EUF-151; No.

of Pages 9

EUROPEAN UROLOGY FOCUS XXX (2016) XXX–XXX

available at www.sciencedirect.com
journal homepage: www.europeanurology.com/eufocus

Review – Benign Prostatic Hyperplasia

Efficacy and Safety of Hexanic Lipidosterolic Extract of Serenoa

repens (Permixon) in the Treatment of Lower Urinary Tract
Symptoms Due to Benign Prostatic Hyperplasia: Systematic
Review and Meta-analysis of Randomized Controlled Trials

Giacomo Novara a, Gianluca Giannarini b, Antonio Alcaraz c, José-M. Cózar-Olmo d,

Aurelien Descazeaud e, Francesco Montorsi f, Vincenzo Ficarra b,g,*
a
Department of Surgery, Oncology, and Gastroenterology, Urology Clinic, University of Padua, Padua, Italy; b Academic Medical Centre Hospital ‘‘Santa Maria
della Misericordia’’, Urology Unit, Udine, Italy; c Urology Department, Hosp. Clı´nic University, IDIBAPS, University of Barcelona, Barcelona, Spain; d Urology
Department, Complejo Hospitalario Universitario de Granada, Granada, Spain; e Service d’Urologie, CHU Dupuytren, Limoges, France; f Division of Oncology/
Urology Unit, Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; g Department of Experimental and Clinical Medical Sciences, Urology
Unit, University of Udine, Italy

Article info Abstract

Article history: Context: A recent Cochrane Collaboration meta-analysis of randomized controlled trials
Accepted April 11, 2016 (RCTs) evaluating the efficacy of different extracts of Serenoa repens in relieving lower
urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) concluded that
Associate Editor: these extracts were no more effective than placebo. However, among all Serenoa repens
James Catto extracts, Permixon (Pierre Fabre Medicament, Paris, France) has the highest activity and
the most accurate standards of drug preparation and extraction.
Objective: To evaluate the efficacy and safety of Permixon in the treatment of LUTS/BPH.
Keywords: Evidence acquisition: A systematic review and meta-analysis of the literature was
Lower urinary tract symptoms performed in January 2016 using the Medline, Scopus, and Web of Science databases,
searching for the term Serenoa repens in all fields of the records. Only RCTs reporting on
Benign prostatic hyperplasia
efficacy and safety of Permixon in the treatment of LUTS/BPH were selected.
Phytotherapy Evidence synthesis: The systematic search identified 12 RCTs: 7 compared Permixon
Serenoa repens with placebo; 2 compared Permixon with tamsulosin; 2 compared Permixon plus
Permixon tamsulosin with, respectively, placebo plus tamsulosin and tamsulosin alone; and
a-Blockers 1 compared Permixon with finasteride. Permixon was significantly more effective than
placebo in reducing the number of nocturnal voids (weighted mean difference [WMD]
Tamsulosin 0.31; p = 0.03) and increasing maximum flow rate (Qmax; WMD 3.37; p < 0.0001). The
5a-Reductase inhibitors rates of overall adverse events (odds ratio [OR] 1.12; p = 0.92) and withdrawal (OR 1.52;
Finasteride p = 0.60) were similar for Permixon and placebo. Permixon was as effective as tamsu-
Erectile dysfunction losin monotherapy and short-term therapy with finasteride in improving International
Prostate Symptom Score (WMD 1.15; 95% confidence interval [CI], 1.11 to 3.40;
Randomized controlled trial
p = 0.32) and Qmax (WMD 0.16; 95% CI, 0.60 to 0.28; p = 0.48). The combination of
Systematic review Permixon and tamsulosin was more effective than Permixon alone for relieving LUTS
Meta-analysis (WMD 0.31; 95% CI, 0.13–0.48; p < 0.01) but not for improving Qmax (WMD 0.10; 95% CI
0.02 to 0.21; p = 0.10). Permixon had a favorable safety profile, with a very limited
impact with regard to ejaculatory dysfunction compared with tamsulosin (0.5% vs 4%;

