Saw Palmetto Extracts for Treatment of Benign Prostatic Hyperplasia:  A Systematic Review FREE

SYMPTOMATIC BENIGN prostatic hyperplasia (BPH) is one of the most common medical conditions in older men. As many as 40% of men aged 70 years or older have lower urinary tract symptoms consistent with BPH.¹ Treatment goals in the vast majority of men are to relieve irritative (urgency, frequency, and nocturia) and obstructive (weak stream, hesitancy, intermittency, and incomplete emptying) symptoms. In the United States, treatment of BPH exceeds $2 billion in costs, accounts for 1.7 million physician office visits,² and results in more than 300000 prostatectomies annually.³ Treatment options include lifestyle modification, device and surgical therapies, and pharmaceutical and phytotherapeutic preparations.^4- 5

Phytotherapy or the use of plant extracts for treating BPH symptoms was first described in Egypt in the 15th century BC. Currently, phytotherapy is common in Europe and is increasing in the western hemisphere. The sale of all botanical medications in the United States is $1.5 billion per year and the use of phytotherapies increased nearly 70% among US adults in the past year.^6- 7 Phytotherapeutic agents represent nearly half the medications dispensed for treatment of BPH in Italy, compared with 5% for α-blockers and 5% for 5 α-reductase inhibitors.⁸ In Germany and Austria, phytotherapy is the first-line treatment for mild-to-moderate lower urinary tract symptoms and represents more than 90% of all drugs prescribed for the treatment of BPH.⁹ In the United States, phytotherapies for BPH are readily available as nonprescription dietary supplements. Most of these compounds are unlicensed and often promoted to "maintain a healthy prostate" and as a natural and harmless treatment of BPH symptoms.

There are about 30 phytotherapeutic compounds used for the treatment of BPH.¹⁰ The most widely used is the extract of the dried ripe fruit from the American dwarf saw palmetto plant Serenoa repens (also known by its botanical name Sabal serrulata). Berries from saw palmetto were first used by the American Indians in Florida in the early 1700s to treat testicular atrophy, erectile dysfunction, and prostate gland swelling or inflammation.¹⁰ The medicinal value of S repens for relief of prostate gland swelling has been reported in medical literature since the 1800s. The mechanism of action of S repens is not known but may include alteration of cholesterol metabolism,¹¹ antiestrogenic, antiandrogenic, and anti-inflammatory effects,^12- 14 and a decrease in available sex hormone–binding globulin.¹⁵ Although S repens has been evaluated in several randomized trials its clinical efficacy has not been clearly demonstrated.

Our goal was to systematically review the existing evidence regarding the therapeutic efficacy and safety of the saw palmetto plant extract S repens. We specifically assessed whether S repens is more effective than placebo and as effective as other pharmacological therapies in improving symptoms and/or urodynamic measurements in men with BPH.

Randomized controlled trials were included if participants had symptomatic BPH; the treatment intervention was a preparation of S repens (S serrulata, Sabalis serrulata , Serenoa serrulata , Permixon, PA109, Serendar, Talso, Curbicin, Prostagutt, Prostaselect, Prostagalen, Prostavigol, Strogen forte, and SPRO 160/120) alone or in combination with other phytotherapeutic agents; a control group received either placebo or other pharmacological therapies for BPH; and the treatment duration was at least 30 days.

We searched MEDLINE for studies from 1966 to 1997 by crossing an optimally sensitive search strategy for trials from the Cochrane Collaboration with the medical subject headings prostatic hyperplasia, phytosterols, plant extracts , sitosterols , Serenoa repens, or Sabal serrulata , including all subheadings.¹⁶ EMBASE, (1974-July 1997), Phytodok (Munich, Germany), and the Cochrane Library, including the database of the Cochrane Prostatic Diseases and Urologic Malignancies Group and the Cochrane Field for Complementary Medicine, were searched in a similar fashion. Reference lists of all identified trials and previous reviews were searched for additional trials. Expert relevant trialists and pharmaceutical companies were asked to identify additional published or unpublished trials. There were no language restrictions.

