Serenoa repens and Pygeum Africanum in the treatment of BPH

Abstract

Introduction /Aim: Serenoa repens (SR) and Pygeum Africanun (PA) exhibit marked anti-inflammatory, anti-androgenic and anti-proliferative effects. For this reason, they have been subject of research as potential treatment of benign prostatic hypertrophy (BPH). The aim of this study is to present current knowledge on the topic.
Methods: A non-systematic search was performed in electronic libraries for clinical trials, experimental studies and systematic reviews on the topic using the terms: “prostate”, “benign prostatic hypertrophy”, “lower urinary tract symptoms” combined with the key words: “phytotherapy”, “Saw palmetto”, “Serenoa repens”, “Serenoa serrulata”, “Pygeum Africanum”, “Prunus africana” in various combinations. Results: A sufficient number of studies of the efficacy of SR for the treatment of LUTS and BPH exists. Most of them examine the role of saw palmetto as add-on to other agents and less as monotherapy. Few similar studies for PA have been published up to date. Αlmost all examine its role as monotherapy. According to our research, there is no clear evidence of clinical superiority
of phytotherapy over conventional treatment however a potent synergistic effect was shown. SR seems to be more efficient than PA though non produce some of the therapeutic effects of PA. Conclusions: Combination of SR and PA with other medications
can offer significant improvements of urinary status while having a favourable safety profile and for this reason may be considered a viable therapy for treating LUTS in certain groups of patients.

Full text

HELLENIC UROLOGY
VOLUME 31 | ISSUE 3
33
Serenoa repens and Pygeum Africanum in the treatment of BPH, p. 33-40
Review
Serenoa repens and Pygeum Africanum
in the treatment of BPH
Konstantinos Stamatiou1, Vittorio Magri2, Evangelia Samara1, Gianpaolo Perletti3
1
Urology Dpt, Tzaneion Hospital, Piraeus, Greece
2
Urology Secondary Care Clinic, ASST-Nord, Milan, Italy
3
Faculty of Medicine and Medical Sciences, Ghent University, Ghent, Belgium
Corresponding author:
Dr. Konstantinos Stamatiou
Urology Dpt, Tzaneion Hospital, Piraeus, Greece
E-mail: stamatiouk@gmail.com
Abstract
INTRODUCTION /AIM: Serenoa repens (SR) and Pygeum Afri-
canun (PA) exhibit marked anti-inammatory, anti-androgenic
and anti-proliferative eects. For this reason, they have been
subject of research as potential treatment of benign prostatic
hypertrophy (BPH). The aim of this study is to present current
knowledge on the topic.
METHODS: A non-systematic search was performed in electron-
ic libraries for clinical trials, experimental studies and systematic
reviews on the topic using the terms: “prostate”, “benign pros-
tatic hypertrophy”, “lower urinary tract symptoms” combined
with the key words: “phytotherapy”, “Saw palmetto”, “Serenoa
repens”, “Serenoa serrulata”, “Pygeum Africanum”, “Prunus
africana” in various combinations.
RESULTS: A sucient number of studies of the ecacy of SR for
the treatment of LUTS and BPH exists. Most of them examine
the role of saw palmetto as add-on to other agents and less as
monotherapy. Few similar studies for PA have been published up
to date. Αlmost all examine its role as monotherapy. According
to our research, there is no clear evidence of clinical superiority
of phytotherapy over conventional treatment however a potent
synergistic eect was shown. SR seems to be more ecient than
PA though non produce some of the therapeutic eects of PA.
CONCLUSIONS: Combination of SR and PA with other medications
can oer signicant improvements of urinary status while having
a favourable safety prole and for this reason may be considered
a viable therapy for treating LUTS in certain groups of patients.
Konstantinos Stamatiou, Vittorio Magri, Evangelia Samara, Gianpaolo Perletti
Serenoa repens and Pygeum Africanum in the treatment of BPH
Hellenic Urology 2019, 31(4): 33-40

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Introduction
Benign prostatic hyperplasia (BPH)
is often accompanied by lower urinary
tract symptoms (LUTS) that can signi-
cantly aect the quality of life (QoL) of
the patients. A variety of phytothera-
peutic agents are widely used in tradi-
tional and alternative medicine to treat
LUTS. The most commonly used preparations originate
from the species of palm-like tree Serenoa repens (SR),
commonly known as saw palmetto (Serenoa serrulata)
and from the African prune tree Pygeum Africanum (PA)
also known as Prunus Africana. The extract of the fruits
and the husk of these plants is highly enriched in fatty
acids and phytosterols and exhibit anti-inammatory
anti-androgenic and antiproliferative eects [1-3]. For
this reason, they have been the subject of clinical and
experimental research in the treatment of symptoms of
BPH. In this paper we aim to review relevant published
data in order to compare their ecacy in this eld.
