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- Original Article -
Randomized clinical trial of an ethanol extract of
Ganoderma lucidum in men with lower urinary tract symptoms
Masanori Noguchi1, Tatsuyuki
Kakuma2, Katsuro Tomiyasu1, Akira
Yamada3, Kyogo Itoh3, Fumiko
Konishi4, Shoichiro
Kumamoto4, Kuniyoshi
Shimizu5, Ryuichiro Kondo5, Kei
Matsuoka1
Departments of 1Urology,
2Bio-statistics, 3Immunology, Kurume University School of Medicine, Kurume 830-0011, Japan
4Research Laboratories, Chlorella Industry Co Ltd, Chikugo 833-0056, Japan
5Department of Forest and Forest Products Science, Faculty of Agriculture, Kyushu University, Fukuoka 812-8582, Japan
Abstract
Aim: To evaluate the safety and efficacy of an extract of
Ganoderma lucidum that shows the strongest
5α-reductase inhibitory activity among the extracts of 19 edible and medicinal mushrooms by a double-blind, placebo-controlled,
randomized and dose-ranging study in men with lower urinary tract symptoms
(LUTS). Methods: In this trial, we randomly assigned 88 men over the age of 49 years who had slight-to-moderate LUTS to 12 weeks of treatment with
G. lucidum extract (6 mg once a day) or placebo. The primary outcome measures were changes in the International
Prostate Symptom Score (IPSS) and variables of uroflowmetry. Secondary outcome measures included changes in
prostate size, residual urinary volume after voiding, laboratory values and the reported adverse effects.
Results: G. lucidum was effective and significantly superior to placebo for improving total IPSS with 2.1 points decreasing at the
end of treatment (mean difference, _1.18 points; 95% confidence interval, _1.74 to _0.62;
P < 0.0001). No changes were observed with respect to quality of life scores, peak urinary flow, mean urinary flow, residual urine, prostate
volume, serum prostate-specific antigen or testosterone levels. Overall treatment was well tolerated with no severe
adverse effects. Conclusion: The extract of
G. lucidum was well tolerated and improved IPSS scores. These results
encouraged a further, large-scale evaluation of phytotherapy for a long duration using the extract of
G. lucidum on men with LUTS. (Asian J Androl 2008 Sep; 10: 777_785)
Keywords: lower urinary tract symptoms; phytotherapy; outcome; randomized trial;
Ganoderma lucidum
Correspondence to: Masanori Noguchi, M.D., Ph.D., Department of Urology, Kurume University School of Medicine, 67 Asahi-machi,
Kurume 830-0011, Japan.
Tel: +81-942-31-7572 Fax: +81-942-34-2605
E-mail: noguchi@med.kurume-u.ac.jp
Received 2007-09-25 Accepted 2007-10-26
DOI: 10.1111/j.1745-7262.2008.00361.x
1 Introduction
The use of non-traditional therapies in men with lower
urinary tract symptoms (LUTS) has increased greatly in
recent years owing to a variety of factors [1], including
patient dissatisfaction with standard pharmacologic and
surgical treatments, increased marketing of
non-prescription products through the media and the Internet, and a
philosophic congruence between alternative therapies and
patient values and beliefs [2]. Interest in complementary
and alternative approaches to medical care continues to
grow worldwide, especially in the USA. The US public's
use of complementary and alternative medicine increased
substantially during the 1990s. It was estimated that
19% of the US population took a dietary supplement in
2002 [3]. In the field of men's health, phytotherapeutic
agents have gained widespread use in the treatment of
LUTS, including urinary incontinence, overactive bladder,
and benign prostatic hyperplasia (BPH). Plant extracts
are often prescribed as first-line therapy for men with
LUTS in many European countries, either in addition to
or instead of conventional prescription medications. In
Europe alone, more than 100 botanical preparations are
available to treat LUTS [4]. Some preparations are
produced from a single plant, whereas others contain
extracts from two or more botanical species. Various
companies use different extraction procedures. Therefore,
the composition and components of one individual
product might be different from that of another manufacturer,
even if it originates from the same plant. When strict
criteria of evidence-based medicine are applied, the
available data have not yet provided clear evidence of
efficacy for most phytotherapeutic preparations. As a result,
the role of phytotherapeutic agents in treating LUTS
secondary to BPH is continuously debated.
The principal prostatic androgen is dihydrotestosterone
(DHT), synthesized by steroid enzyme 5α-reductase from
its substrate testosterone. Two isoforms of
5α-reductase have been cloned, expressed, and characterized (types 1
and 2) that display different tissue expression patterns,
enzyme kinetic parameters, and chromosomal
localization [5]. Both isozymes are overexpressed in BPH tissue
[6]. Because BPH therapy can reduce DHT levels by
blocking its conversion from testosterone, 5α-reductase
inhibitors could be useful in BPH treatment [7]. A
number of compounds have been identified as such,
including both a steroidal and a non-steroidal inhibitor. However,
it has been reported that these inhibitors might cause
adverse effects such as gynecomastia, impaired muscle
growth and severe myopathy [8]. Therefore, the
emergence of therapeutic materials with fewer side effects,
especially edible natural products, has been considered
desirable if the safety of these products can be guaranteed.
