Saw Palmetto for Benign Prostatic Hyperplasia: An Update

By E-P. Barrette, MD, FACP

With the graying of america, men are paying more attention to their health. When bothersome urinary symptoms disrupt a night’s sleep, they seek remedies. Saw palmetto extract (SPE) remains one of the top-selling herbal therapies in the United States for benign prostatic hyperplasia (BPH). In many European countries it is the therapy of first choice for BPH. In spite of its popularity, many U.S. physicians remain skeptical.

Since last reviewed in these pages,1 further trials of SPE have been published. Overall, studies suggest that SPE appears to have a modest effect on the symptoms of BPH without changing the prostate specific antigen (PSA). Currently, the National Center for Complementary and Alternative Medicine (NCCAM) is funding a randomized trial of SPE in the United States and planning a much larger trial.

History

Native Americans used the extract of the fruit of the dwarf palm tree (Serenoa repens, or alt. Sabal serrulata), indigenous to the southeastern United States, for urinary complaints. In the 19th century, naturopathic physicians treated various ailments with SPE. The National Formulary listed SPE but eventually dropped it.

Current Use

In Germany, Italy, and France, herbal therapy is the preferred initial therapy for BPH. Although several agents often are used, including African plum tree (Pygeum africanum), stinging nettle (Urtica dioica), South African star grass (Hypoxis rooperi), and pumpkin seeds (Cucurbita pepo), saw palmetto is the most popular. Ironically, Florida provides saw palmetto for herbal pharmaceuticals sold in Europe, continent-wide. The commercial harvest of saw palmetto berries in Florida yielded $50 million in 1998.2 Since the passage of Dietary Supplement Health and Education Act in 1994, SPE has become one of the top 10 herbal agents sold in the United States.

Mechanism of Action

SPE is a complex mixture of fatty acids, long-chain alcohols, and plant sterols including b-sitosterol, stigmasterol, cycloartenol, lupeol, lupenone, and methylcycloartenol. The precise active agent in SPE is unknown, although several studies of b-sitosterol alone have shown significant improvement in men with BPH.3,4 Several mechanisms have been proposed:5 inhibition of 5-alpha-reductase, anti-inflammatory effects, alpha-adrenergic receptor blockade, and growth factor alteration. Most research has focused on inhibition of 5-alpha-reductase, which is the mechanism of action of the pharmaceutical agent finasteride.6 Conversion of testo-sterone to dihydrotestosterone by 5-alpha-reductase within the prostate is part of the pathology of BPH. Most studies, but not all, of SPE on 5-alpha-reductase activity have shown inhibition.

Clinical Studies

Well-documented improvement in both symptoms and urinary flow has been seen in men with BPH receiving placebo in large prospective trials.7 This improvement can persist beyond six months. Consequently, all uncontrolled trials lacking a placebo arm and all positive trials of less than six months duration should be interpreted with caution.

An early review summarized the studies up to 1998.8 This meta-analysis of all controlled trials of SPE in men with symptomatic BPH of at least 30 days published from 1966 through 1997 included 18 randomized controlled trials. Sixteen of 18 were double-blind trials; all 18 were conducted in Europe. The trials studied 2,939 men. Of the 18 trials, 10 studied SPE vs. placebo, two compared SPE to an active control (finasteride), four compared SPE compounded with a second agent vs. placebo, one compared SPE vs. pygeum vs. placebo, and one compared oral vs. rectal SPE. In 10 studies, nocturia was reduced by SPE, with a weighted mean difference of -0.76 times per night (95% confidence interval [CI] -1.22 to -0.32). Compared with placebo, SPE improved self-rating of urinary symptoms (six studies), risk ratio 1.72 (95% CI 1.21-2.44), and increased peak flow rates (eight studies), with a weighted mean difference of 1.93 mL/sec (95% CI 0.72-3.14). The peak flow improved 24% compared with placebo.

Weaknesses of these studies included the short duration of follow-up (four weeks in five trials, six weeks in two trials, and eight weeks in three trials) and small sample size (£ 30 in five trials, £ 80 in 12 trials). Only nine of 18 studies had adequate blinding and only three trials used a standardized symptoms score.

In a second meta-analysis of 11 trials, Permixon (a European formulation of SPE) improved peak flow rates by 1.87 mL/sec (P < 0.001) and decreased nocturia by 0.55 episodes (P < 0.001) more than placebo.9 Symptom score improvement was not analyzed.

