put zinc in “conflicting evidence category.” • Lycopene Studies suggest the protective role of lycopenes against prostate cancer. A few RCTs have reported a protective role for lycopene against BPH progression. Schwarz et al23 showed decreased progression in prostate enlargement measured by transrectal ultrasound and drop of prostate-specific antigen values in the treatment group. The study did not show any clinically meaningful change in International Prostate Symptom Score after 6 months. Although the human studies on lycopene are significantly limited, we still categorized lycopene as an ingredient with good evidence based on “RCT based in human studies.” • β-Sitosterol In a systematic review by Wilt et al,24 β-sitosterol was shown to improve both urinary symptoms and flow measures in short term. Therefore, we put β-sitosterol in the category of ingredients with good evidence based on “systematic review of human studies.” We failed to find any more recent study on this ingredient. • Pygeum africanum A systematic review by Ishani et al25 suggests that P. africanum modestly, but statistically significantly, improves urologic symptoms and flow measures. Although the study only showed modest improvement in symptoms, still we considered P. africanum an ingredient with good evidence based on “systematic review of human studies.” • Urtica dioica U. dioica supplement is derived from the roots of this herbaceous flowering plant. Nahata et al26 suggested a protective role for U. dioica in rats. In a human RCT by Safarinejad et al,27 patients using U. dioica had a statistically significant improvement in terms of International Prostate Symptom Score, peak flow, and post void residual when compared with the placebo arm. We considered U. dioica an ingredient with good evidence based on “RCT in human studies.” References 1 D.M. Eisenberg, R.B. Davis, S.L. Ettner, et al. Trends in alternative medicine use in the United States, 1990-1997: results of a follow-up national survey JAMA, 280 (1998), pp. 1569-1575 CrossRefView Record in Scopus 2 A.M. Schultz, Chao S.M., J.M. 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