Material and methods
A database and a manual search were conducted in
the MEDLINE database of the National Library of Medi-
cine, Pubmed, Cochrane Library and other libraries using
the terms: “prostate”, “benign prostatic hypertrophy”,
“lower urinary tract symptoms” combined with the key
words: “phytotherapy”, “Saw palmetto”, “Serenoa rep-
ens”, “Serenoa serrulata”, “Pygeum Africanum”, “Prunus
Africana” in various combinations. Bibliographic infor-
mation in the selected publications was checked for
relevant publications not included in the initial search.
Because of the close relationship between inamma-
tion and prostatic hypertrophy and the fact that these
two conditions share similar symptoms, we also took
in consideration few studies examining the ecacy of
phytotherapy in the treatment of symptoms secondary
to prostatitis in BPH patients.
Results
SR in the treatment of symptoms of BPH has been
tested either alone or in combination or in comparison
with other phytotherapeutic, alpha-blockers and inhibi-
tors of 5-alpha reductase (5-ARI). There are more studies
examining the role of saw palmetto as add - on therapy
to other agents and less as monotherapy.
With regard to studies using SR extract as monother-
apy for men with BPH related LUTS,
these of Lopatkin et al, and Giulianelli
et al, showed signicant improvement
in symptoms (as measured in IPSS
questionnaire) over the six-month
treatment and follow up period. Im-
provement in both erectile and void-
ing function was also achieved [4, 5].
Sinescu et al., demonstrated a statistically signicant
improvement of mild or moderate LUTS and improve-
ments in overall QoL, urinary ow (Qmax), residual uri-
nary volume (RV) and erectile function (EF) during the
long-term study period [6]. Others found that higher
doses of SR cannot additionally improve neither LUTS
nor EF [7, 8].
When compared with placebo, SR extract demon-
strated a statistically signicant dierence in improve-
ment of mild or moderate LUTS. However, SR treatment
showed no measurable eect on Qmax [9]. Recently, Ye
et al, in a placebo-controlled study found signicant im-
provements in Qmax, IPSS, QoL and EF in theSRextract
group. Adverse events were very rare and comparable
between the two groups (1.89 and 1.18% in thestudy
and the placebo group respectively)[10]. Finally, Gi-
annakopoulos
et al, found signicant improvements
in the IPSS quality-of-life scores, Qmax and RV over the
placebo. In contrast, Helfand et al, found no dierences
between improvements in urinary symptoms between
SRextract and placebo group at 72weeks of follow-up
[8, 11]. Two similar synchronous trials found no dier-
ence in the eectiveness of SR versus placebo [12-13].
In none of the abovementioned studies were observed
signicant side eects.
Ecacy of SR was also compared to that of es-
tablished BPH treatments. Alcaraz et al, found that in
real-life practice, SR shows an equivalent ecacy to
alpha-blockers and 5-ARI in LUTS improvement with
fewer side eects [14]. In accordance to these ndings,
Pytel et al. (2002 and 2004) enrolled patients with doc-
umented BPH and LUTS. Outcome was estimated upon
IPSS, QoL, index of sexual function (MSF-4), size of the
prostate, urodynamic and biological parameters. Fol-
low-up lasted 24 months. Apart from the abovemen-
tioned parameters, plasma hormones (testosterone,
DHT, estradiol, LH, androstenedione) did not change
[15,16]. A prospective multicentre double-blind ran-
domized study comparing tamsulosin (0.4mg/24h) with
SR (320mg/24h) in a sucient number of patients with
symptomatic BPH (IPSS≥10) found no dierences in
IPSS improvement after 12 months of follow up. Nota-
Key words
phytotherapy,
Serenoa repens,
Pygeum Africanum
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HELLENIC UROLOGY
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bly, Qmax and PSA improvement was similar in both
groups. Both treatments were equally well tolerated
[17]. Ryu et al showed that the combination SRand
tamsulosin was more eective than tamsulosin mono
-
therapy, only in reducing storagesymptomsafter 6
months of treatment. Adverse events were comparable
(16.9 and 20% for the monotherapy and combinational
therapy groups) [18]. Statistically signicant dierence in
clinical improvements in LUTS/BPH severity was found
between Silodosin plus SR and SR alone, and Silodosin
plus SR and Silodosin alone as well [19]. In contrast,
according to Argirović and Argirović, in the treatment
of BPH, none of SR and tamsulosin had superiority over
another and, combined therapy (tamsulosin + SR) does
not provide extra benets. In this study, adverse events
occurred only with tamsulosin [20]. Similar conclusions
were provided by Glemain et al. and Hizli & Uygur [21,
22]. Finally, a multicentre study compared the ecacy
of the combination SR plus alpha-blocker versus SR
alone and found similar changes in the uroowmetry
after 6 months of follow-up [23].