A recent randomized double-blind controlled trial (RDBCT) that was conducted in the United States enrolled 85 men with moderate BPH.10 Subjects received SPE 160 mg bid or placebo for six months. Greater improvement of symptom scores was seen with SPE (16.7 to 12.3, change = -4.4) when compared with placebo (15.8 to 13.6, change = -2.2). Although this difference was statistically significant (P = 0.038), the absolute difference between SPE and placebo was -2.2. It is generally accepted that the minimally perceptible change in symptom score is 3.11 This degree of change was seen with SPE over six months, but not when compared with placebo. Peak flow rates improved in both arms (P = 0.73).

Comparisons to Finasteride

Two large double-blind studies compared SPE to finasteride. In the larger study, 1,098 men were randomized to 160 mg SPE twice daily or 5 mg finasteride daily for six months.12 Both treatments improved the symptom score (37% vs. 39%, P = 0.17) and quality of life equally well. Peak urinary flow increased slightly more with finasteride (30% vs. 25%, P = 0.035).

The second trial followed 543 men with mild-to-moderate BPH for 48 weeks.13 The SPE was compounded with 120 mg stinging nettle extract. The symptom score, quality of life, and peak urinary flow rates improved equally in both arms. Unfortunately, neither trial included a placebo arm.

Comparisons to Alpha-Adrenergic Antagonists

Very little is known regarding the comparative efficacy of SPE to the first-line agents most commonly used in the United States, alpha-adrenergic antagonists. No studies comparing SPE to doxazosin or terazosin have been published. A European multicenter double-blind trial compared SPE with tamsulosin (Flomax, 0.4 mg/d).14 Seven hundred and four men with moderate BPH were followed for one year. Results, available only in abstract, showed equal improvement in symptom score (27% decrease) and peak flow. No placebo arm was included.

Two earlier studies suggested that alpha-adrenergic antagonists may be better than SPE. Prazosin appeared to be slightly better than SPE when studied for 12 weeks in 45 men;15 however, non-standardized symptom scores were used. Alfuzosin, an alpha-adrenergic antagonist not available in the United States, also improved urinary symptoms and flow rates better than SPE.16 Unfortunately, this trial was only three weeks in duration.

Adverse Effects and Drug Interactions

Mild side effects have been noted at rates similar to placebo. No interactions with drugs have been reported. However, many trials have excluded men on medications. One case report of a serious intra-operative hemorrhage is the only published serious adverse event occurring with SPE.17 Bleeding time was prolonged and no other cause was found. Whether SPE was causally related is unknown. Follow-up bleeding time after restarting SPE was not reported.

Dosage and Formulation

The usual dose of SPE is 160 mg twice daily. A single report compared SPE 160 mg twice daily vs. 320 mg daily in a RDBCT with 100 men for three months and found them equivalent.18 SPE often is sold compounded with many other herbal ingredients. In Europe, SPE frequently is compounded with stinging nettle (U. dioica) or pumpkin seeds (C. pepo). The most rigorous studies have used SPE alone (160 mg bid) or SPE with nettle (160/120 mg bid).

Future Studies

The NCCAM, the National Institute of Diabetes, Digestive, and Kidney Disorders (NIDDK), and the National Institutes of Health (NIH) are sponsoring a randomized placebo-controlled trial of SPE in 225 men with moderate-to-severe BPH followed for one year. Results are expected in late 2003.

The NCCAM, NDDK, NIH, and the Office of Dietary Supplements are planning a randomized placebo-controlled trial comparing SPE, P. africanum, and placebo.19 The goal is to enroll 3,100 men with BPH and follow them for 4-6 years. This will be the largest SPE trial to date.

Conclusion

Two meta-analyses suggest that SPE has a modest benefit for BPH symptoms, with improved urine flow and decreased nocturia. All of these studies contain one or more deficiencies, i.e., short study period, non-validated symptom scores, small numbers of subjects, and inadequate blinding. Several new studies lend further support that SPE improves symptoms of BPH. However, no definitive trial has been published. Too little is known about the relative efficacy of SPE and alpha-adrenergic antagonist to make a fully informed decision. Moreover, most SPE products tested are manufactured in Europe and are not readily available in the United States. It is not certain whether SPE that is manufactured in the United States is equivalent to SPE manufactured in Europe.

Table

American Urological Association (AUA) Urinary Symptom Index for Prostatism

Score

Not at  < 1 in 5   < ½ the   = ½ the > ½ the Almost
Symptom All Times Time Time  Time  Always

1. Over the past month or so, how often  have you had a sensation of not emptying your bladder completely after you finished urinating?

