ELSEVIER CLINICAL REVIEW PHYTOTHERAPY IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA: AN UPDATE FRANKLIN C, LOWE anp ELLIOT FAGELMAN I has been almost 3 years since the previous re- view of phytotherapeutic agents for benign pros-> tatic hyperplasia (BPH) by Lowe appeared in Urol- ogy.! During this period, there has been a rapid increase in the use of these products in the United States as well as substantial widespread use in Eu- rope. It has been estimated that total sales of me- dicinal botanicals in the United States has risen from more than $500,000 to approximately $1 bil- lion during this time. In the urology practice of one of us (F.C.L.), more than 90% of the newly referred patients with lower urinary tract symptoms (LUTS) secondary to BPH have already tried or are using some form of alternative/complementary medications.* The most commonly used agents are saw palmetto berry (SPB) extract, “men’s health pills” (which contain multiple botanicals), zinc, selenium, and vitamin E. A recent national survey conducted by National Family Opinion Inc. and reported in JAMA determined that the widespread use of these agents was due to philosophical congruence with peoples’ own values, beliefS, and orientation to- ward health and life.? In fact, the younger, better educated, healthier people tended to be the greatest users of comple- mentary medications.® Therefore, it is not surpris- ing that many of these medicinal botanicals/phyto- therapeutic agents are being sold over the Internet. Last year, more than 100 websites marketing SPB or some other formulation of “men’s health” or Prostate health” pills containing SPB were ident- Pde Despite the increased use of these agents in the United States, most American urologists have little knowledge or understanding of them. In fact, most American physicians are very skeptical about the use of phytotherapeutic agents because of the lim- From the Department of Urology, St. Luke's Roosevelt Hospital Center and Columbia University, College of Physicians and Sur- ‘eons, New York, New York Reprint requests: Franklin C. Lowe, M.D., 425 West 59th Street, 3A, New York, NY 10019 Submitted: October 28, 1998, accepted (with revisions): De- cember 7, 1998 oe ited evidence of their efficacy. However, over the past 3 years numerous studies assessing the effi- cacy and determining the mechanism of action of these agents have been published. These reports are critically evaluated herein COMPARABILITY OF PLANT EXTRACTS. Numerous plant extracts have been used in the treatment of LUTS secondary to BPH (Table 1. Some of these extracts are derived from the roots, seeds, bark, or fruits of the plants shown in Table I These phytotherapeutic agents are available as ei- ther a single agent (monopreparation) or more likely as a combination product. This variation ob- viously makes comparisons between products dif- ficult. ‘Additionally, plant extracts are composed of nu- merous components (Table II), The extracts are synthesized by different extraction procedures. Therefore, the botanical product of one company may be different from that of another with regard to specific composition and effective components (because we do not know what the active compo- nents of these products are), even if they originate from the same plant. There is also natural variabil- ity among the plants themselves. Because the results of basic research and clinical trials cannot be automatically accepted and/or transferred from one new manufacturer's product to another, the different preparations from each individual manufacturer need to be evaluated indi- vidually. This necessity was emphasized by the Committee on Other Medical Therapies of the Fourth International Consultation on Benign Pros- tatic Hyperplasia? SERENOA REPENS (SAW PALMETTO BERRY EXTRACT) SPB extract remains the most popular and widely used phytotherapeutic agent for LUTS secondary to BPH. Two extensive reviews of this agent have been published since our last review in this jour- nal.78TABLE I. Origin of plant extracts used in treatment of benign prostatic hyperplasia Vernacular Name Scie ific Name African plum Pygeum africanum Purple cone flower Echinacea purpurea Pumpkin seeds Cucurbita pepo Rye Secale