Study characteristics, demographic information, enrollment criteria, therapy allocation, adverse effects, outcomes and numbers, and reasons for dropouts were extracted independently by 2 reviewers. Missing information was sought from authors and/or sponsors. Extracted data were reviewed by the principal reviewer and discrepancies resolved by discussion.

The main outcome was the efficacy of S repens vs placebo or active control in improving urologic symptom scale scores or global report of urinary tract symptoms (improved vs stable or worsened). Secondary outcomes included peak and mean urine flow, residual urine volume, prostate size, and nocturia.

As a measure of overall methodological study quality, we assessed the quality of concealment of treatment allocation according to a scale developed by Schulz et al,¹⁷ assigning 1 as poorest quality and 3 as best quality. The treatment allocation included (1) trials in which concealment was inadequate (eg, such as alternation or reference to case record numbers or to dates of birth); (2) trials in which the authors either did not report an allocation concealment approach at all or reported an approach that did not fall into one of the other categories; and (3) trials deemed to have taken adequate measures to conceal allocation (eg, central randomization; numbered or coded bottles or containers; drugs prepared by the pharmacy; serially numbered, opaque, sealed envelopes, etc, that contained elements convincing of concealment). Additionally, we assessed whether study participants and investigators were blinded to the treatment provided.

A random-effects model was used to combine data for all outcomes. For continuous variables weighted mean differences and their 95% confidence intervals (CIs) were calculated using RevMan 3.0 software.¹⁸ For categorical variables weighted risk ratios (RRs) and 95% CIs were calculated.¹⁹ For continuous measurements, a difference between treatment means and its correlated SE of the difference were calculated using the methods of Lau¹⁹ and Laird and Mosteller.²⁰ Because studies did not report the SE of the difference between the means (S repens and control), analyses were carried out for 3 different assumed values of correlation (0.25, 0.50, 0.75). This approach was taken to test the sensitivity of the results to this unknown parameter. Because there were no statistically significant differences in the outcomes, according to the different correlation coefficients, we used SEMs calculated with a correlation coefficient of 0.50. χ² Tests were used for analysis of bivariate comparisons. To assess the percentage of patients having improvement in urologic symptoms, a modified intention-to-treat analysis was performed (ie, men who dropped out or were lost to follow-up were considered to have had worsening symptoms).²¹ The denominator for the modified intention-to-treat analysis included the number randomized to treatment at baseline, and the numerator included the number completing the trial and showing improvement.

The combined search strategies identified 24 reports of trials; 18 met inclusion criteria.^22- 39 Reasons for exclusion included duration unknown or less than 30 days (n=2 trials)^40- 41; no clinical outcomes (examining enzyme or tissue effects (n=3)^15,42- 43; and no indication of randomization (n=1).⁴⁴ Main comparisons in the remaining studies were S repens alone vs placebo (n=10); S repens in combination with other phytotherapeutic agents vs placebo (n=3); S repens alone vs active control (n=2); S repens vs another phytotherapeutic agent and vs placebo (n=1); S repens in combination with other phytotherapeutic agents vs active control (n=1); and S repens orally vs a rectal suppository form of S repens, a therapeutic bioequivalence study (n = 1). A total of 2939 participants were randomized in the 18 trials (1118 in trials of S repens alone or in combination vs placebo and 1821 in trials of S repens alone or in combination vs active control).

A description of the individual studies is available from the authors on request. The mean age of enrollees was 65 years (range, 40-88 years). The mean study duration was 9 weeks (range, 4-48 weeks). The percentage of men who dropped out or were lost to follow-up was 9.6% (n=283) and ranged from 4% to 15%. Treatment allocation concealment was adequate in 9 studies (50%) and 16 studies (89%) were double-blinded.

