Reviewed: Vela-Navarrete R, Reviewed: Reviewed: Vela-Navarrete R, Alcaraz A, Rodríguez-Antolín A, et al. Efficacy and safety of a hexanic extract of Serenoa repens (Permixon®) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH): systematic review and meta-analysis of randomised controlled trials and observational studies. BJU Int. 2018;122(6):1049-1065. doi: 10.1111/bju.14362.
As men age, the risk of developing lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH) increases. LUTS associated with BPH (LUTS/BPH) can significantly decrease quality of life, increase health care costs, and lead to other morbidities. Treatment options include α-1 blockers, 5-α-reductase inhibitors (5ARIs), muscarinic receptor antagonists, phosphodiesterase 5 inhibitors, and phytomedicines.
Saw palmetto (Serenoa repens, Arecaceae) berry has a long history of use for LUTS/BPH, and saw palmetto extracts have been evaluated in numerous randomized controlled trials (RCTs). However, systematic reviews and meta-analyses of these RCTs have produced conflicting results. One explanation is that some meta-analyses have included different types of saw palmetto extracts. As noted by the authors of this meta-analysis: “The current European LUTS/BPH EAU (European Association of Urology) guidelines propose that different brands of phytotherapy should be assessed individually because differences in potency mean that results cannot be extrapolated from one brand to another.”
To draw better conclusions about the efficacy and tolerability of one brand of saw palmetto extract on LUTS/BPH, these authors conducted an exhaustive systematic review and meta-analysis of studies that evaluated a daily dose of 320 mg of saw palmetto as a hexanic extract (Permixon®; Pierre Fabre Médicament; Castres, France).
The Cochrane Library, ISI Web of Knowledge, MEDLINE, and Scopus databases were searched using the terms “Serenoa repens,” “saw palmetto,” “Sabal serrulata,” “Permixon,” “benign prostatic hyperplasia,” “BPH,” “prostatic adenoma,” “prostatic hypertrophy,” “lower urinary tract symptom,” and “LUTS,” in combination with keywords such as “efficacy,” “tolerability,” and “outcome.” Bibliographic reference lists from related articles were hand-searched. All RCTs, non-randomized controlled trials, case-control studies, and prospective observational studies (OSs) up to April 2017 were included if they reported data on the selected outcomes and evaluated 320 mg/day of Permixon.
Two researchers working independently evaluated the results for inclusion in the review, and a third researcher resolved disagreements. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) protocol was used to perform the meta-analysis, and the findings were reported using Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) recommendations. Included studies were evaluated using the Downs and Black Quality Index (DBQI) checklist, which ranks study quality on a scale from 0 to 27, with higher numbers reflecting better quality.
The researchers extracted these data from the studies: International Prostate Symptom Scores (IPSSs), peak urinary flow (Qmax), frequency of nocturia, quality of life (QoL; question 8 of the IPSS) ratings, prostate volume, and sexual function questionnaire responses. Adverse event (AE) and adverse drug reaction (ADR) reporting were considered for the safety analysis. Mean decreases in IPSS of at least 3.1 were considered clinically relevant. For the statistical analysis, numerical data (IPSS, nocturia, QoL, and Qmax) were expressed as mean pre-post treatment differences (MDs). ADRs were expressed as proportions. Sensitivity analyses excluded studies that did not provide standard deviations (SDs) or standard errors (SEs). Heterogeneity among the studies was assessed using the I2 statistic. Funnel plots were used to assess publication bias and forest plots were used to display results.Subgroup analyses of data from studies lasting one year or longer were conducted to evaluate long-term effects.
Included in the meta-analysis were 27 studies (15 RCTs and 12 OSs), with a total of 5,800 patients allocated as follows: Permixon (n = 3,926); α-1 blockers (n = 775; tamsulosin [n = 377], unspecified [n = 398]); 5ARIs (n = 578; finasteride [n = 484], unspecified [n = 94]); placebo (n = 301); control group (no treatment; n = 190); and gestonorone caproate (n = 30).
ADR data were extracted only from one RCT and one OS because the efficacy data lacked precision. The studies were published between 1983 and 2016. The sample sizes ranged from 10 to 1,713 participants. Treatment durations ranged from one month to 60 months, with the most frequent study duration of three months. DBQI scores ranged from three to 25; most of the studies with low DBQI scores were conducted in the 1980s and early 1990s before the publication of the first Consolidated Standards of Reporting Trials (CONSORT) guidelines in 1996.
