Investigating Contamination of Phytotherapy Products for Benign

Prostatic Hyperplasia With �-Blockers and 5�-Reductase Inhibitors

Dean Sol Elterman, Nathan Lawrentschuk, Emma Guns, Karen Hersey,Hans Adomat, Catherine A. Wood and Neil Fleshner*,†

From the Princess Margaret Hospital, Toronto, Ontario, and Prostate Centre at Vancouver General Hospital (EG, HA, CAW), Vancouver,British Columbia, Canada

Purpose: Complementary and alternative medicine, including phytotherapeuticagents, or those derived from plant or herb extracts to treat symptoms, is widelyaccepted in the community. Men with bothersome lower urinary tract symptomsdue to benign prostatic hyperplasia increasingly use such preparations. Phyto-therapeutic agent quality is unregulated and in most instances the contents areunknown while erectile dysfunction and prostate cancer treatments have showncontamination with standard pharmaceuticals. Since trial results for benignprostatic hyperplasia phytotherapeutic agents are inconsistent, they may also becontaminated. Thus, we determined whether pharmacological doses of �-blockersand/or 5�-reductase inhibitors were present in a sample of phytotherapeuticagents for benign prostatic hyperplasia.Materials and Methods: We analyzed 15 phytotherapeutic products marketedfor benign prostatic hyperplasia. Only oral tablets or capsules were consideredwith teas, tonics and foods excluded from study. We made random purchasesfrom shop front health stores and Internet retailers. All batches of commercialphytotherapy were analyzed by high performance liquid chromatography. Anal-ysis was semiquantitative using extracts from alfuzosin, doxazosin, terazosin,tamsulosin, dutasteride and finasteride.Results: In the 15 batches of different phytotherapeutic agents tested no inter-ference secondary to contamination with �-blockers or 5�-reductase inhibitorswas observed.Conclusions: All phytotherapeutic agents for benign prostatic hyperplasia inthis study tested negative for �-blockers and 5�-reductase inhibitors. Inconsis-tent results in trials using phytotherapeutic agents are probably not explained bythe presence of standard pharmaceuticals.

Key Words: prostate, prostatic hyperplasia, phytotherapy, complementary

Abbreviations

and Acronyms

BPH � benign prostatichyperplasia

CAM � complementary andalternative medicine

ES– � electrospray negative

ES� � electrospray positive

HPLC � high performance liquidchromatography

LUTS � lower urinary tractsymptoms

SIR � single ion recording

Submitted for publication September 9, 2009.* Correspondence: Division of Urology, Prin-

cess Margaret Hospital, Suite 3-130, 610 Univer-sity Ave., Toronto, Ontario, M5G 2M9, Canada(telephone: 416-946-4501; FAX: 416-946-6590;e-mail: neil.fleshner@uhn.on.ca).

† Financial interest and/or other relationshipwith AstraZeneca, Sanofi-Aventis, Merck, Pfizerand Novartis.

therapies, drug contamination

IN 1994 the definition of a dietary sup-plement was broadened in the UnitedStates by the Dietary SupplementsHealth and Education Act. It openedthe pharmaceutical and nutraceuticalmarkets to many CAMs, which areherbals, botanicals and other food in-gredients that would have otherwise

needed safety testing before being sold

0022-5347/10/1835-2085/0THE JOURNAL OF UROLOGY®

© 2010 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RES

to the general public.1 Since then, var-ious CAMs have been popularized formale health symptoms and the preven-tion of related disease, such as prostatecancer. A recent American report indi-cated that 38% of adults use CAMs.2

Unfortunately the success of someagents has been clouded by issues of

safety and contamination, which are

Vol. 183, 2085-2089, May 2010Printed in U.S.A.