Baseline and outcome data from individual studies for urologic symptoms, nocturia, peak urine flow, and residual urine volume are available from the authors on request. These results indicate that on average, participating men had urinary tract symptoms and urinary flow measures consistent with moderate BPH. The mean (SD) baseline values for these variables did not differ by treatment group and included urologic symptom scale score (International Prostate Symptom Scale [IPSS]) in 2 studies with active control (14.4 [5.9] points; scale range, 0-35; moderate BPH symptoms, 8-19); urologic symptom scale score in 1 study with placebo (7.0 [2.8] points; scale range, 0-19, based on an addition of subscores for 6 variables: pollakiuria, nocturia, dysuria, hesitancy, urgency, and perineal heaviness); nocturia (2.5 [1.47] times per night; peak urine flow, 11.2 [3.9] mL/s; and residual urine volume, 55.8 [41.5] mL). Baseline values (SD) for mean urine flow (5.7 [2.1] mL/s) and prostate volume (43.9 [21.6] cc) also did not differ by treatment group. Symptom score results were reported in 10 studies, nocturia results in 12 studies, peak urine flow in 13 studies, and residual volume in 12 studies. Many studies did not report results in a method that permitted data to be combined in a meta-analysis.

See Table 1 and Table 2 for a description of individual studies and a summary of outcomes data, respectively.

Urinary Tract Symptoms.— Summary treatment effect sizes were determined for S repens alone or in combination vs placebo and vs active controls. Results from participant and physician assessment indicated that S repens was superior to placebo and comparable with finasteride in improving urologic symptoms. The weighted mean difference for urinary symptom scale scores for S repens vs placebo was −1.41 points (scale range, 0-19) (28% absolute improvement vs placebo) (95% CI, −2.52 to −0.30) (n=1 study) and vs finasteride was 0.37 IPSS points (scale range, 0-35) (37% absolute improvement from baseline for S repens vs 40% absolute improvement from baseline for finasteride) (95% CI, −0.45 to 1.19) (n=2 studies) (Figure 1). The weighted mean difference for the combination preparation Sabal-Urtica vs placebo was −3.50 IPSS points (scale range, 0-35) (17% absolute improvement vs placebo) (95% CI, −6.75 to −0.25) (n=1 study).

Participants and their physicians were both more likely to report improvement in symptoms in men treated with S repens than with placebo. The weighted RR for participant self-rating of improvement in urinary tract symptoms for S repens vs placebo was 1.72 (95% CI, 1.21-2.44) (n=6 studies) (Figure 2). The weighted RR for physician rating of improved urologic symptoms for S repens vs placebo was 1.72 (95% CI, 1.11-2.65) (n=3 studies). Overall, 242 (74%) of 329 men (6 studies) taking S repens reported an improvement of urologic symptoms compared with 168 (51%) of 330 men taking placebo (P<.001). Physician-assessed improvement of symptoms was reported in 165 (63%) of 262 men taking S repens and 101 (38%) of 262 men taking placebo (P<.001) (3 studies).

Serenoa repens reduced nocturia 25% (absolute difference) compared with placebo. The weighted mean difference was −0.76 times per evening vs placebo (95% CI, −1.21 to −0.32) (n=10 studies) (Figure 3). Serenoa repens was comparable with active controls regarding nocturia. The weighted mean difference was −0.05 (95% CI, −0.49 to 0.39) (n=1 study) vs finasteride and −0.20 (95% CI, −1.69 to 1.29) (n=1 study) vs Pygeum africanum.