0 1 2 3 4 5

2. Over the past month or so, how often  have you had to urinate again less than two hours after you finished urinating?

0 1 2 3 4 5

3. Over the past month or so, how often have you found you stopped and started several times when you urinated?

0 1 2 3 4 5

4. Over the past month or so, how often have  you found it difficult to postpone urination?

0 1 2 3 4 5

5. Over the past month or so, how often have you had a weak urinary stream?

0 1 2 3 4 5

6. Over the past month or so, how often have you had to push or strain to begin urination?

0 1 2 3 4 5

7. Over the past month or so, how many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning?

0 times 1 time 2 times  3 times 4 times 5 times
Interpretation of AUA Symptom Index AUA Symptom Score = Sum of Questions 1-7 = ________________

Mild prostatism £ 7

Moderate prostatism 8-18

Severe prostatism > 18

Highest possible score = 35

Adapted from: Barry M, et al. The American Urological Association symptom index for benign prostatic hyperplasia. J Urol 1992;148:1549-1557.

Recommendation

Until definitive trials are published, one must use the available evidence. Decisions to initiate referral to a urologist or start therapy with SPE, finasteride, or an alpha-adrenergic antagonist need to be negotiated with the patient. For patients wishing to try SPE for mild-to-moderate BPH, a trial of SPE alone (160 mg bid) or SPE with nettle (160/120 mg bid), for several months is not unreasonable. An attempt to monitor symptoms objectively with an easy and rapid questionnaire, e.g., the America Urological Association symptom index (see Table), will help determine the benefits of treatment. Unlike finasteride, SPE will not affect the PSA.

References

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2. Marks LS, Tyler VE. Saw palmetto extract: Newest (and oldest) treatment alternative for men with symptomatic benign prostatic hyperplasia. Urology 1999;53: 457-461.

3. Berges RR, et al. Randomised, placebo-controlled, double-blind clinical trial of b-sitosterol in patients with benign prostatic hyperplasia. Lancet 1995;345: 1529-1532.

4. Wilt TJ, et al. b-Sitosterol for the treatment of benign prostatic hyperplasia: A systematic review. BJU Int 1999;83:976-983.

5. Lowe FC. Phytotherapy in the management of benign prostatic hyperplasia. Urology 2001;58(6 Suppl 1): 71-77.

6. Bayne CW, et al. Serenoa repens (Permixon): A 5a-reductase types I and II inhibitor—new evidence in a coculture model of BPH. Prostate 1999;40:232-241.

7. Nickel JC. Placebo therapy of benign prostatic hyperplasia: A 25-month study. Canadian PROSPECT Study Group. Br J Urol 1998;81:383-387.

8. Wilt TJ, et al. Saw palmetto extracts for treatment of benign prostatic hyperplasia: A systematic review. JAMA 1998;280:1604-1609.

9. Boyle P, et al. Meta-analysis of clinical trials of permixon in the treatment of symptomatic benign prostatic hyperplasia. Urology 2000;55:533-539.

10. Gerber GS, et al. Randomized, double-blind, placebo-controlled trial of saw palmetto in men with lower urinary tract symptoms. Urology 2001:58:960-965.

11. Barry MJ. Evaluation of symptoms and quality of life in men with benign prostatic hyperplasia. Urology 2001;58(6 suppl 1):25-32.

12. Carraro JC, et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: A randomized international study of 1,098 patients. Prostate 1996;29:231-240.

13. Sökeland J, Albrecht J. Kombination aus Sabal- und Urticaextrakt vs. Finasterid bei BPH (Stad. I bis II nach Alken): Vergleich der therapeutischen Wirksamkeit in einer einjährigen Doppelblindstudie. Urologe A 1997;36:327-333.

14. Debruyne F. Phytotherapy (LSESR) vs an a-blocker for treatment of lower urinary tract symptoms secondary to benign prostate enlargement: A randomized comparative study. Presented at: The American Urological Association Annual Meeting; Anaheim, CA; June 2-7, 2001.

15. Semino MA, et al. Tratamiento sintomatico de la hipertrofia benigna de prostata. Estudio comparativo entre prazosin y Serenoa repens. Arch Esp Urol 1992; 45:211.

16. Grasso M, et al. Comparative effects of alfuzosin versus Serenoa repens in the treatment of symptomatic benign prostatic hyperplasia. Arch Esp Urol 1995; 48:97-103.

17. Cheema P, et al. Intraoperative haemorrhage associated with the use of extract of saw palmetto herb: A case report and review of literature. J Intern Med 2001;250: 167-169.

18. Stepanov VN, et al. Efficacy and tolerability of the lipidsterolic extract of Serenoa repens (Permixon) in benign prostatic hyperplasia: A double-blind comparison of two dosage regimens. Adv Ther 1999;16: 231-241.

19. The National Institutes of Health. Available at: http://grants1.nih.gov/grants/guide/rfa-files/RFA-DK-02-026.html. Accessed May 24, 2002.