EARCH, INC. DOI:10.1016/j.juro.2009.12.097www.jurology.com 2085

CONTAMINATION OF BENIGN PROSTATIC HYPERPLASIA PHYTOTHERAPY PRODUCTS2086

contributed to by the lack of regulation and stan-dardization in production and manufacturing. Majorexamples in urology of contamination include PC-SPES®, which had success in treating prostate can-cer but was later found to contain the hormone di-ethylstilbestrol.3 Also, herbal erectile dysfunctionproducts have been tainted with phosphodiesterasetype 5 inhibitors, which helps explain their efficacy.4

This has led many physicians to question the valid-ity of the most commonly used CAMs in men,5 thatis phytotherapeutic agents for LUTS.1,6 The UnitedStates government was so concerned about investi-gating CAM quality and efficacy that it set up theNational Center for Complementary and Alterna-tive Medicine in 1998 to oversee the investigation ofsuch agents (http://nccam.nih.gov/about/ataglance).

LUTS in men are most commonly secondary toBPH, a prevalent condition that increases with age.Approximately 70% of 70-year-old and 90% of 90-year-old men are affected by this condition.7 Hyperplasia ofthe prostate transition zone may lead to bladder outletobstruction with symptoms such as frequency, ur-gency, hesitancy, intermittency and urinary retention.If left untreated, BPH has consequences, includingurinary retention, hematuria, bladder calculi, hydro-nephrosis and even chronic renal failure. Pharmaco-logical treatment for symptomatic BPH is availablewith 2 classes of drugs, including 1) �-adrenergic an-tagonists (�-blockers), which decrease prostate andbladder neck stromal smooth muscle tone, and 2) 5�-reductase inhibitors (finasteride and dutasteride),which interfere with the conversion of testosterone todihydrotestosterone. Such agents result in prostateshrinkage and symptomatic improvement.

There has been a large resurgence in the use ofphytotherapeutic agents for LUTS since the 1990s.1,6,8

These products have been marketed as part of abalanced approach to wellness, promoting overallprostatic health. In fact, interest in these plant ex-tracts has taken them from the realm of Europeanholistic based medicine to a multibillion dollar in-dustry in North America.5 These products have alsogained popularity since they are easily accessiblewithout a prescription in health food stores andpharmacies, and online. CAMs are promoted as safeand natural but scientific evidence is largely lackingto support these claims. The mode of action of phy-totherapeutic agents is unknown.9 The archetypalagent for BPH is saw palmetto but conflicting dataremain, although there is evidence of efficacy in asystematic review.10–12 Despite such contradictoryfindings herbal extracts continue to be consumed ata significant rate, especially in Europe where, forexample, half of German urologists prefer prescrib-ing plant based extracts to synthetic drugs.13

Given the large market for CAMs targeted toward

LUTS coupled with disparate data on product effi-

cacy and knowledge of the contamination of otherurological agents, we investigated whether there isevidence of contamination of CAMs for BPH withstandard prescription pharmaceuticals.

MATERIALS AND METHODS

We randomly purchased 15 brands of marketed herbalproducts for BPH (see table). Purchases were limited tooral tablets or capsules of products with claims of efficacyfor LUTS. Five brands were purchased from online retail-ers via the Internet and the remainder was purchasedfrom local health food stores. Purchased products were arandom sampling representing a range of price points andmanufacturer origins. For each product sampled therewere several similar products available. Tablets and cap-sules were removed from the original bottle, placed in alight shielded plastic container and assigned a study letter(A through O) by one of us (DE). After products wereobtained they were transported to the laboratory andstored at room temperature until HPLC was done. Stan-dards for the pharmaceutical samples of �-blockers and5�-reductase inhibitors were available at our laboratory.

Briefly, laboratory scientists were blinded to samplecontents. All commercially available herbal preparationsunderwent HPLC after 100% methanolic extraction. Anal-ysis was semiquantitative using extracts from alfuzosin,doxazosin, tamsulosin, terazosin, dutasteride and finas-teride, and diluted to 40 or 50 �g/ml for calibration.