* Corresponding author. Urology Unit, Academic Medical Centre Hospital ‘‘Santa Maria della Mis-
ericordia,’’ Piazzale Santa Maria della Misericordia 15, IT-33100 Udine, Italy. Tel. +39 0432552931;
Fax: +39 0432552930.
E-mail address: vincenzo.ficarra@unipd.it (V. Ficarra).

http://dx.doi.org/10.1016/j.euf.2016.04.002
2405-4569/# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Novara G, et al. Efficacy and Safety of Hexanic Lipidosterolic Extract of Serenoa repens
(Permixon) in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: Systematic Review and
Meta-analysis of Randomized Controlled Trials. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.04.002
EUF-151; No. of Pages 9

2 EUROPEAN UROLOGY FOCUS XXX (2016) XXX–XXX

p = 0.007) and with regard to decreased libido and impotence compared with short-term
finasteride (2.2% and 1.5% vs 3% and 2.8%, respectively).
Conclusions: The conclusions of the recent Cochrane meta-analysis on Serenoa repens in
the treatment of LUTS/BPH apparently do not apply to Permixon. Our meta-analysis
showed that Permixon decreased nocturnal voids and Qmax compared with placebo and
had efficacy in relieving LUTS similar to tamsulosin and short-term finasteride. Moreover,
Permixon had a favorable safety profile with a very limited impact on sexual function,
which is significantly affected by all other drugs used to treat LUTS/BPH.
Patient summary: A systematic review of the literature showed that Permixon was
effective for relieving urinary symptoms due to prostate enlargement and improving
urinary flow compared with placebo. Permixon had efficacy similar to tamsulosin and
short-term finasteride in relieving urinary symptoms. Permixon was well tolerated and had
a very limited impact on sexual function.
# 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.

1. Introduction repens extracts in inhibiting 5a-reductase type I and II

Benign prostatic hyperplasia (BPH) is a common cause of
lower urinary tract symptoms (LUTS) in adult men.
a-Blockers, 5a-reductase inhibitors (5-ARIs), antimuscari-
nics, and phosphodiesterase type 5 inhibitors, either alone
or in combination, are the standard medical treatments for
patients with uncomplicated bothersome LUTS/BPH unre-
sponsive to behavioral management [1,2].
Phytotherapy is currently prescribed in both Europe and
the United States for the treatment of male LUTS/BPH, and a
2010 publication reported that approximately 17% of the
patients with LUTS used this category of drug as mono-
therapy [3]. Moreover, a recent population study from
France suggested that phytotherapy was taken by 32% of
patients using combination therapies [4]. Extracts of saw
palmetto, known as Serenoa repens, are the most commonly
used phytotherapeutic compounds. Specifically, Serenoa
repens is a lipidosterolic extract of the berry of the dwarf
palm tree that has antiandrogenic action, antiproliferative
proapoptotic effects, and anti-inflammatory properties
[5]. This last effect could be of interest considering the
most recent in vitro and in vivo studies highlighting the
potential role of inflammation in LUTS/BPH [6].
A recent Cochrane Collaboration meta-analysis pooled
all available randomized controlled trials (RCTs) evaluating
all of the different extracts of Serenoa repens and demon-
strated that they were no more effective than placebo in
relieving male LUTS/BPH [7]. However, quality of plant
extracts is strictly related to the quality of the botanical
source as well as to the method of preparation and drug
extraction. Consequently, different products derived from
the same plant can have different activity and different
safety profiles [8]. Some preclinical studies confirmed that
major differences exist among different brands of Serenoa
repens. Specifically, Habib and Wyllie [9] compared the
concentrations of free fatty acids, methyl and ethyl esters,
long-chain esters, and glycerides in 14 brands of Serenoa
repens and demonstrated major differences among the
extracts; Permixon (Pierre Fabre Medicament, Paris, France)
had the highest percentage of free fatty acids considered to
be responsible, at least in part, for the therapeutic effects of
Serenoa repens. Moreover, Scaglione et al. [10] evaluated the
efficacy of different batches of seven different Serenoa
enzymes and demonstrated major differences among the
different extracts and between different batches of the same
extracts, with Permixon showing the highest efficacy and
the lowest variability from batch to batch. In a recent
publication by the same group [11], among nine more
Serenoa repens extracts that were different from those
studied previously, Permixon showed the highest activity,
reinforcing the evidence that potency differs among
extracts. Taken together, these data raise questions about
the conclusions of the Cochrane meta-analysis because of
the pooling of different, potentially nonbioequivalent
extracts, as also suggested by the European Association of
Urology guidelines [1].
With a focus solely on Permixon, which showed the
highest efficacy in preclinical studies and has the most
accurate standards of drug preparation and extraction, we
performed a systematic review and meta-analysis of all
RCTs assessing the efficacy and safety of Permixon for the
treatment of LUTS/BPH.
2. Evidence acquisition
The systematic review of the literature was performed in
January 2016 using the Medline, Scopus, and Web of Science
databases. All searches used free-text protocols searching
for the keyword Serenoa repens in all record fields. No
limitations were used. Moreover, the Cochrane Database of
Systematic Reviews was also searched using the same
keyword.
Three authors assessed the eligibility of the papers
relevant to the review topic. Specifically, all RCTs reporting
on efficacy and safety from the use of Permixon in LUTS/BPH
were selected. One author extracted information on
patients, interventions, and outcomes that was checked
by other two authors, and discrepancies were resolved by
open discussion with the senior author. The quality of the
retrieved RCTs was assessed using the Jadad score [12].
Meta-analysis was conducted using Review Manager
software v.5.0 (Cochrane Collaboration, Oxford, UK).
Statistical heterogeneity was tested using the x2 test. A
value of p < 0.10 was used to indicate heterogeneity.
Random-effects models were used for the meta-analyses.
The results were expressed as weighted mean difference