cereale Saw palmetto berry/ Serenoa repens dwarf palm South African star grass Stinging nettle Hipoxis rooperi Urtica dioica ‘Adapted with permission of Eleier Science ftom Urology, 48, F.C. Lowe and. . Ku, Phytotherapy in eeatment of benige prosaic hyperplasia: a ertcl review, TABLE II. Some of the components of plant extracts* Phytosterols Phytoestrogens Terpenoids Fatty acids Lectins Plant oils Polysaccharides Flavonoids + Data from Drethor ta? MECHANISM OF ACTION Most in vitro studies that have sought to eluci- date the mechanisms of action of SPB extract have been performed using Permixon, the liposterolic extract of SPB. In recent publications, it has been postulated that the liposterolic extract of Serenoa repens has antiandrogenic effects,? inhibits the type Land type 2 isoenzymes of 5-alpha-reductase,°-? inhibits prolactin and growth factor-induced cell proliferation," and has antiestrogenic!’ and an- ti-inflammatory’* effects, However, most of these in vitro studies were per- formed in cell cultures or used supraphysiologic dosages of SPB extract. Therefore, the significance of these mechanism studies is uncertain. Di Silverio et al.,)” in a recent ex vivo study, sup- ported the concept that the liposterolic extract of SPB (Permixon) has antiandrogenic effects that in- hibit the type 1 and type 2 isoenzymes of 5-alpha- reductase. Ina randomized study, 33 patients with BPH underwent suprapubic transvesical prostatec- tomy alter being treated with either finasteride (5 mg/day for 3 months), flutamide (750 mg/day for 2 months) or Permixon (320 mg/day for 3 months) or received no treatment. None of these treatments caused a significant alteration in tissue concentra- tions of testosterone. However, both Permixon and finasteride exhibited a 50% reduction in prostate dihydrotestosterone (DHT) levels (P <0.01) compared with flutamide or with no treatment. For en both agents, this effect was primarily in the peri- urethral zone tissues. In contrast, Weisser et al."® performed a prospec- tive, randomized, double-blind trial using an ex- tract of Sabal serrulata (IDS-89) to determine the passible influence on epithelial and stromal en- zymes in BPH tissue. Patients were treated with either placebo or IDS-89 for 3 months, at which time they underwent suprapubic transyesical pros- tatectomy. The tissues were evaluated for 5-alpha- reductase, 3-alpha- and -—_-3-beta-hydroxy- steroid oxidoreductase, and creatine kinase activ- ity. There was no difference in 5-alpha-reductase and 3-alpha- and 3-beta-hydroxysteroid activity between those treated with IDS-89 versus placebo. However, creatine kinase activity was statistically significantly increased in patients treated with IDS- 89. Because the synthesis of creatine kinase is es- trogen dependent, it is possible that IDS-89 might affect the balance of androgens in relation to estro- gens. The clinical significance of this possibility is not known. Between-group pathologic comparisons of the tissue were also analyzed and reported separate- ly.19 Those pretreated with S. serralata showed a significant reduction in periglandular and stromal edema, mucoid degeneration, intraglandular con- gestion, and “congestive prostatitis.” The clinical significance of these pathologic findings is unclear. In contrast, previous laboratory studies by Rhodes et al.2° did not demonstrate any inhibition of DHT binding to rat prostatic androgen receptor or inhibition of DHT activity. Additionally, several clinical studies measured serum testosterone, DHT, prostate-specific antigen (PSA), and follicle- stimulating hormone (FSH) levels in patients given SPB extracts for variable periods of time up to 6 months.