Materials and Sample PreparationSamples of each of the 15 herbal preparations were emp-tied from capsules or tablets were crushed. Preparationswere transferred into 15 ml polypropylene screw toptubes. We similarly prepared 4 mg alfuzosin, 4 mg dox-azosin, 0.4 mg tamsulosin, 2 mg terazosin, 0.5 mg dutas-teride and 5 mg finasteride tablets. Samples and stan-dards were extracted with 10 ml 100% Model A-452-4HPLC Methanol (Fisher Scientific, Pittsburg, California)by vortexing to disaggregate, followed by sonication with aModel 150-T (VWR International, West Chester, Pennsyl-vania) for 30 minutes at room temperature. Aliquots ofsamples and standards were clarified by centrifugation at10,000 � gravity. Standards were further diluted in 100%methanol to bring them to 40 or 50 �g/ml.

High Performance Liquid ChromatographyA Waters 2695 Separations Module equipped with a Wa-ters ZQ2000 detector (Waters, Milford, Massachusetts)was used for semiquantitative analysis of alfuzosin, dox-azosin, dutasteride, finasteride, tamsulosin and terazosinwith this screening protocol. Separation was done at 30Cusing a 2.1 � 50 mm 3.5 �m Exterra C18 column (Waters)with a 2.1 � 10 mm guard column. Gradient separationwas done using 10% to 90% acetonitrile from 0.5 to 7.5minutes, followed by 3 minutes of 90% acetonitrile toachieve adequate separation. Throughout 0.1% formicacid was also present. Total run time was 15 minutes. Atriple quadrupole Quattro Micro mass analyzer (Waters)was used for followup analysis of samples when mass

interference was noted.

CONTAMINATION OF BENIGN PROSTATIC HYPERPLASIA PHYTOTHERAPY PRODUCTS 2087

Detector settings for the scan function were capillary 3kV; desolvation, source and cone temperature 350C, 100C

Data on tested agents

AgentRecommended Use

(No. tablets/No. times daily) BPH �/o

Internet:ProvelexTM 3/2 BPH � LUTS

HP8 (InterHealth BiosciencesAustralia, Burleigh Heads,Queensland, Australia)

3/2 BPH � LUTS

Prostate Power Rx® 2/On demand BPH � LUTSprostate fu

The Prostate® Formula 3/On demand BPH � LUTShealth � fl

Prost-Flow® 2/On demand BPH � LUTS

Local store:Prost LB7 (Albi Naturals,

Burnaby, British Columbia,Canada)

1/On demand BPH � LUTS

ModuProstTM 1/2 BPH � LUTS

Saw palmetto extract(Trader Darwin’sTM)

1/3 BPH � LUTS

Pro-5X (Nature’s Method,Surrey, British Columbia,Canada)

2/On demand BPH � LUTS

Prostate Formula (GNC®) 1/2 BPH � LUTS

Organic saw palmetto fruitextract (Bioforce USA,Ghent, NY)

1/On demand LUTS

Alive Herbs high potencysaw palmetto berry

1 (160mg)/On demand LUTS

Alive Herbs high potencyPygeum � saw palmettostandardized extract

1/On demand LUTS

Solaray® GuaranteedPotency Pygeum � sawpalmetto with vitaminB6 � zinc

1/On demand LUTS

Solaray Guaranteed PotencySPP formula

2/On demand BPT � LUTS

and 20C; extractor, RF lens and multiplier voltage 5, 0.5

and 650 V; desolvation and cone gas flow 400 and 50 l perhour, respectively; and cone voltage 30 and 50 V for ES�

Ingredients Side Effects Cost ($/mo)

Soy phytosterol, �-sitosterol,campesterol, stigmasterol,quercetin, Swedish flowerpollen, Pygeum africanumextract, selenium, stingingnettles

Allergic reactions 48

Saw palmetto, bromelain,licorice root, free fattyacids, selenium

None mentioned 37

y Saw palmetto, Pygeumafricanum, stinging nettle,quercetin, lycopene, �-sitosterol, diazein,genistein, rosaminic acid