Permixon vs. Placebo
The seven RCTs that evaluated Permixon compared to placebo did not report IPSS data and were of moderate quality, with DBQI scores ranging from six to 15. Meta-analysis showed that Permixon significantly improved nocturia with 0.64 fewer voids per night (P < 001). Meta-analysis of the four studies that reported Qmax data indicated Permixon significantly increased peak urine flow by 2.75 mL/s (P = 0.014). There was no significant heterogeneity or publication bias found for the nocturia and Qmax data.
Permixon vs. α-1 Blockers
Two RCTs and one OS compared Permixon to α-1 blockers and reported IPSS data; all three studies were of high quality, with DBQI scores between 19 and 25. Although the improvement in mean IPSS was greater with Permixon, the difference between groups was not statistically significant (P = 0.35). Two RCTs compared Permixon to the α-1 blocker tamsulosin and reported nocturia and Qmax data; there were no significant differences between groups for either measure at the end of the studies. Similarly, two studies found no significant difference between Permixon and α-1 blockers in the effect on prostate-specific antigen (PSA) levels (P = 0.60).
Permixon vs. 5ARIs
Two RCTs compared the effects of Permixon and 5ARIs on IPSS and PSA values. Mean IPSS improvement did not differ significantly between the groups (P = 0.30). However, 5ARIs significantly reduced PSA values (P < 0.001), while there was no change with Permixon. No heterogeneity was observed for either outcome.
Overall Changes from Baseline
Analysis of the change from baseline data in this meta-analysis showed that Permixon significantly improved IPSS, Qmax, nocturia, QoL, and prostate volume, but not PSA levels, while having no effect on sexual function (P = 0.64). Compared to baseline, and accounting for any potential publication bias or outliers, there was a mean improvement of –5.38 points in IPSS (P < 0.001); mean increase of 2.26 mL/s in Qmax (P < 0.001); mean reduction of 1.56 voids per night (P < 0.001); mean QoL score increase of 1.07 points (P < 0.001); and mean prostate volume reduction of –2.36 mL (P < 0.001). The effect on PSA was not clinically significant.
When comparing the results of the RCTs and OSs, there was no statistically significant difference between the two types of studies when analyzing for IPSS, Qmax, or QoL. However, there was a significant difference between study types for nocturia and prostate volume; there was only one OS that reported nocturia, and, for prostate volume, the five OSs reported significantly different findings.
Meta-analysis of the data from the three studies with a treatment duration of one year or longer showed there was a mean improvement in IPSS of –6.06 points (P < 0.001) from baseline in the Permixon group, or –4.85 points (P < 0.01) after exclusion of outliers. Qmax increased 2.29 mL/s (P < 0.001), or 1.81 mL/s (P < 0.01) after excluding outliers. QoL improved 1.31 points (P < 0.001) with no heterogeneity among the studies; and prostate volume decreased by 5.37 mL (P = 0.034). Two of these studies measured PSA levels; there was no significant change in PSA levels with Permixon (P = 0.18) and no heterogeneity.
The four types of ADRs with a mean incidence of more than 1% were gastrointestinal disorders (3.8%), nausea and vomiting (2.6%), hypertension (1.2%), and tinnitus (1.2%). Long-term use of Permixon was safe and well-tolerated. There was a lower incidence of ejaculation disorders with Permixon compared to the α-1 blocker tamsulosin in one long-term study (P = 0.001).
This systematic review and meta-analysis found that a dose of 320 mg of Permixon daily was superior to placebo and comparable to α-1 blockers and short-term treatment with 5ARIs on most relevant outcomes, including clinically significant improvements in IPSS, and equivalent efficacy to α-1 blockers on Qmax. When compared to baseline, Permixon was associated with a clinically significant improvement in QoL.
The authors commented that in “an increasingly polymedicated population, such as elderly men affected by LUTS/BPH, the availability of an effective treatment with a very low rate of ADRs and very limited drug interactions is of relevance.” They also emphasized that potency has been shown to vary considerably between brands of saw palmetto extracts, and these results cannot be generalized to other preparations.
Acknowledged limitations of this review include the low quality and relatively short duration of some studies.