For thousands of years, mushrooms have been known
as a source of medicine. They are widely sold as
nutritional supplements and touted as beneficial for health.
Therefore we have focused on edible and medicinal
mushrooms as a 5α-reductase inhibitory ingredient. In our
previous screening of 19 edible and medicinal mushrooms,
we discovered that the extract of Ganoderma
lucidum showed the strongest 5α-reductase inhibitory activity [9].
In addition, the treatment of G. lucidum itself, or the
ethanol extract prepared from it, significantly inhibited
the growth of the ventral prostate induced by
testosterone in rats. The inhibitory concentration leading to 50%
activity loss (IC50) of the ethanol extract of
G. lucidum was estimated to be 93.6 µg/mL. It should be noted that
finasteride [10], known as a potent steroidal inhibitor,
showed an IC50 of 0.73 µmol/L in our assay system [11].
These results indicated that the fruiting body of
G. lucidum contained some triterpenoids with
5α-reductase inhibitory activity, although their inhibitory activity was
lower than that of finasteride. However, safety is a
primary consideration for phytotherapy and functional
foods. Consequently, moderate inhibitory activity is
preferred from the viewpoint of safety.
The fungi G. lucidum has been used for centuries in
East Asia. Its fruiting body is called "Reishi" in Japan
and "Lingzhi" in China. In these areas,
G. lucidum has been a popular folk medicine to treat various human
diseases, such as hepatitis, hypertension,
hypercholesterolemia, and gastric cancer [12]. However, the role of
G. lucidum in treating LUTS has never been reported.
Recently, we completed a double-blind, placebo-controlled, randomized, and dose-raising clinical trial to
evaluate the safety and feasibility, and to determine the
effective dose of the extract of G. lucidum in men with
LUTS [13]. In the trial, 50 men with slight-to-moderate
LUTS were randomized to four arms to receive placebo
or G. lucidum at doses of 0.6 mg, 6 mg, or 60 mg. The
G. lucidum 6 mg and 60 mg doses were tested for
8 weeks and were safe and effective in improving LUTS.
In the present study, we used widely accepted outcome
measures and a matched placebo tablet, and conducted a
randomized, double-blind trial to evaluate the safety and
efficacy of the extract of G. lucidum in men with
mild-to-moderate LUTS.
2 Methods and materials
2.1 Participants
The study protocol was approved by the Kurume University School of Medicine Ethics Committee
(Kurume, Japan), and the study was carried out in
accordance with the Declaration of Helsinki. This
double-blind, placebo-controlled, randomized study was carried
out at a research room in Kurume Research Park, Kurume, from June 2005 to April 2006. All participants
provided written informed consent. Men over the age of
49 years who had slight-to-moderate LUTS, as defined
by a score of 5_19 on the International Prostate
Symptom Score [14] (IPSS; 0_35), were recruited from the
Kurume city area by letters to primary care providers,
posters, and local radio and television advertisements.
Participants were screened for eligibility by an interview
on the first visit, and randomized on the second. Men
were ineligible if they: had concomitant urological disease;
were diagnosed with or suspected of carcinoma of the
prostate; received previous radiation therapy of the
pelvic region; had previous prostate surgery or invasive BPH
treatments; had a prostate-specific antigen (PSA) level
of more than 4 ng/mL; had used androgens,
α-blockers, or herbal preparations for urinary problems in the
previous 4 weeks; or had insulin-dependent diabetes, severe
cardiopulmonary disease, active liver disease, or
significant disease of the central nervous system.
2.2 Intervention
Eligible participants were randomized to receive an
extract of G. lucidum of 6 mg or a placebo in tablets of
similar appearance, once daily. The weight of each
tablet was 2 g, and two tablets were taken once daily. In
brief, dried and chipped G. lucidum was extracted with
30% ethanol at room temperature for 24 h by use of a
blender. The extracts were filtered through Advantec
No. 2 filter paper (Toyo Co. Ltd., Tokyo, Japan),
concentrated under a vacuum, then freeze-dried. The basic
contents of each tablet were 83.65% maltitol (Towa
Chemical Industry Co., Tokyo, Japan), 10% cornstarch
(San-ei Sucrochemical Co., Chita, Japan), 3% vitamin C
(BASF Japan, Kawasaki, Japan), 0.2% gardenia yellow
(Hodogaya Chemical Co., Tokyo, Japan) and 3% sucrose
fatty acid ester (Dai-ichi Kogyo Seiyaku Co., Kyoto,
Japan). The tablet for the G. lucidum group included
3 mg (0.15%) of the extract of G.
lucidum (Chlorella Industry Co., Tokyo, Japan), and the tablet for the
placebo was adjusted by naringin (Inabata Koryo Co., Osaka,
Japan) for the same taste. Each tablet had also the same
smell. Participants were advised to take the study
medication once a day with meals and to bring all unused
tablets to each study visit. Participants made five visits
to the study room during the 16 weeks of
post-randomization follow-up.