None mentioned 25

Stinging nettle leaf powder,pumpkin seed powder, L-lysine, L-glutamic acid,glycine

Stomach irritation 35

Saw palmetto, Pygerum,stinging nettle, licorice

None mentioned 17

Saw palmetto, juniperberries, pumpkin seedextract, corn silk, buchuleaves, uva ursi, Pygerumafricanum

None mentioned 30

Harxol (plant sterols �sterolins), saw palmettoextract, nettle extract,lycopene, green tea

Contraindicated for organtransplants, diabetes,multiple sclerosis

14

Saw palmetto None mentioned 9

Eploibium parviflorum (smallflower willow herb)

None mentioned 50

Vitamin E, zinc, selenium,copper, saw palmetto berryextract, citrus pectin,pumpkin seed meal,Pygeum africanum barkextract, lycopene

None mentioned 18

Saw palmetto None mentioned 23

Saw palmetto None mentioned 12

Saw palmetto, vitamin B6,Pygeum bark extract

None mentioned 14

Pygeum africanum, sawpalmetto, vitamin B6, zinc,pumpkin seed oil, nettleextract, vitamin E, L-alanine, glutamic acid

None mentioned 24

Saw palmetto, pumpkinseed, corn silk, parsley,ginger, nettle root, kelp

None mentioned 10

r LUTS

, healthnction

,ow

and ES– modes with 0.5-second scans from 200 to 700 amu

CONTAMINATION OF BENIGN PROSTATIC HYPERPLASIA PHYTOTHERAPY PRODUCTS2088

in each mode. Injects (2 �l) of standard extracts wereanalyzed using the scan function to determine retentiontime for analytes and select the optimal cone voltage toapply to SIR functions. Other parameters were the sameas for scan mode. Fragmentation characteristics were de-termined using the daughter scan mode of the mass ana-lyzer for select analytes and for parameters selected formultiple reaction monitoring. The instrument was run atunit resolution at 0 and 2 V for collision cell entrance andexit voltages, respectively, using ultra high purity argoncollision gas at about 3.0 millibars. Other instrument pa-rameters were the same as for the detector.

RESULTS

The table lists the CAMs tested. Most CAMS con-tained combinations of agents. Prices were $9 to $50per month (mean $24). Saw palmetto was the mostcommon ingredient, followed by Pygeum africanum.Indications were generally BPH and LUTS com-bined but some CAMS discriminated between the 2descriptions. One to 3 tablets daily were recom-mended but it was unclear how these doses werecalculated or determined, ie no study or productmaterial on bioavailability was available for theproducts tested. Only 3 of 15 materials mentionedpotential side effects and no products had directionsor instructions on how to seek medical attention inthe advent of failure to treat symptoms.

Analysis of all standards with HPLC was moresensitive in ES� than in ES–. Effectively no inter-ference was noted for the standards at the concen-trations used.

Two point calibration curves were generated forall analytes in each mode using SIR data on thestandards. These calibrations were applied to herbalpreparation analysis. Chromatographic traces of theherbal extracts in general were qualitatively morecomplex with greater peak numbers. ES� and ES–results were compared to identify the potential pres-ence of known analytes in the preparations withsubstantial positive results for each mode used asthe identity criterion. The ES– finasteride responsewas poor and positive results in this channel weredisregarded. Using these criteria positive responseswere achieved in test samples C, F and L with 0.06,0.15 and 0.11 �g/ml alfuzosin, finasteride and dutas-teride, respectively (ES� calibration).

Followup analysis of the same extracts using thegreater selectivity of triple quadrupole analysis re-vealed negative results, indicating that the low levelpositive responses initially suggested by SIR mea-surements were not due to the presence of any pre-scription drugs in test samples.