Urinary Flow Measures and Prostate Size.—Serenoa repens was superior to placebo and comparable with finasteride in improving peak and mean urine flow rates and residual urine volume. The weighted mean differences for peak urine flow were 1.93 mL/s vs placebo (24% absolute improvement vs placebo) (95% CI, 0.72-3.14) (n=8 studies) (Figure 4), −0.74 mL/s vs finasteride (95% CI, −1.66 to 0.18) (n=2 studies), 2.0 mL/s vs gestonorone caproate (95% CI, 1.36-2.64) (n=1 study), and 1.6 mL/s for Sabal-Urtica vs placebo (95% CI, −0.67 to 3.87) (n=1 study). The weighted mean differences for mean urine flow were 2.22 mL/s vs placebo (28% absolute improvement vs placebo) (95% CI, 1.17-3.27) (n=4 studies) and −0.40 mL/s vs finasteride (95% CI, 0.15-0.95) (n=1 study). For residual volume the weighted mean difference was −22.05 mL vs placebo (43% absolute decrease vs placebo) (95% CI, −40.78 to −3.32) (n=6 studies) and 5.70 mL vs finasteride (95% CI, −5.42 to 16.82) (n=1 study). Serenoa repens did not reduce prostate size; the weighted mean differences for prostate size were −2.14 cc (95% CI, −10.92 to 6.65) (n=2 studies) vs placebo, and 4.08 cc (95% CI, 1.42-8.18) (n=1 study) vs finasteride.

Adverse effects due to S repens were generally mild and comparable with placebo. Withdrawal rates were S repens, 9.1%; placebo, 7.0%; and finasteride, 11.2% (P=.02 for S repens vs placebo and P =.87 vs finasteride). Erectile dysfunction was reported in 1.1% of men taking S repens; placebo, 0.7%; and finasteride, 4.9% (P=.58 for S repens vs placebo and P<.001 vs finasteride). Gastrointestinal adverse effects were reported in 1.3% of men taking S repens , placebo, 0.9%; and finasteride, 1.5% (P>.50 vs placebo and finasteride).

This systematic review summarizes the evidence from randomized controlled trials regarding the efficacy and safety of extracts from the saw palmetto berry S repens in men with lower urinary tract symptoms attributable to BPH. The available data indicate that S repens (alone or in combination with other phytotherapeutic agents) improves urinary tract symptoms and urinary tract flow measures. Compared with placebo, S repens improved urinary tract symptoms by 28%, nocturia by 25%, peak urine flow by 24%, mean urine flow by 28%, and residual urine volume by 43%. Men taking S repens were nearly twice as likely to report improvement in symptoms than men taking placebo. When compared with finasteride, S repens provided similar responses in urologic symptoms and flow measures and was associated with a lower rate of erectile dysfunction.

Participant baseline characteristics regarding age, prostate volume, peak urine flow, and symptom scale scores were comparable with previous trials and meta-analyses involving pharmacological management of BPH.^45- 48 Therefore, our results are generalizable. They did not substantially change when we restricted our analysis to studies that had adequate treatment allocation concealment (level 3) or were double-blinded. Furthermore, the treatment effect sizes with regard to symptom scale scores, peak and mean urinary flow, nocturia, and residual volume are considered clinically important and similar to effects reported with other pharmacological agents.^45- 48

Previous reviews of phytotherapy in the treatment of BPH were not structured systematic reviews or quantitative meta-analyses.^9- 10 They included information from nonrandomized or uncontrolled studies and, therefore, may have overestimated treatment effectiveness. The number of randomized trials included in these previous studies was less than we identified. The inclusion of an EMBASE and Phytodok search identified 5 studies not listed in MEDLINE. If our search had been restricted to English-language journals, we would have missed 12 trials (67%).

Our results should be viewed with caution. Despite abstracting and analyzing 18 randomized trials that included nearly 3000 participants, many studies did not report outcomes data in a consistent fashion. Several did not report means and SDs making completion of a quantitative systematic review difficult. Funnel plot analysis for urinary tract symptoms comparing study weight with weighted mean difference revealed no publication bias.⁴⁹ Multiple attempts to contact the trialists enabled us to obtain information from additional studies.⁵⁰

Only 3 studies reported results from standardized and validated urologic symptom scales.^25,34,38 One trial reported results from a scale that had not been standardized or validated.²³ All these studies were rated as having adequate treatment allocation concealment. Most studies were conducted prior to the development of validated urologic symptom scale scores. Results from these scales have been demonstrated to be the most valid and clinically relevant end points for assessing treatment effectiveness in men with mild to moderate symptoms of BPH.³ Secondary outcomes were combined in only a minority of trials: mean urine flow (5 trials), peak urine flow (12 trials), residual volume (6 trials), nocturia (11 trials), and prostate size (3 trials). The treatment duration was short with only 2 studies having follow-up of at least 6 months' duration. Studies used different doses and preparations of S repens or were performed in combination with other phytotherapeutic compounds. The most frequently reported dosage was 160 mg of S repens twice per day.