*°4 None of these studies showed any al- teration in testosterone, DHT, PSA, and FSH levels Therefore, the effect on hormone metabolism and 5-alpha-reductase activity by S. repens (including Permixon) has yet to be determined conclusively. CuinicaL STUDIES Since our previous review, another placebo-con- trolled study has been published in which 176 of 215 nonreponders to placebo were randomized to receive Permixon 160 mg twice daily or placebo for 30 days.2° Subsequent evaluation showed that dys- uuria, daytime frequency, nocturia, and peak uri- nary flows were all improved in Permixon-treated patients compared with baseline values and place- bo-treated patients (Table II1). However, at the end of the study, when the patients and physicians were asked to assess global efficacy of the different treatments, there was no statistical difference in satisfactory responses between Permixon therapy (71% and 57%) and placebo treatment (68% and Uracy «fa 1000TABLE II. Comparison of Permixon and placebo for benign prostatic hyperplasia* TABLE lV. Outcomes of therapy after 26 weeks with Permixon or finasteride (Proscar)* Placebo _Permixon P Value Permixon Proscar Mean change in daytime —0.2% -0.8 0.012 IPSS frequency episodes Absolute change 58 -6.2 % change -2.9% ~11.3% 9% change 37% 39% Mean change in nocturia. 0.3 -0.7 0,028 Qmax {ml/s) episodes Absolute change 27 3.2 % change ~17.7% -32.5% % change +25% +30% Mean change in Qmax Quality of life ‘Absolute change +11 +34 0.038 Absolute change 14 -15 % change +8.5% +28.9% % change 38% 41% Patient global efficacy 67.5% — 71.3% NS Ker IPSS = International Prostate Symptom Score; Qmax = maximal urinary flow. Physician giobal efficacy 47.2% 56.6% NS Duta fam Casaosa etal" Kev: max = maximal urinary flow; NS = not sigificat * Data from Desots eta 47%), respectively. Thus, this “positive” study of Permixon therapy did not show any actual per- ceived clinical benefit by the patients or their phy- sicians. Because conclusive clinical trial data do not exist with regard to the efficacy of SPB extract in treating BPH, a meta-analysis of all the clinical trials of Per- mixon therapy was undertaken.” Using state of the art statistical methodology, 12 Permixon trials, involving 2794 men (1929 receiving Permixon) were evaluated for the available information re- garding peak urinary flow rate and nocturia. Be- cause these studies were performed before the ad- vent of the American Urological Association Symptom Index and the International Prostate Symptom Score (IPSS), only the symptom results for nocturia were available in all 12 studies. Over all the trials, the placebo effect was seen as an average increase in peak flow (Qmax) of 0.94 ms (standard error [SE] 0.49). The estimated ef- fect of Permixon therapy relative to placebo was a further increase of 1.87 mL/s (SE 0.55, P <0.001) The frequency of nocturia was decreased by an av- erage of 0.65 (SE.0.17) for placebo. Permixon ther- apy further reduced nocturia by 0.55 (SE 0.1, P <0.001) The conclusions of this meta-analysis must be tempered by the fact that mast of the studies were small (eight had fewer than 100 patients) and of short duration (none longer than 6 months) and lacked standardized symptom scores. However, publication bias was avoided by including all the studies. The number of studies included and the total aggregate sample size were large, and state of the art statistical methodology was used. Comparative Triat The most frequently referenced and discussed tial concerning SPB extract (Permixon) was the comparative trial with finasteride.2” This 6-month, double-blind, randomized trial of 1098 patients was conducted to demonstrate that the efficacy of Permixon was equivalent to finasteride (Proscar) (Table IV). Both Permixon and finasteride decreased the to- tal IPSS by a similar extent: ~37% and ~39%, re- spectively (approximately six points). Peak flow increased by 3,2 mL in the finasteride group com- pared with 2.7 mL/s in the Permixon group. These differences were statistically significant (P <0.01) compared with baseline values. There was also a statistically significant decrease in residual urine in the finasteride group. PSA levels were unchanged in the Permixon group and fell in the finasteride group by 41%. Prostate size decreased more in the finasteride group than in the Permixon group (by 18% versus 6%) This well-designed and well-executed trial sup- ports the equivalency of Permixon to finasteride in treating men with moderate to severe symptoms of BPH, with less decrease in sexual function. How- ever, the lack ofa placebo group clouds the efficacy issue." With the study being only 6 months in duration, it is possible that the effect is due to the placebo effect, which will eventually fade with time. Additionally, the study by Lepor et al. in- dicated that finasteride was not statistically better than placebo. Therefore, comparing Permixon with finasteride might simply be showing equiva- lency to placebo, Uropynamic Errects Ina 6-month, open-label study utilizing SPB ex- tract (Nutraceutical Corp, Ogden, Utah), 50 men were evaluated urodynamically at baseline and at completion of the study.