Please cite this article in press as: Novara G, et al. Efficacy and Safety of Hexanic Lipidosterolic Extract of Serenoa repens
(Permixon) in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: Systematic Review and
Meta-analysis of Randomized Controlled Trials. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.04.002
EUF-151; No. of Pages 9

EUROPEAN UROLOGY FOCUS XXX (2016) XXX–XXX 3

(WMD) with a 95% confidence interval (CI) for continuous
outcomes and as an odds ratio (OR) with a 95% CI for
dichotomous variables. The presence of publication bias
was evaluated through a funnel plot [13].
The study complies with the Preferred Reporting Items
for Systematic Reviews and Meta-Analyses statement [14].
3. Evidence synthesis
3.1. Quality of evidence
0.59 to 0.03; p = 0.03). Moreover, maximum urinary flow
rate (Qmax) at study end was significantly higher in the
patients treated with Permixon (WMD 3.37; 95% CI, 1.71–
5.03; p < 0.0001). With regard to safety, the overall adverse
event rates were similar for Permixon and placebo (OR 1.12;
95% CI, 0.13–9.75; p = 0.92). Finally, withdrawal rates were
similar following Permixon or placebo (OR 1.52; 95% CI,
0.32–7.33; p = 0.60).
Figure 2 shows the forest plots for efficacy and safety
data of Permixon in comparison to placebo.