2.3 Randomization, protocol and evaluation procedures
Participants who satisfied all eligibility criteria
underwent randomization in equal proportions to the
G. lucidum and placebo groups. Randomization was used
with a blocked stratified procedure, where each block
consisted of two treatment assignments with two strata,
two age groups (< 65 years, ¡Ý 65 years), and two groups
with different baseline IPSS scores (< 12,
¡Ý 12). Randomization codes were concealed in sealed envelopes and
opened only after the last man had completed treatment.
Participants were assessed at day _14, day 0,
4 weeks, 8 weeks and 12 weeks into the double-blind
treatment period, and followed up in week 16. Efficacy
assessments included the seven-item IPSS and one
quality of life (QoL) question, for which the answers ranged
from "delighted" (0) to "terrible" (6) (at day _14, day 0,
4 weeks, 8 weeks, 12 weeks, and 16 weeks). Peak
urinary flow rate (Qmax) and mean urinary flow rate were
assessed using a uroflowmeter (Uropower201; World of
Medicine [WOM], Berlin, Germany), for which a voided
volume of ¡Ý 150 mL is required for an accurate reading
(at day 0, 4 weeks, 8 weeks, 12 weeks and 16 weeks).
Prostate volume and residual volume after voiding were
also measured by abdominal ultrasonography (SSD-900;
Aloka, Tokyo , Japan) on day 0 and after 12 weeks. Vital
signs (heart rate and blood pressure) were assessed in the
afternoon at day _14, day 0, 4 weeks, 8 weeks, 12 weeks,
and 16 weeks. Treatment-emergent adverse effects,
adverse effects leading to discontinuation of treatment,
and serious adverse effects were monitored and recorded
throughout the double-blind treatment period.
Laboratory tests, including PSA and testosterone, were carried
out on blood samples taken on day _14 and at 12 weeks.
2.4 Statistical analysis
The sample size was chosen to detect a change of
¡Ý 2.5 units in the IPSS between treatment and placebo
with a standard deviation of 4, 80% power, and at
α = 0.05 significant level. The sample size was estimated based
on the previous dose-raising study [13]. These
calculations and values required the enrolment of 74 men, and
the number was increased to a target enrolment of 88 to
account for a potential dropout rate of up to 20%. Data
were entered into an online database with a security
system by two research nurses using the electronic data
capturing system (System Lab, Kurume, Japan) then analyzed using commercial software (SAS version 9.1
for Windows; SAS, Cary, NC, USA). In order to control the effects on the baseline measure, treatment
efficacies were tested by analysis of covariance (ANCOVA)
where the baseline measure was used as a covariate. The
results from ANCOVA were conformed by linear mixed
models, where all repeated measures were used while
accounting for their serial correlations, as well as baseline
effects treated as random effects. Although no
adjustment was made for multiple comparisons, significant
treatment efficacy was reported only when the overall
treatment group F-test was significant on ANCOVA.
3 Results
3.1 Recruitment and baseline characteristics
Of the 130 men who were screened for eligibility by
interview on the first visit, 88 satisfied all eligibility
criteria and were randomized to receive 6 mg
G. lucidum (44 men) and placebo (44 men). Figure 1 shows the source
of recruitment for potential participants and reasons for
exclusion. There were no randomized men who had been previously treated by
androgens, α-blockers, or herbal preparations for urinary problems. The majority
of randomized men completed the study. One man in
each group was lost to follow-up, for a completion rate
of 98%. Four men in the placebo group and two men in
the G. lucidum group discontinued the study medication
but completed all outcome assessments. The adherence
rate was high, with 96.8% in the G. lucidum group and
97.1% in the placebo group, and no significant difference
in adherence between groups. There was no significant
difference in the baseline demographics or clinical
characteristics of the participants between the two groups
(Table 1).
