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By E-P. Barrette, MD, FACP
Losing sleep over urinary symptoms seems like adding insult to infirmity. It’s not much fun. Since saw palmetto extract (SPE) was first reviewed in these pages,1 further studies have been published.2-4 Overall, SPE appears to have a modest positive effect on the symptoms of benign prostatic hyperplasia (BPH). Currently the National Center for Complementary and Alternative Medicine (NCCAM) is funding a large randomized trial of SPE.
Native Americans used the extract of the fruit of the dwarf palm tree (Serenoa repens), indigenous to the southeastern United States, for urinary complaints. In the 19th century, naturopathic physicians treated various ailments with SPE, and it was listed in, though eventually dropped from, the National Formulary.
In Germany, herbal therapy is the preferred initial therapy for BPH. Although several agents—Pygeum africana, stinging nettle (Urtica dioica), South African star grass (Hypoxis rooperi), and pumpkin seeds (Cucurbita pepo)—often are used, saw palmetto is the most widely used for BPH.
With the resurgence of natural therapies since the passage of the Dietary Supplement Health and Education Act (DSHEA), SPE has become one of the top 10 herbal agents in the United States. The commercial harvest of saw palmetto berries in Florida yielded $50 million in 1998.5 The majority of this is shipped to Europe, where SPE remains the first choice of therapy for BPH. A recent survey in an American academic urology practice showed significant use of phytotherapeutic agents for lower urinary tract symptoms.6
Mechanism of Action
SPE is a complex mixture of fatty acids, long-chain alcohols, and plant sterols including beta-sitosterol, stigmasterol, cycloartenol, lupeol, lupenone, and methylcycloartenol. Although the precise active agent in SPE is unknown, there is growing support for pure beta-sitosterol treatment for BPH.7,8
The bulk of in vitro evidence supports a mechanism similar to finasteride, i.e., inhibition of 5-alpha-reductase. Clinical trials with finasteride, a potent inhibitor of type II 5-alpha-reductase, have demonstrated a decrease in prostate volume and a decrease in prostate specific antigen (PSA) values. However, trials of SPE have not shown any effect on prostate volume or PSA values, suggesting that SPE may be exerting its effects via alternative pathways. For example, recent evidence supports blocking alpha-adrenergic receptors as an alternative mechanism.9
A comprehensive 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.10 Sixteen of 18 were double-blind, and all these trials were conducted in Europe. The trials studied 2,939 men. Of the 18 trials, 10 trials studied SPE vs. placebo, two trials compared SPE to an active control (finasteride), four trials compared SPE compounded with a second agent vs. placebo, one trial compared SPE vs. pygeum vs. placebo, and one trial compared oral vs. rectal SPE.
In 10 studies, SPE reduced nocturia, weighted mean difference -0.76 times per night (95% CI, -1.22 to -0.32). Compared to 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), weighted mean difference 1.93 ml/sec (95% CI, 0.72-3.14). Peak flow improved 24% compared to placebo.
Weaknesses of these studies included the short duration of follow-up (four weeks in five trials, six weeks in two trials, 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 symptom score.
The lack of any improvement in the placebo arm in many of these studies suggests problems with blinding or study design, since all the large trials of pharmaceutical agents have shown significant improvement in the placebo-treated subjects. In a second meta-analysis of 11 trials of Permixon (a European formulation of SPE), the peak flow rates improved 1.87 ml/sec (P < 0.001) and nocturia decreased by 0.55 episodes (P < 0.001) more than the placebo arm.11
Two large double-blind studies compared SPE to finasteride. In the larger study, 1,098 men were randomized to 160 mg SPE bid or 5 mg finasteride qd for six months.12 Both treatments improved the International Prostate Symptom Score (IPSS) (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 IPSS, quality-of-life, and peak urinary flow rates improved equally in both arms. Unfortunately neither trial included a placebo arm.