** The IPSS (mean * stan- dard deviation) improved from 19.5 + 5.5 to 12.5 + 7.0 (P <0.001). Although a greater than 50% improvement in IPSS was identified in 21%, 30%, and 46% of patients at 2, 4, and 6 months, respectively, no demonstrable changes in peak uri-nary flow rate, postvoid residual volume, or detru- sor pressure at peak flow were found. This study demonstrated no correlation between relief of uro- dynamic signs of obstruction and a decrease in LUTS. Without an appropriate control arm, the attributable drug effect of SPB extract cannot be demonstrated.° Thus, the effect may be largely at- tributable to the placebo effect.2+ SUMMARY OF CLINICAL TRIALS OF S. REPENS Obviously, all the uncontrolled and comparative twials utilizing SPB extract without placebo control arms are net useful in defining the efficacy of this, product in the treatment of BPH, The randomized, placebo-controlled studies are hampered by short duration, variable inclusion/exclusion criteria, and lack of uniform symptom score analysis.!’ The meta-analysis of Permixon suggests clinical effi- cacy for this product2®; however, the analysis was performed using supoptimal studies. Although De- scotes et al demonstrated that patients could have statistically significant improvements in noc- turia and peak urinary flow with Permixon ther- apy, patient and physician global assessments of efficacy were no different between Permixon and placebo. Despite its being the most widely evaluated phy- totherapeutic agent, the efficacy of SPB extract therapy in the treatment of LUTS secondary to BPH has yet to be conclusively determined. Appropriate long-term, placebo-controlled trials are still needed for each individual manufacturer's product, to ascertain its true efficacy PYGEUM AFRICANUM (AFRICAN PLUM) Pygeum africanum extract (Tadenan) comes from the bark of the African plum wee and is widely used in France and throughout Europe. Other formula- tions (Prostata and numerous others) are available in health food and nutrition shops throughout the United States. Almost all the research and clinical trials of this product have been done using the product Tadenan. (MECHANISM OF ACTION In vitro data indicate that the Tadenan extract, has several effects: inhibition of b-fibroblast growth factor- and epidermal growth facto duced fibroblast proliferation,2~%3 inhibition of production of chemotactic leukotrienes and other 5-lipoxygenase metabolites (anti-inflammatory ef- fect), and antiestrogenic effects.>° Recent studies by Levin et al.3°3” suggest that the effects of P. africanum (Tandenan) on LUTS might be mediated through alterations in bladder func- tion, Using a rabbit model with partial bladder out- let obstruction (a model for bladder dysfunction 674 secondary to BPH), Levin et al.3° demonstrated that changes in bladder mass, decrease in compliance, and alterations in contractile response to various forms of stimulation could be protected and tem. pered by Tadenan pretreatment. Ina second study, after 2 weeks of bladder ob. struction in a rabbit model, treatment with Tade- nan (100 mg/kg body weight) reversed both con- tractile dysfunction and compliance changes that were previously identified >” However, doses of up to 100 mg/kg body weight are highly supraphysi- ologic; the recommended daily dose in humans is only 100 mg. Therefore, the applicability of this findings to humans is uncertain. (CUNICAL STUDIES A review of the published experience with P. af- ricanum (Tadenan) identified 2262 patients treated with this extract: 1810 patients in open-label stud- ies and 452 in comparative trials.3* Twelve double- blind, placebo-controlled studies were completed between 1972 and 1990. Only one study had more than 100 patients, and none were longer than 12 weeks. None of those trials meet the guidelines recommended by the International