Figure 1 summarizes the literature review process that led
to the identification of the 12 RCTs used in the meta-
analysis. Specifically, seven RCTs compared Permixon with
placebo [15–21], two RCTs compared Permixon with
tamsulosin [22,23], two RCTs compared Permixon plus
tamsulosin with placebo plus tamsulosin [24] and with
tamsulosin alone [25], and a single RCT compared Permixon
with finasteride [26]. Among these publications, there were
four RCTs of good methodological quality (level of evidence
2) [22–24,26] and eight RCTs of poor methodological quality
(level of evidence 3) [15–21,25]. Clinically speaking, all
studies but three [22,24,25] evaluated short-term treat-
ment schedules; standard outcome measures, such as the
International Prostate Symptom Score (IPSS) and the
American Urological Association symptom index, were
used in only five studies [22–26].
3.2. Permixon versus placebo
Table 1 summarizes the studies reporting the efficacy and
safety of Permixon in comparison to placebo [15–21].
The number of nocturnal voids at study end were
significantly lower with Permixon (WMD 0.31; 95% CI,
3.3. Permixon or combination therapy versus tamsulosin
Table 2 summarizes the studies reporting efficacy and
safety of Permixon or combination therapy compared with
tamsulosin.
In the studies comparing Permixon with tamsulosin
[22,23], no statistically significant difference was found in
terms of mean change in IPSS from baseline to study end
(WMD 1.15; 95% CI, 1.11 to 3.40; p = 0.32) and mean change
in Qmax from baseline to study end (WMD 0.16; 95% CI,
0.60 to 0.28; p = 0.48) (Fig. 3a and 3b). With regard to safety,
prevalence of adverse events (OR 0.95; 95% CI, 0.72–1.26;
p = 0.72) and withdrawal rate (OR 0.96; 95% CI, 0.66–1.40;
p = 0.83) were lower with Permixon than with tamsulosin,
albeit not significantly (Fig. 3c and 3d). In one study [22],
however, ejaculatory dysfunction was significantly less
common with Permixon than with tamsulosin (0.5% vs 4%;
p = 0.007). Figure 3 shows the forest plots for efficacy and
safety data of Permixon compared with tamsulosin.
In the studies comparing Permixon plus tamsulosin with
tamsulosin alone [24,25], mean IPSS significantly decreased
from baseline to study end with the combination therapy
versus tamsulosin alone (WMD 0.31; 95% CI 0.13–0.48;

Records identified through database searching

(Medline, n = 345; Scopus, n = 437; Web of Science, n = 470)

1252 records screened

- Duplicate publications
- Noncomparative studies
- Nonrandomized studies
- RCTs reporting clinical data on other
Serenoa repens extracts
- RCTs reporting not pertinent end points
- Secondary analyses of RCTs

12 RCTs used for systematic review and meta-analysis

Permixon vs Permixon vs Permixon or combination vs Permixon vs

placebo (n = 7) tamsulosin (n = 2) tamsulosin monotherapy (n = 2) finasteride (n = 1)

Fig. 1 – Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram outlining the study selection process.
RCT = randomized controlled trial.

Please cite this article in press as: Novara G, et al. Efficacy and Safety of Hexanic Lipidosterolic Extract of Serenoa repens
(Permixon) in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: Systematic Review and
Meta-analysis of Randomized Controlled Trials. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.04.002
EUF-151; No. of Pages 9

4 EUROPEAN UROLOGY FOCUS XXX (2016) XXX–XXX

Table 1 – Efficacy and safety data of studies comparing Permixon with placebo

Study Arms Duration, RCT Nocturnal voids at Change in nocturnal voids Qmax, ml/s,
wk study end, mean  SD from baseline, mean  SD mean  SD

Efficacy data

Boccafoschi and Annoscia, 1983 [15] Permixon (n = 11) 8 Yes 1.8  2.01 NR 13.7  7.03
Placebo (n = 11) 2.1  1.79 12.2  7.03
Emili et al., 1983 [16] Permixon (n = 15) 4 Yes 1.67  0.98 NR 13.7  3.56
Placebo (n = 15) 2.33  1.11 9.4  2.72
Mandressi et al., 1983 [17] Permixon (n = 20) 4 Yes NR 2.06 ( 42%) NR
Placebo (n = 20) 0.96 ( 4%)
Pygeum (n = 20) 1.6 ( 38%)
Cukier et al., 1985 [18] Permixon (n = 71) 10 Yes 2.2  1.97 NR NR
Placebo (n = 76) 2.9  1.99
Tasca et al., 1985 [19] Permixon (n = 14) 8 Yes 0.9  2.02 NR 16.2  7.03
Placebo (n = 13) 1.9  1.99 11.8  7.03
Reece Smith et al., 1986 [20] Permixon (n = 33) 12 Yes 1.86  1.2 NR NR
Placebo (n = 37) 1.9  1.4
Descotes et al., 1995 [21] Permixon (n = 82) 4 Yes 1.4  1.7 0.7 15.3  11.89
Placebo (n = 94) 1.5  1.1 0.3 13.5  8.59