In the smaller study, prazosin appeared to be slightly better than SPE when studied for 12 weeks in 45 men.14 Alfuzosin, an alpha-adrenergic antagonist not available in the United States, also improved urinary symptoms and flow rates better than SPE.15 The former trial used non-standardized symptoms scores and the latter trial was only three weeks in duration.
Two small U.S. trials recently have been published. In an open-labeled, uncontrolled study, 50 men with moderate BPH (IPSS ³ 10) received 160 mg SPE bid for six months.16 The IPSS improved from 19.5 to 12.5 (P < 0.001). Forty-six percent (21 of 46) had 50% or more improvement in their urinary symptoms. Interestingly, no change in either peak flows or multiple urodynamic parameters were seen.
In the second recent study, a six-month, double-blind, randomized, controlled trial of 44 men showed slightly more symptom improvement with SPE than with placebo, although it was not statistically significant.17 Taken three times daily, SPE (106 mg) was compounded with 80 mg nettle root extract, 160 mg pumpkin seed extract, lemon bioflavonoid extract, and beta-carotene. Pre- and post-treatment prostate biopsies demonstrated a decrease in the percent epithelium in the transition zone of the prostate from 17.8% to 10.7% (P < 0.01) with SPE but no change in the placebo-treated men. These changes are similar to those seen with finasteride.
Adverse Effects and Drug Interactions
Mild side effects have been noted to occur at rates similar to placebo. No interactions between SPE and drugs have been reported. However, many trials have excluded men on medications.
Dosage and Formulation
The usual SPE dose is 160 mg bid. SPE frequently is sold compounded with many other herbal ingredients. In Europe SPE often is compounded with stinging nettle or pumpkin seeds. The most rigorous five trials of all the published evidence used SPE alone, 160 mg bid (three trials), or SPE with nettle, 160/120 mg bid (two trials).
In two large well-designed trials, SPE appeared to be as effective as finasteride. Unfortunately, neither trial included a placebo control and a recent trial of finasteride showed it to be no better than placebo.18 Also, there are no trials comparing SPE to the commonly prescribed alpha-adrenergic antagonists terazosin, doxazosin, and tamsulosin.
Two meta-analyses suggest SPE has a modest benefit for BPH symptoms, improving urine flow and decreasing nocturia. However, no single trial included in these two meta-analyses is definitive. 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. Moreover, the SPE products tested are manufactured in Europe and are not readily available in the United States. It is not certain whether U.S.-manufactured SPE is equivalent to SPE from Europe. Fortunately, a large one-year NIH- and NCCAM-sponsored placebo-controlled trial of SPE in moderate-to-severe BPH is starting.
Until definitive trials are published, one must use the available evidence. Decisions to start therapy for BPH with SPE, finasteride, an alpha-adrenergic antagonist, or to initiate referral to a urologist 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 easily completed questionnaire, such as the American Urological Association symptom index (See Table 1), will help determine the benefits of treatment.
Table 1: American Urological Association Benign Prostatic Hyperplasia Symptom Index
|Questions for patients
to answer regarding
their Benign Prostatic Hyperplasia condition
|1.|| Over the past month, how often have you
had a sensation of not emptying your bladder
completely after you finished urinating?
|2.|| Over the past month, how often have you
had to urinate again less than two hours
after you finished urinating?
|3.||Over the past month, how often have you
stopped and started again several times
when you urinated?
|4.|| Over the past month, how often have you
found it difficult to postpone urination?
|5.||Over the past month, how often have you
had a weak urinary stream?
|6.||Over the past month, how often have you
had to push or strain to begin urination?
|7.||Over the past month, 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? (Check the column
that best represents the number of times you
awoke each night, on average.)
|Add the point value for each
question to determine the symptom score. A total score of 0-7 means
considered mild; a total score of 8-19 means symptoms are considered moderate; a total score of 20-35 means symptoms
are considered severe.
|Adapted from: American Urological Association. Available at: www.edaptechnomed.com/aua.htm. Accessed February 20, 2001.|
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