Consultation Conferences on BPH; thus, the data concerning the efficacy of P. africanum are not conclusive In December 1996, the Tadenan®1PSS trial, a double-blind, placebo-controlled trial comparing Tadenan 100-mg and 400-mg daily dosage with placebo was commenced in Europe; 750 men were to be randomized. The trial should be completed by December 1998, with data available in 1999. It is hoped that this trial will provide some conclu- sive data on the efficacy of this agent. UncontroiteD Cunicat Stuptes Breza et al. recently completed a 2-month open-label trial utilizing a 100-mg daily dosage of P. africanum (Tadenan). The IPSS was 16.17 * 3.68 at baseline and 9.71 + 4.57 at the end of treatment; this 40% reduction in symptom scores was statistically significant (P <0.0125). Mean peak urinary flow rates were 10.97 * 3.58 mLs at baseline and 13.07 * 5.56 mL/s at the end of ther- apy (P <0.001). No side effects were identified in the study group. Obviously, this uncontrolled study only suggests a benefit of this agent. No fur- ther conclusions can be made from this study. Comparative TRiAt ‘Abbou et al. compared alfusosin, an alphar, selective agent, with an extract of P. africanum; 331 men completed this 8-week trial. Alfusosin was found to be more effective than P. africanum with regard to peak flow rate, decrease in residual urine, and decrease in irritative symptoms. This non-pla- cebo-controlled study unfortunately adds little to UROLOGY 53 (4), 1999our knowledge of the efficacy of P. africanum but is presented for completeness. UropYNAMIC EFFECTS Ina recent review of the baseline and post-treat- ment uroflow tracings from 20 patients treated with 100 mg of Tandenan daily for 2 months,*! 7 patients were deemed “greatly improved,” and 5 were deemed “slightly improved.” True pressure- flow evaluations were not completed; therefore, these uroflowmetry data, which were analyzed by mathematical modeling, add little useful informa- tion regarding the effect of P. africanum on bladder function and outlet obstruction ‘SUMMARY OF P. AFRICANUM Until the Tadenan-IPSS study is completed, the available data concerning the efficacy of P. africa- num in treating LUTS secondary to BPH are lack- ing. There is a large pool of suboptimal data con- cerning Tadenan use; however, there are few significant data available with regard to any of the other P. africanum extracts, URTICA DIOICA (STINGING NETTLE) Extracts from the roots of a stinging nettle are widely used in Germany > The extracts of the roots of the stinging nettle contain a complex mixture of water- and alcohol-soluble compounds. It is clear that the extraction procedures significantly vary from company to company. MECHANISM OF ACTION There have been three recent studies that suggest different mechanisms of action for stinging nettle. These include inhibition of prostatic growth factor interaction”? inhibition of membrane sodium and potassium-adenosine triphosphatase in the pros- late, with resulting suppression of prostate cell me- tabolism and growth,*? and modulation of binding of sex hormone-binding globulin to its receptor on prostate cell membranes.** These laboratory stud- ies only suggest possible mechanisms of action. Cunicat Srupies The only recent study with a stinging nettle ex- tract used a liquid preparation. The liquid prep- aration has subsequently been removed from the market because its unacceptable taste was rejected by patients.? In that study, 42 patients were ran- domized to receive either placebo or the stinging nettle preparation, They were treated for a period of 3 months. Treated patients had superior im- provement compared with placebo recipients in terms of IPSS results.‘ TABLE V. Prostaglutt forte versus placebo* IPSS ‘Qmax (mL/s) Treated Placebo Treated Placebo Baseline “18.6 19.0 14.65 15.05 Week 247 11.1 176 1795 15.50 Week 48" 9.8 133 1910 17.50 Ker: Abbreviations as Tables I and WV. * Data from Metsher and Martin.® * End of double-blind period, * End of open SUMMARY OF U. DI0;cA This agent has been studied less extensively than either S. repens or P. africanum. The data to date available do not confirm its efficacy in the treat- ment of LUTS secondary to BPH. CLINICAL TRIALS WITH COMBINATION PRODUCTS Although there are no data to suggest either in- creased efficacy or synergy by combining plant ex- tracts, most “prostate health” pills are combina- tions. Two studies of the preparation Prostagutt forte (combination of S. repens and U. dioica) were recently reported.