Several statistical issues in combining the data in our analysis need to be mentioned. For the "self-rating of symptom improvement" outcome, there was significant heterogeneity in the treatment effects. Ideally, when significant heterogeneity of treatment effect is present, meta-regression should be explored to understand reasons for the differences. However, this was not possible here because of an insufficient number of studies and lack of standardized reporting of meaningful clinical covariates. Nonetheless, if an overall quantitative estimate is deemed to be useful, then a random-effects model that incorporates between-studies heterogeneity would be more appropriate as we have done. The random-effects model typically produces wider CIs compared with the fixed-effects model. Five of 6 studies^{23- 24,26,32,34} had significant treatment effects and the second largest study also had trends in the same direction, thus reducing the likelihood that the pooling produced a false-positive result.

Because of the high baseline response rate in the control groups and the wide range of the baseline rates of several studies, the choice of treatment effect metric used to combine outcomes may also affect the results. Compared with the pooled random-effects RR (RR, 1.71; 95% CI, 1.22-2.39), the pooled odds ratio (OR) is much higher (OR, 5.74; 95% CI, 2.14-15.35). The OR is frequently used to approximate the RR in the clinical trial setting. In this case, the high pooled OR creates a false impression that S repens is far more efficacious. We chose the more conservative metric provided by the RR in our analysis.

We were not able to determine if S repens prevented long-term complications of BPH, such as acute urinary retention or the need for surgical interventions. Previous studies have demonstrated that, in men with large prostates (ie, >40 cc) producing moderate to severe symptoms, finasteride is effective in relieving BPH symptoms and reducing the development of acute urinary retention and the need for surgical intervention.^45- 46 However, fewer than one third of men with BPH have prostate glands more than 40 cc in size.⁵¹ In men with "large prostates," the absolute rate of acute urinary retention or symptomatic progression requiring surgical intervention is less than 3% per year. In our review, the mean prostate volume in studies reporting prostate size was 44 cc. The available data did not allow us to determine if prostate volume was an important predictor of outcomes. Additionally, there were no reported studies comparing S repens with α-adrenergic blockers that met criteria. One study compared S repens with alfuzosin, but the duration of follow-up was only 3 weeks.⁴¹

The medication charges of S repens are less than other pharmacological therapies. A 90-day supply of saw palmetto berry (320 mg/d of S repens) is between $10 and $50. However, available dosages and preparations frequently vary from those used in the published trials. The pharmacy charges for a 90-day supply of finasteride or terazosin (5 mg/d) are approximately $200 and $120, respectively.⁴

Additional placebo-controlled trials are needed as well as studies that compare S repens with α-antagonists.^47- 48 Future trials should be of sufficient size and duration to detect important differences in clinically relevant end points. At a minimum, these studies should assess and report the means and SDs at baseline and conclusion for the following variables: age, number enrolled and completing the study, standardized urologic symptom scale scores, mean and peak urine flow, voided volume, prostate size, residual urine volume, complications from BPH, need for subsequent therapy, and long-term adverse effects of S repens. Until then, this systematic review provides the most complete assessment regarding the efficacy and safety of S repens for treatment of symptomatic BPH.

In conclusion, the available evidence suggests that extracts from the saw palmetto plant, S repens, improve urinary tract symptoms and flow measures in men with BPH. Compared with finasteride, S repens produces similar improvements in urinary tract symptoms and flow measures, has fewer adverse treatment effects, and costs less. The long-term effectiveness and safety of S repens and its ability to prevent complications from BPH are not known.