Safety data

Study Arms Overall drug-related Libido Withdrawal, Withdrawal due to

adverse event, % decrease, % % adverse events, %

Boccafoschi and Annoscia, 1983 [15] Permixon (n = 11) 0 NR 0 0

Placebo (n = 11) 10 0 0
Emili et al., 1983 [16] Permixon (n = 15) 0 NR 0 0
Placebo (n = 15) 0 0 0
Tasca et al., 1985 [19] Permixon (n = 15) 6.7 NR 6.7 6.7
Placebo (n = 15) 15 13.3 0
Reece Smith et al., 1986 [20] Permixon (n = 40) 10 0 17 5
Placebo (n = 40) 0 0 7 0

NR = not reported; Qmax = maximum urinary flow rate; RCT = randomized controlled trial; SD = standard deviation.

p < 0.01). A non–statistically significant trend in favor of the
combination therapy was demonstrated for Qmax improve-
ment (WMD 0.10; 95% CI, 0.02 to 0.21; p = 0.10). With
regard to rate of adverse events, a non–statistically
significant trend favoring tamsulosin monotherapy was
shown (OR 1.63; 95% CI, 0.94–2.84; p = 0.08). Figure 4 shows
the forest plots concerning efficacy and safety data of
Permixon plus tamsulosin compared with tamsulosin.
3.4. Permixon versus finasteride
A single study compared efficacy and safety of Permixon
and finasteride [26]. Specifically, Carraro et al. randomized
1098 patients with moderate to severe LUTS/BPH to 26-wk
treatment with Permixon (n = 553) or finasteride (n = 484).
Mean prostate volume was 43 and 44 ml in the Permixon
and finasteride arms, respectively. Both drugs showed
similar efficacy with regard to improvement in IPSS ( 5.8
with Permixon vs 6.2 with finasteride; p = 0.17) and
improvement in the IPSS item for quality of life ( 1.5 vs
1.4, respectively; p = 0.14), although increase in Qmax was
slightly higher with finasteride (+2.7 vs +3.2, respectively;
p = 0.035). However, decreased libido and impotence were
less common in the Permixon arm (2.2% and 1.5%,
respectively) than in the finasteride arm (3% and 2.8%,
respectively). Sexual function score was significantly lower
(corresponding to better function) with Permixon than with
finasteride (7.9 vs 9.3; p < 0.01).
3.5. Publication bias
Funnel plots of all studies used in this meta-analysis were
generated for all evaluated comparisons. Only a single
study lies outside the 95% CI with an even distribution
about the vertical, suggesting little evidence of publication
bias.
3.6. Discussion
a-Blockers, 5-ARIs, or their combination are among the
standard drug therapies for bothersome LUTS/BPH
[1,2]. Both categories of drugs are effective for improving
symptoms, with 5-ARIs also able to reduce the risk of
disease progression [1,2]. However, such therapies are
associated with significant side effects, including postural
hypotension and ejaculatory dysfunction for a-blockers and
erectile dysfunction and loss of libido for 5-ARIs, that may
reduce patient adherence to therapies [27,28]. Impairment
of sexual function is of particular concern, considering that
concomitant sexual dysfunction and LUTS are highly
prevalent in adult men [29].
Phytotherapy is a common therapeutic option for LUTS/
BPH and is used in approximately 17% of patients
[3]. Specifically, Tacklind et al. reported on behalf of the
Cochrane Collaboration a large meta-analysis of all RCTs
evaluating Serenoa repens, which is the most common
phytoterapeutic drug, and demonstrated no advantage for

Please cite this article in press as: Novara G, et al. Efficacy and Safety of Hexanic Lipidosterolic Extract of Serenoa repens
(Permixon) in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: Systematic Review and
Meta-analysis of Randomized Controlled Trials. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.04.002
EUF-151; No. of Pages 9

EUROPEAN UROLOGY FOCUS XXX (2016) XXX–XXX 5

Fig. 2 – Forest plots of comparisons in studies with Permixon versus placebo: (a) number of nocturnal voids at study end; (b) maximum urinary flow
rate at study end; (c) rate of overall adverse events; (d) withdrawal rate.
CI = confidence interval; IV = inverse variance; M-H = Mantel-Haenszel; SD = standard deviation.