DISCUSSION

Herbal preparations have long been the cornerstone

of medical treatment before the age of modern phar-

maceutical therapy. The ancients used naturallyoccurring substances such as bark and roots tocure ailments. Today CAMs continue to grow inpopularity among health consumers. Many indi-viduals see herbal products as natural and, thus,less likely to have adverse side effects and morelikely to be better for health. Urological conditionssuch as LUTS have long been treated with CAMssuch as saw palmetto, which has been used to helpalleviate BPH symptoms for centuries and continuesto be one of the most successfully commercializedherbal products.8,14

In our study the randomly sampled group of CAMpreparations for LUTS tested negative for adulter-ation with alfuzosin, doxazosin, tamsulosin, terazo-sin, dutasteride or finasteride. This contrasts with asimilar study performed by our group that assessedphosphodiesterase inhibitor type 5 contamination ofproducts used to treat erectile dysfunction.4 Furtherevidence for skepticism arose when PC-SPES hadencouraging results for prostate cancer but it waslater found that the effects of this CAM were due tothe hormone diethylstilbestrol.3

Given the previous contamination results, it isnot surprising that many groups have questionedthe validity of the most common CAMs in men,5

such as saw palmetto. However, evidence of efficacyis accumulating along with that of other CAMs. Forexample, the recent multicenter TransEuropean Re-search into the Use of Management Policies forLUTS Suggestive of BPH in Primary Health Carestudy of LUTS/BPH treatment revealed significantimprovement in 43% of patients on Serenoa repensor Pygeum africanum compared to 57% of those onfinasteride and 68% on �-blockers.15 In a systematicreview Wilt et al concluded that saw palmetto is effi-cacious for LUTS.16 Other reviews of phytotherapy,such as Pygeum africanum17 and rye grass pollen ex-tract (cernilton),18 provide evidence that each agentprovides modest symptomatic improvement in menwith LUTS. However, the studies analyzed were lim-ited by sample small size and short duration, andlacked standardization.

CAMs are currently not recommended by Ameri-can Urological Association and European Associa-tion of Urology BPH guidelines.9,19 Despite this, amultibillion dollar industry has evolved in the lastdecade based on CAM sales due to the underlyingbelief that herbals are natural and, thus, safe. TheCAM industry is essentially unregulated and pro-ducers are not required to follow good manufactur-ing practices. Failure to do so results in productvariation among batches, heavy metal and pesticidecontamination, and even therapeutic drug contami-

nation.5

CONTAMINATION OF BENIGN PROSTATIC HYPERPLASIA PHYTOTHERAPY PRODUCTS 2089

CONCLUSIONS

CAMs are not subjected to the same scientific rigorand safety standards as prescription pharmaceuti-cals. In terms of CAMs for BPH saw palmetto is themost studied agent. Even so, the exact mechanism ofaction remains unclear. The most widely suggestedmechanism in in vitro studies is that the plant li-posterolic extract has anti-androgen effects that in-hibit 5�-reductase isoenzymes. However, no clinicalstudies have shown any decrease in serum dihydrotes-tosterone or prostate specific antigen.20 Clearly morebasic research of CAMs for BPH is warranted. That iswhy the National Center for Complementary and Al-ternative Medicine was created.

Our study was limited by the inability to test allCAMs that are marketed to treat BPH. Thus, ourseries represents only a sampling of what is avail-able to patients. Agents marketed in some countriesare not marketed in others and international stan-dards for labeling and active ingredient doses have

not been established for CAMs in this field. Further-

REFERNCES

screening population. Urology 2004; 63: 288. 2003; 92: 267.

more, given the lack of good manufacturing practices,we may simply have missed contaminated batches bychance.