Cai et al found greater improvement of patient’s
quality of life, with the combination SR, Pinus masso-
niana Bark Extract and Crocus sativus when compared
with SR alone [24]. Morgia and colleagues evaluated
the eectiveness of the combination SR, lycopene and
selenium (SR, LY, SE) versus SR alone in patients with
LUTS/BPH/CNBP. They found a slightly higher IPSS im-
provement in the group of combined therapy after eight
weeks of treatment [25]. Again, Morgia and colleagues
evaluated the eectiveness of the combination SR, LY, SE
(group A), versus tamsulosin alone (group B) and versus
the combination SR, LY, SE and tamsulosin (group C). At
one year from baseline, the changes of IPSS and Qmax
were greater for Group C versus monotherapies [26].
According to some authors atwo-month period
oftreatmentwithPAextract50mg twice daily induced
signicant improvement in IPSS and uroowmetry pa-
rameters [27, 28]. Positive eects were accompanied
by a satisfactory safety prole and a substantial im-
provement in QoL [28]. PA extract administration (200
mg/24h), for 60 days improved urinary sexual and and
prostatic echographical parameters with no signicant
alteration in serum hormonal levels (testosterone, DHT)
before and after therapy [29]. In contrast, a small similar
study by Donkervoort et al., found no signicant eect
[30].
In a placebo-controlled study, Pygeum extract giv-
en for 6 weeks in a daily dose of 2x100 mg showed
signicantly better improvement in IPSS over placebo
[31]. In another placebo-controlled study a daily dose
of 4x 50 mg provided greater improvement in all the
subjective and objective parameters than the placebo
[32]. A similar multicenter study found a signicant dif-
ference between the PA group and the placebo group
with respect to therapeutic response as measured by
IPSS (55 versus 31% respectively) after two months of
treatment [33]. Mild side eects (diarrhea, constipation,
dizziness and visual disturbance) were observed in 2.3%
of PA group patients.
Of note, comparison of once and twice daily dosage
forms of Pygeum africanum showed equal eectiveness
and safety at 2 months [34].
Several authors investigated the ecacy and safety
of the combination of PA with other phytotherapeutic
agents: An orally dosed herbal preparation contain-
ing Cucurbita pepo, Epilobium parviorum, lycopene,
Pygeum africanum and Serenoa repens provided sig-
nicant reduction in IPSS median score (36% in the
active group vs 8% for the placebo group), during the
3-months intervention. The day-time and night-time
urinary frequency were also reduced in the active group
[35]. Krzeski et al., compared the standard dose of an
Urtica dioica/PA preparation (300/25mg) with half the
standard dose twice daily for 8 weeks and found no
dierence in Qmax, RV and nycturia improvement [36].
Main outcomes of the comparative studies included
in this review are displayed in table 1.
Discussion
Evaluation of SR and PA ecacy in BPH related LUTS
treatment is actually dicult for two main reasons. First,
the exact mechanism by which they treat BPH remains
unknown. Among mechanisms proposed to explain SR’s
and PA’s eects is the inhibition of the activity of the
enzyme 5-a reductase (5-aR), the impediment of apop-
totic processes in prostate’s cells and the hindrance of
inammatory mediators [37, 38]. Τhe above have been
attributed by specic studies to dierent compounds
and chemical ingredients included in the extracts. How-
ever, the mechanism of action is yet to be thoroughly
and fully specied.
5-aR is a basic modulator of the conversion of testos-
terone to dihydrotestosterone (DHT), which is responsi-
ble for the overgrowth of the prostate’s epithelial cells.