*°47 The randomized, placebo- controlled study included only 20 patients in each arm.*” After a 2-week placebo lead-in period, there was 6 months of double-blind treatment, followed by 6 months of open-label treatment (Table V). In that study, both IPSS and peak flow rate showed greater improvement with treatment than with pla- cebo. The IPSS went from 18.6 down to 11.1 with Prostaglutt and from 19 to 17.6 with placebo (P = 0.002). During the open-label extension phase, the placebo group improved from 17.6 to 13.3; surprisingly, the Prostaglutt-treated group also continued to improve, dropping from 21.1 to 9.8. In terms of peak flow rates, the Prostaglutt-treated patients improved by 2.3 mL/s over the first 6 months and by an additional 1.15 mL/s over the open-label second 6-month period. The placebo group showed minimal change during the initial placebo period (0.45 mL/s); however, during ac- tive treatment there was a 2-ml/s improvement. Thus, this study indicated that further improve- ment with Prostaglutt therapy can be achieved with longer treatment (from 6 to 12 months). This finding further supports the need for double-blind, placebo-controlled studies of at least 1 year in du- ration to evaluate plant extract therapy. COMPARATIVE TRIAL Prostaglutt forte was also compared with finas- teride (Proscar) in a comparative trial that did not have a placebo control arm*®; 489 patients were randomized and followed up for 48 weeks. TheIPSS improved from 11.3 to 6.5 for Prostaglutt- treated patients and from 12.6 to 6.9 in finasteride- treated patients. Although the improvement was slightly greater in the finasteride-treated patients (5.7 versus 4.8), there was no statistical signifi~ cance between the treatment groups. In terms of improvement in peak urinary flow, Prostaglutt- treated patients improved by 1.9 mL/s and finas- teride-treated patients by 2.7 mL/s (P = 0.189), also not statistically significant between groups. The significance of this study is obviously ques- tionable without a placebo control arm. SECALE CEREALE (RYE POLLEN) The rye pollen extract is obtained by microbial digestion of the pollen, followed by extraction with both water and organic solvents. Thus, the total extract consists of both a water-soluble and a fat- soluble fraction. Habib et al.‘ studied the water- soluble fraction and found that it inhibited the growth of immortal prostate cancer cell lines as ‘well as epithelial and stromal cells derived from BPH tissue in cell culture. Whether this in vitro action also occurs in vivo is uncertain. Cunicat TRIALS No new double-blind, placebo-controlled triais have been performed since our previous review. There was one comparative trial between Cer- nilton (rye pollen) and Tadenan (P. africanum), which did not have a placebo control arm. This, 4-month study with 89 patients suggested that Cernilton provided better improvement in symp- tom score, peak flow, and residual urinary volume than Tadenan.*° The significance of this study is also inconclusive. SUMMARY OF S, CEREALE Further long-term, double-blind, placebo-con- trolled trials need to be performed to determine the efficacy of rye pollen extracts HYPOXIS ROOPERI (SOUTH AFRICAN STAR GRASS) This extract mainly contains beta-sitosterol (Harzol), along with various amounts of several other sterols. Beta-sitosterol is thought to be a ma- jor active component in plant extracts. Mecuaniso oF ACTION In laboratory studies, Harzol was found to en- hance the production and secretion of plasmino- gen activators in isolated and epithelial cells. Ad- ditionally, prostate stromal cell cultures when conditioned with beta-sitosterol were found to have elevated levels of transforming growth factor (TGF)-beta,. TGF-beta, is an important differenti- ation factor and apoptosis inducer.! None of these effects have been shown to occur in vivo or to be clinically relevant. Cuicat Triats Harzol was previously evaluated in a 6-month, double-blind, placebo-controlled study.” Statisti, cally significant improvements were noted for IPSS, quality of life, peak flow rates, and residual urinary volumes. The placebo group showed an appropriate mild improvement in these variables The IPSS improved by 2.3 for placebo and 7.4 for beta-sitosterol-treated patients.