Serenoa repens in comparisons with placebo in relieving
LUTS [7]. However, the latest version of the Cochrane meta-
analysis suffers from some limitations. All of the different
brands of Serenoa repens were pooled together, which is a
questionable choice, as Bilia et al. clearly stated in the
feedback on the Cochrane meta-analysis [7]. Specifically,
some differences exist among the different brands of
Serenoa repens, as reported by some preclinical studies,
with Permixon seeming to be the brand with the highest
percentage of free fatty acids and the highest in vitro
efficacy [8–10]. Consequently, the conclusion of the
Cochrane meta-analysis might be affected by the fact that
various kinds of extracts were pooled in the analysis. Indeed,
this conclusion changed when the Cochrane Collaboration
included in its meta-analysis well-designed RCTs but with
different extracts of Serenoa repens obtained through
different extraction processes [30,31]. Specifically, Barry
et al. used Prosta-Urgenin Uno, an ethanolic Serenoa repens
extract produced by Rottapharm Madaus (Selangor,
Malaysia) [30], whereas Bent et al. evaluated a carbon
dioxide Serenoa repens extract (Indena, Milan, Italy)
[31]. That issue may explain why the Cochrane Collaboration
concluded in a previous meta-analysis that Serenoa repens
improves urologic symptoms and flow measures compared
with placebo [32]. In fact, the same authors of the Cochrane
meta-analysis stated that they did not know if their

Please cite this article in press as: Novara G, et al. Efficacy and Safety of Hexanic Lipidosterolic Extract of Serenoa repens
(Permixon) in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: Systematic Review and
Meta-analysis of Randomized Controlled Trials. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.04.002
 6

EUF-151; No. of Pages 9

Meta-analysis of Randomized Controlled Trials. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.04.002
(Permixon) in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: Systematic Review and
Please cite this article in press as: Novara G, et al. Efficacy and Safety of Hexanic Lipidosterolic Extract of Serenoa repens

Table 2 – Efficacy and safety data of studies comparing Permixon or combination therapy with tamsulosin

Study Arms Duration, RCT Change in IPSS Change in IPSS Change in IPSS Change in IPSS Nocturnal Qmax increase, PVR, ml,
wk from baseline, storage subscore, voiding subscore, QoL score, voids, ml/s, mean  SD
mean  SD mean  SD mean  SD mean  SD mean  SD mean  SD

Efficacy data

Debruyne 52 Yes 4.4  5.5 1.7  2.8 2.8  3.7 NR NR 1.9  4.8 NR
et al., 2002 [22] Permixon (n = 340) 4.4  5.1 1.5  2.4 2.9  3.7 1.8  4.8

EUROPEAN UROLOGY FOCUS XXX (2016) XXX–XXX

Tamsulosin (n = 345)
Latil 12 Yes 4.3  3 NR NR 0.87  1.6 NR 1.77  2.1 15.2  33.6
et al., 2015 [23] Permixon (n = 102) 6.6  3 1.29  1.6 2.09  2 4.04  34
Tamsulosin (n = 101)
Glémain 52 Yes 6.0  6 1.9  2.9 4.1  4.4 1.3  1.4 NR 1.2  4.6 NR
et al., 2002 [24] Permixon plus 5.2  6.4 1.9  3.1 3.3  4.6 1.0  1.4 1.3  5.2
tamsulosin (n = 157)
Placebo plus
tamsulosin (n = 159)
Ryu 52 Yes 5.8  0.43 1.9  0.33 3.9  0.41 2.4  0.43 NR 2.1  0.31 8.3  1.45
et al., 2015 [25] Permixon plus 5.5  0.54 0.9  0.3 4.5  0.42 2.5  0.4 2.0  0.26 10.6  1.79
tamsulosin (n = 60)
Tamsulosin (n = 60)
Safety data