When compared with the most known 5-aR inhibitor,
nasteride, SR shows similar or inferior eectiveness
in the treatment of mild and moderate LUTS, nocturia
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and discomfort [39-41]. However clinical trials found
SR extract no more eective than placebo in blocking
benign prostate growth [42]. Evidence suggests that
the main activity of SR is anti-apoptotic and it is rather
the association of SR with some natural compounds
(such as lycopene, other carotenoids and selenium) that
reduce prostate size than SR alone [43]. This happens
as the Ly-Se-SR association is more eective than SR in
augmenting the pro-apoptotic Bax and caspase-9 and
blunting the anti-apoptotic Bcl-2 mRNA. In addition,
Ly-Se-SR more eciently suppresses the EGF and Vas-
cular Endothelial Growth Factor (VEGF) expressions in
hyperplastic prostates [44]. Finally, research suggests
an anti-inammatory activity of SR, provided by be-
ta-sitosterols, which inhibits the production of prosta-
glandins in the prostate. A strong anti-inammatory is
also achieved through the inhibition of inammatory
mediators MCP-1/CCL2 and VCAM-1 [45].
Despite slight decrease in levels of testosterone
associated with PA administration, inhibition of 5-aR
by PA is considered minimal and not clinically signif-
icant [46]. Antiandrogenic and antiestrogenic eects
(which may block the initiation of hyperplasia), were
also achieved through the activity of ferulic esters
which decrease prolactin (which stimulates intrapros-
tatic dihydrotestosterone synthesis and testosterone
uptake) and cholesterol (which increases the binding
sites for dihydrotestosterone), though such eects do
not appear to reverse the progression of BPH [47]. An
anti-inammatory eect attributed to several contents
of PA extract -such as pentacyclic triterpenes and ferulic
esters- was proposed to explain -in part- the in vitro
therapeutic eect of Pygeum [48]. In conrmation to the
above, a signicant downregulation of genes involved
in inammation and oxidative-stress pathways has been
recently shown [49].According some investigators, a
powerful anti-proliferative eect on prostate cells, re-
sulting from inhibition of epidermal growth factor (EGF),
basic broblast growth factor (bFGF), and insulin-like
growth factor 1 (IGF-I) counteract the structural and
biochemical changes associated with BPH [50, 51].
Research suggests that PA reverses altered myosin
isoform expression and causes a decrease in the contrac-
tility of the detrusor muscle by reducing its sensitivity
Table 1 Main outcomes
Placebo SR 5ARI alpha-blockers IDIProst
plus SR SR, LY, SE alpha-blocker
SR, LY, SE
alpha-blocker
SR PA
Dedhia + +
Bent + +
Ye + + +
Barry + +
Alcaraz + + +
Debruyne + +
Cai + + +
Morgia + + +
Morgia + + + +
Ryu + + +
Boeri + + + +
Argirović + + +
Bertaccini + +
Gerber + + +
Helfand + +
Glemain + + +
Hizli & Uygur + + +
Dufour + + +
Bassi + + +
Barlet + + +
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to electric stimulants such as phenylephrine, adenosine
triphosphate and carbachol [52].
The abovementioned properties of SR and PA ex-
plain in part their eects on BPH however remains a
gap between in vivo and in vitro studies. Especially for
PA most studies are old and out-dated.
Second, due to the heterogeneity of the existing
herbal formulations, the short duration of most studies,
the variability in study design and variation in outcome
measures, the literature is somehow limited. In fact,
most SR extracts vary considerably in composition, ef-
fectiveness and supporting evidence, since their activity
depends on the concentration of free fatty acids and the
method of extract preparation [53]. Unfortunately, most
studies provided generic or inadequate descriptions of
the preparations used with regards to the free fatty acid
and phytosterol percentage of the extract and no study
gave extra information on the method of SR extraction
and the pivotal aspect of the preparation’s lauric acid
content that would show compliance with the European
Pharmacopoeia recommendation. On the other hand,
it is possible that placebo eect inuenced by positive
patients’ expectation on phytotherapeutic agents alter
the ndings of questionnaire based clinical studies [54].
This review didn’t nd evidence of superiority of SR
and PA over conventional BPH treatment and no direct
comparison between the two phytotherapeutic agents
exists. According to this research, both SR and PA oer
improvements of urinary status while having a favorable
safety prole. However, it should be also noted that
most PA studies are old and include small numbers of
patients while there are no studies comparing its e-
cacy and safety to that of established BPH treatments.
For this reason, it could be assumed that SR eects on
urine ow rate and residual urine content might be
better. Both have a favourable safety prole though, SR
is better tolerated. On the other hand, SR seems not to
produce the eects of PA on bladder detrusor.