*? Similarly, peak urinary flow rates improved by 1.1 mL/s for pla- cebo recipients and by 5.2 mL/s for treated pa- tients, The magnitude of this improvement in flow rates had not been observed with any other medical therapy previously evaluated for BPH. This study was favorably evaluated by reviewers,? Atthe Fourth International Consultation on BPH, in Paris in 1997, Senge reported on the 18-month follow-up data for these aforementioned patients. In patients who continued to receive Harzol, IPSS improvements were maintained. Placebo recipi- ents who were then treated with Harzol also dem- onstrated similar levels of improvement in IPSS and flow rate. Most surprisingly, patients who were initially treated with Harzol but then received pla- cebo over the next 12 months still maintained sim- ilar levels of improvement. This finding suggests the possibility that intermittent therapy might be a viable option. We await final publication of this study to evaluate it critically. Another agent containing mainly beta-sitosterol (Azuprostat) was evaluated in a 6-month random- ized, placebo-controlled trial.®> Treated patients received 65 mg twice daily during the 6 months of treatment. Significant improvements in IPSS, uri- nary flow rates, and postvoid residual volumes were noted. The IPSS improved by 2.8 for placebo- treated patients and by 8.2 for beta-sitosterol- treated patients. Peak flow rates improved by 4.4 mL/s for placebo recipients and by 8.8 mL/s for treated patients. Therefore, the attributable drug effect was 4.5 mL/s. The magnitude of improve- ment of 8.8 mL/s with beta-sitosterol in treated patients in this study is dramatic and has not been previously reported for any medical therapy for BPH. If these results are reproducible, they would rival those of surgical intervention. ‘SumMaRy oF BETA-SITOSTEROL The aforementioned trials by Berges et al. and Klippel et al.®> are exciting. They were performed according to the recommendations of the Interna- tional Consultations on BPH. The results of the studies are certainly dramatic. We await confirma-tory studies to ascertain whether this magnitude of, improvement can be duplicated, COMMENT In the present review, the recent laboratory and clinical trials using phytotherapeutic agents were evaluated, Two other recent articles have reviewed aspects of this topic.*° Such critical appraisal and review of the topic reconfirms that appropriate long-term, placebo-controlled, double-blind clini- cal trials using these phytotherapeutic agents are still needed. Although several studies suggest the clinical efficacy of certain agents, confirmatory studies with these specific products are still needed. Clearly, the widespread use of phytothera- peutic products necessitates our ascertaining the true magnitude and level of efficacy of these prod- ucts, Continued laboratory analysis is also re- quired (0 determine the active ingredient or ingre- dients and their mechanism of action. Overall, the efficacy of phytotherapeutic agents for BPH has yet to be determined; however, prelim- inary trials suggest a benefit for this type of ther- apy. REFERENCES 1. Lowe FC, and Ku JC: Phytotherapy in treatment of be- nign prostatic hyperplasia: a critical review. Urology 48: 12- 20, 1996. 2. Marwick C: Growing use of medicinal botanicals forces assessment by drug regulators. JAMA 273: 607-609, 1995, 3. Dreikorn K, Borkowski A, Braeckman J, et al: Other medical therapies, in Denis L, Griffiths K, and Murphy G (Eds): Proceedings of the Fourth International Consultation on Benign Prostatic Hyperplasia (BPH), July 1997. Plymouth, UK, Health Publications, 1998, pp 635-659. 4. Lowe F: What I tell patients about phytotherapeutic agents for benign prostatic hyperplasia. AUA News 3: 12, 1998. 5. Astin JA: Why patients use alternative medicine: result of a national study. JAMA 279: 1548~1553, 1998. ‘6. 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