Study Arms Overall Withdrawal, Withdrawal Ejaculatory Postural Headache, Dizziness,

AEs, % % due to AEs, % dysfunction, % hypotension, % % %

Debruyne 66* 15 8 0.5 1 8 3

et al., 2002 [22] Permixon (n = 349) 67* 16 8 4 1 11 2
Tamsulosin (n = 354)
Latil 29 8 NR NR NR NR NR
et al., 2015 [23] Permixon (n = 102) 31 3
Tamsulosin (n = 101)
Glémain 16 18 4 8 1 NR 2
et al., 2002 [24] Permixon plus 10 20 3 5 0 2
tamsulosin (n = 168)
Placebo plus
tamsulosin (n = 161)
Ryu 20 0 0 6 4 10 4
et al., 2015 [25] Permixon plus 17 0 0 7 4 11 2
tamsulosin (n = 60)
Tamsulosin (n = 60)
AE = adverse event; IPSS = International Prostate Symptom Score; NR = not reported; PVR = postvoid residual urine; Qmax = maximum urinary flow rate; QoL = quality of life; RCT = randomized controlled trial;
SD = standard deviation.
*
These figures include both drug-related and drug-unrelated AEs.
EUF-151; No. of Pages 9

EUROPEAN UROLOGY FOCUS XXX (2016) XXX–XXX 7

Fig. 3 – Forest plots of comparisons in studies with Permixon versus tamsulosin: (a) change in International Prostate Symptom Score at study end; (b)
change in maximum urinary flow rate at study end; (c) rate of overall adverse events; (d) withdrawal rate.
CI = confidence interval; IV = inverse variance; M-H = Mantel-Haenszel; SD = standard deviation.

conclusions were generalizable to proprietary products of
Serenoa repens such as Permixon, inviting investigation of the
issue [7,33], which was the objective of the current meta-
analysis. Moreover, some inaccuracies are evident in their
data analysis and extraction. For example, Qmax values for
two studies [21,34] reported in the Cochrane meta-analysis
were not consistent with those reported in the original
papers.
Consequently, to assess the validity of the Cochrane
meta-analysis data for all brands of Serenoa repens with
regard to Permixon, we performed a systematic review and
meta-analysis of the RCTs assessing efficacy and safety of
Permixon. We found that Permixon was more effective than
placebo in reducing the number of nocturnal voids and Qmax
and as effective as tamsulosin and short-term finasteride in
improving LUTS. Moreover, combination therapy of Per-
mixon and tamsulosin might provide some benefits in
comparison to tamsulosin monotherapy in terms of LUTS
improvement. In all comparisons with the other drugs,
Permixon was associated with a favorable profile of adverse
events, especially with regard to ejaculatory and erectile
functions.
The findings of the present study were partially similar to
those of Boyle et al, who reported a systematic review of RCTs
and open-label studies on Permixon in 2004 [35]. Specifically,
Boyle et al. demonstrated that Permixon was able to increase
Qmax by roughly 2 ml/s, to reduce the mean number of
nocturnal voids by roughly one, and to cause a five-point
decrease in IPSS in comparison to placebo. Our analysis, which
included studies comparing Permixon with tamsulosin or
short-term finasteride, reconfirmed the same figures with
regard to improvement in number of nocturnal voids and
Qmax.
The present data showed stronger evidence for Per-
mixon, the hexanic extract of Serenoa repens, either as
monotherapy or in combination with tamsulosin, than the
extract suggested by current guidelines for the whole
category of phytoterapeutic drugs and for other Serenoa
repens brands. This finding is supported by the recent
assessment report on Serenoa repens released by the
European Medicines Agency [36]. In this report, only the
hexanic extract of Serenoa repens has been recognized as a
well-established medicinal product thanks to its proven
efficacy and tolerability in controlled trials. Conversely,