We found no evidence of contamination with stan-dard prescription medication in our sampling of themany CAM preparations available for BPH symp-toms. Nevertheless, the other issues surroundingCAMs remain relevant. Particularly refining andstandardizing preparations are required. Our datasuggest that some inconsistent results in the litera-ture were not due to adulteration but may be ex-plained by other phenomena, such as the placeboeffect, and trial design and analysis. We believe thatit is prudent for physicians to understand CAMs,their potential benefits and effects. Also, interac-tions with other medications and interference withlaboratory testing have not been well studied. Weawait further trials of standardized BPH CAMs us-ing good manufacturing practices that may helpguide physicians and move such agents from being

alternative treatment to the mainstream.

1. Gunther S, Patterson RE, Kristal AR et al: Demo-graphic and health-related correlates of herbaland specialty supplement use. J Am Diet Assoc2004; 104: 27.

2. Barnes P, Bloom B, Nahin R: Complementary andAlternative Health Use Among Adults and Chil-dren: United States 2007. National Health Sta-tistics Report 12. Washington, D. C.: Centers forDisease Control, December 2008.

3. Guns ES, Goldenberg SL and Brown PN: Massspectral analysis of PC-SPES confirms the pres-ence of diethylstilbestrol. Can J Urol 2002; 9:1684.

4. Fleshner N, Harvey M, Adomat H et al: Evidencefor contamination of herbal erectile dysfunctionproducts with phosphodiesterase type 5 inhibi-tors. J Urol 2005; 174: 636.

5. Rosecrans R and Dohnal JC: The effect of com-plimentary and alternative medicine products onlaboratory testing. Semin Diagn Pathol 2009;26: 38.

6. Barqawi A, Gamito E, O’Donnell C et al: Herbaland vitamin supplement use in a prostate cancer

7. Berry SJ, Coffey DS, Walsh PC et al: The devel-opment of human benign prostatic hyperplasiawith age. J Urol 1984; 132: 474.

8. Lowe FC and Fagelman E: PhytotherapeuticAgents in the Treatment of Chronic Prostatitis.Oxford, United Kingdom: Isis Medical Media1999.

9. de la Rosette J, Alivizatos G, Madersbacher S et al:European Association of Urology. Guidelines onBenign Prostatic Hyperplasia 2004. Available athttp://www.uroweb.org/fileadmin/tx_eauguidelines/2009/Full/BPH.pdf. Accessed May 19, 2009.

10. Wilt TJ, Ishani A, Stark G et al: Saw palmettoextracts for treatment of benign prostatic hyper-plasia: a systematic review. JAMA 1998; 280:1604.

11. Bent S, Kane C, Shinohara K et al: Saw palmettofor benign prostatic hyperplasia. N Engl J Med2006; 354: 557.

12. Willetts KE, Clements MS, Champion S et al:Serenoa repens extract for benign prostate hy-perplasia: a randomized controlled trial. BJU Int

13. Lowe FC and Ku JC: Phytotherapy in treatment ofbenign prostatic hyperplasia: a critical review.Urology 1996; 48: 12.

14. Gilani AH and Rahman AU: Trends in ethnophar-mocology. J Ethnopharmacol 2005; 100: 43.

15. Hutchison A, Farmer R, Verhamme K et al: Theefficacy of drugs for the treatment of LUTS/BPH,a study in 6 European countries. Eur Urol 2007;51: 207.

16. Wilt T, Ishani A and MacDonald R: Serenoarepens for benign prostatic hyperplasia. CochraneDatabase Syst Rev CD001423, 2002.

17. Wilt T, Ishani A, MacDonald R et al: Pygeumafricanum for benign prostatic hyperplasia. Co-chrane Database Syst Rev CD001044, 2002.

18. Wilt T, MacDonald R, Ishani A et al: Cernilton forbenign prostatic hyperplasia. Cochrane DatabaseSyst Rev CD001042, 2002.

19. Nguyen BD: Positron emission tomography imag-ing of renal vein and inferior vena cava tumorthrombus from renal cell carcinoma. Clin NuclMed 2005; 30: 107.

20. Fagelman E and Lowe FC: Saw palmetto berry as

a treatment for BPH. Rev Urol 2001; 3: 134.