Since initial clinical trials examining SR with oth-
er phytotherapeutic agents and micronutrients have
shown a potent synergistic eect [55], the above com-
bination with a-blockers may oer an alternative (other
than nasteride and alpha blocker) combination ther-
apy to patients with moderate symptoms. The combi-
nation of PA with a- blockers could be investigated as
an alternative (other than anticholinergic and alpha
blocker) combination therapy for patients with irrita-
tive symptoms. Finally, SR and PA exhibit remarkable
anti-inammatory and anti-proliferative eect and
therefore they may have a crucial role in delaying the
development of clinical BPH. For this reason, it could
be important to study their eect in younger patients
with early symptoms. Such a study may be carried out
for each extract separately, depending on the method
of preparation and brand.
Conclusions
Despite the amount of preclinical and clinical stud-
ies, a denite evaluation of the ecacy of SR and PA in
the treatment of BPH related LUTS is actually dicult
for methodological reasons. Current data provides no
clear evidence of clinical superiority of phytotherapy
over conventional treatment. However, combination
of SR and PA with other medications can oer signif-
icant improvements of urinary status while having a
favourable safety prole and for this reason may be
considered a viable therapy for treating LUTS in certain
groups of patients.
U
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ΕΙΣΑΓΓΗ/ΣΚΟΠΟΣ: Τo εκχύλισμα των
Serenoa repens (SR) και Pygeum Africanun
(PA) διαθέτει αντιφλεγμονώδεις, αντιανδρο-
γονικές και αντιπολλαπλασιαστικές ιδιότητες.
Για το λόγο αυτό έχει αποτελέσει αντικείμενο
έρευνας για την θεραπεία της υπερτροφίας
του προστάτη. Σκοπός αυτής της μελέτης είναι
να παρουσιάσει την τρέχουσα γνώση πάνω
σε αυτό το θέμα.
ΜΕΘΟΟΙ: Πραγματοποιήθηκε μια μη συστηματική έρευνα σε
ηλεκτρονικές βιβλιοθήκες για κλινικές δοκιμές, πειραματικές
μελέτες και συστηματικές ανασκοπήσεις θέμα χρησιμοποιώντας
τους όρους: «προστάτης», «καλοήθης υπερτροφία του προστά-
τη», «συμπτώματα κατώτερου ουροποιητικού» σε συνδυασμό με
τις λέξεις: «φυτοθεραπεία», «Saw palmetto», «Serenoa repens»,
«Serenoa serrulata», «Pygeum africanum», «Prunus Africana»
σε διάφορους συνδυασμούς.
ΑΠΟΤΕΛΕΣΜΑΤΑ: Στην βιβλιογραφία υπάρχει επαρκής αριθ-
μός μελετών για το SR στην θεραπεία των συμπτωμάτων της
καλοήθους υπερτροφίας. Οι περισσότε-
ρες από αυτές εξετάζουν το ρόλο του ως
πρόσθετο σε άλλους παράγοντες. Λίγες
μελέτες έχουν δημοσιευθεί μέχρι σήμερα
για το PA. Σχεδόν όλες εξετάζουν το ρόλο
του ως μονοθεραπεία. Σύμφωνα με αυτήν
την έρευνα, δεν υπάρχουν σαφή στοιχεία
κλινικής ανωτερότητας της φυτοθεραπεί-
ας σε σχέση με τις συμβατικές φαρμακοθεραπείες. Ορισμένες
κλινικές δοκιμές που χρησιμοποιούν το SR συνδυαστικά με άλλα
φυτοθεραπευτικά ή με συμβατικά φάρμακα ανέδειξαν μια ισχυ-
ρή συνεργική επίδραση. Από την άλλη πλευρά αυτό στερείται
ορισμένων θεραπευτικών ιδιοτήτων του PA.
ΣΥΜΠΕΡΑΣΜΑΤΑ: Ο συνδυασμός SR με το PA και άλλα φυτο-
θεραπευτικά μπορεί να προσφέρει σημαντικές βελτιώσεις στην
λειτουργία του ουροποιητικού συστήματος ενώ έχει ευνοϊκό
προφίλ ασφάλειας και γι 'αυτό το λόγο μπορεί να θεωρηθεί ως
μια βιώσιμη θεραπεία σε ορισμένες κατηγορίες ασθενών.
Περίληψη
Λέξει
ευρετηριασού
φυτοθεραπεία,
Serenoa repens,
Pygeum Africanum
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