Please cite this article in press as: Novara G, et al. Efficacy and Safety of Hexanic Lipidosterolic Extract of Serenoa repens
(Permixon) in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: Systematic Review and
Meta-analysis of Randomized Controlled Trials. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.04.002
EUF-151; No. of Pages 9

8 EUROPEAN UROLOGY FOCUS XXX (2016) XXX–XXX

Fig. 4 – Forest plots of comparisons in studies with combination of Permixon and tamsulosin versus tamsulosin monotherapy: (a) change in
International Prostate Symptom Score at study end; (b) change in maximum urinary flow rate at study end; (c) rate of overall adverse events.
CI = confidence interval; IV = inverse variance; M-H = Mantel-Haenszel; SD = standard deviation.

ethanolic extracts have been categorized as traditional use
products because of the lack of clinical trials, and
supercritical CO2 extracts have not been assigned any
particular status because clinical studies have not provided
sufficiently reliable data and because the extracts have been
marketed for <15 yr. Moreover, the anti-inflammatory
properties of Serenoa repens may represent a further
potential advantage of this drug to improve storage and
voiding LUTS. Interestingly, this direct anti-inflammatory
effect has not been demonstrated for other drugs commonly
prescribed for the treatment of LUTS/BPH [6].
We acknowledge that the overall quality of the
available studies was limited, with the majority of RCTs
being of low methodological quality. Specifically, most
studies enrolled a limited number of patients, lacked
sample size calculation, and did not use validated tools to
measure LUTS (eg, IPSS and frequency–volume charts).
Moreover, most studies assessed short-term treatment
schedules, especially regarding finasteride. High-quality
RCTs comparing Permixon with placebo, a-blockers, and
5-ARIs in the long term and large clinical trials testing the
anti-inflammatory properties of Permixon are needed to
corroborate our findings. Furthermore, how long Per-
mixon should be continued, who will profit most from
this therapy, and whether Permixon may reduce the risk
of BPH progression and related complications remain
unanswered questions.
4. Conclusions
The conclusions of the recent Cochrane meta-analysis on
effects and harms of Serenoa repens in the treatment of
LUTS/BPH apparently do not apply to Permixon. Our meta-
analysis showed that Permixon decreased the number of
nocturnal voids and improved Qmax compared with placebo
and had efficacy for relieving LUTS similar to that of
tamsulosin and short-term finasteride. Moreover, we
showed that Permixon had a favorable safety profile with
a very limited impact on sexual function, which is
significantly affected by all other available drugs for
LUTS/BPH.
Author contributions: Vincenzo Ficarra had full access to all the data in
the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Ficarra, Novara.
Acquisition of data: Novara, Giannarini.
Analysis and interpretation of data: Novara, Ficarra.
Drafting of the manuscript: Novara, Giannarini.
Critical revision of the manuscript for important intellectual content:
Alcaraz, Cózar-Olmo, Descazeaud, Montorsi, Ficarra.
Statistical analysis: Novara, Ficarra.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Ficarra.
Other (specify): None.
Financial disclosures: Vincenzo Ficarra certifies that all conflicts of
interest, including specific financial interests and relationships
and affiliations relevant to the subject matter or materials discussed
in the manuscript (eg, employment/affiliation, grants or funding,
consultancies, honoraria, stock ownership or options, expert testimony,
royalties, or patents filed, received, or pending), are the following:
None.
Funding/Support and role of the sponsor: None.

Please cite this article in press as: Novara G, et al. Efficacy and Safety of Hexanic Lipidosterolic Extract of Serenoa repens
(Permixon) in the Treatment of Lower Urinary Tract Symptoms Due to Benign Prostatic Hyperplasia: Systematic Review and
Meta-analysis of Randomized Controlled Trials. Eur Urol Focus (2016), http://dx.doi.org/10.1016/j.euf.2016.04.002
EUF-151; No. of Pages 9
EUROPEAN UROLOGY FOCUS XXX (2016) XXX–XXX
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