3.2 Treatment outcomes
Mean changes of total IPSS, QoL scores,
Qmax, and mean urinary flow rate between baseline and 4, 8 and
12 weeks adjusted for baseline measures with 95%
confidence intervals (CI) for each group are shown in
Table 2. Total IPSS score at 12 weeks decreased by 2.1 points
(95% CI, _2.96 to _1.24) in the G. lucidum group, but
the placebo group had a small decrease in total IPSS at
12 weeks of 0.77 points (95% CI, _1.65 to 0.12). There
was a significant difference between groups in the mean
changes of the total IPSS during the treatment period
(difference in mean change, 1.18 points; 95% CI, _1.74
to _0.62; P < 0.0001). QoL scores in both groups
during the treatment were improved but there was no
significant difference between the groups. QoL at 8 weeks
changed by 0.37 points (95% CI, _0.68 to _0.05) in the
G. lucidum group and by 0.33 points (95% CI, _0.65 to
_0.01) in the placebo group (mean difference during
treatment, 0.04 points; 95% CI, _0.22 to 0.14;
P = 0.66). Mean changes in
Qmax and mean urinary flow rate in the
G. lucidum group increased at 4 and 8 weeks, whereas
the changes in Qmax and mean urinary flow rate in the
placebo group showed a trend of small or no increase
during the treatment period. However, there was no
significant difference between groups in the changes in
either Qmax or urinary flow rate during the 12 week study
period. The serial mean changes of total IPSS, QoL
score, Qmax, and mean flow rate during the treatment
period, adjusted for baseline measures with 95% CI for
each treatment group, are shown in Figure 2.
Examination of the secondary outcome measures also
revealed no significant difference between treatment
groups (Table 3). Changes in prostate size, residual
volume after voiding, serum PSA and testosterone levels, and
other laboratory tests did not differ significantly between
the two groups.
A total of 17 adverse events including only one
serious adverse event occurred in 18 participants during the
study: six in men assigned to G. lucidum and 11 in men
assigned to placebo (Table 4). One man in the placebo
group complained of impotence at 4 weeks but it
disappeared by the next visit. The risk of at least one adverse
event did not differ significantly between the two
groups (χ2 = 1.17,
P = 0.174). Mean changes from baseline in
heart rate and blood pressure were small and similar
between the groups. There was no treatment related to
hematologic, hepatic, or renal toxicity.
4 Discussion
Numerous plant extracts have been used in the
treatment of LUTS secondary to BPH including Pygeum
africanum (African plum), Echinacea
purpurea (purple cone flower), Cucurbita
pepo (pumpkin seeds), Secale cereale (rye),
Serenoa repens (saw palmetto berry), Hypoxis
rooperi (South African star grass) and Urtica
dioica (stinging nettle). However, an extract of the
edible and medicinal mushroom G. lucidum has never been
reported in treating LUTS.
Despite the popularity of phytotherapeutic agents,
significant skepticism remains regarding the true value
of herbal remedies among many physicians. In
previously published placebo-controlled trials of one of the
phytotherapeutic agents, such as saw palmetto, some
investigators have noted significant improvement in
urinary symptoms and/or urinary flow rates [15, 16],
whereas others have reported no advantage [17]. However, in several of these studies, patients were treated
for only 1 month, with varying methods used to assess
the subjective improvement in symptoms. In addition,
several investigators have used a meta-analysis of saw
palmetto and concluded that this agent is beneficial in
men with LUTS [18]. These results might be questioned,
however, because the mean duration of the 18 studies
used for the analysis was only 9 weeks, and several of
the trials did not include a placebo group or involve the
use of saw palmetto in combination with other herbal
agents. It has been suggested that any improvement in
symptoms in phytotherapy was largely induced by a
placebo effect. However, saw palmetto yielded some
promising results over a 24-month period in a recent
prospective trial on men with mild symptoms of bladder outlet
obstruction (IPSS < 8). Compared with the control
group, the rate of clinical progression was significantly
lower at the end of the study (16% vs. 22%;
P = 0.03). Significant improvements in the IPSS, QoL and
Qmax parameters were also shown in the group receiving saw
palmetto [19]. There is a continued call for randomized,
placebo-controlled trials of phytotherapeutic agents to
determine their magnitude and level of efficacy.
In this double-blind and placebo-controlled
randomized trial, we found that G. lucidum was effective and
superior to placebo for improving the total IPSS. Total
IPSS at 12 weeks decreased by 2.1 points in the
G. lucidum group, and there was a significant difference
between groups in the mean changes of the total IPSS
score during the treatment period. The main medical
therapies recommended for men with LUTS secondary to BPH, are
a-blockers and 5α-reductase inhibitors. The reported reduction in IPSS was 4_6 points for the
α-blockers and 3_4 points for 5α-reductase inhibitors [20].
However, the improvement in IPSS in the G.
lucidum group was relatively small. This suggests that
G. lucidum might have a mild-to-moderate effect on LUTS
compared to α-blockers or 5α-reductase inhibitors. Another
reason for this finding might have been our inclusion of
participants with a low IPSS (mean 9.5 points; 5_19). It
is well recognized that patients with more severe
symptoms actually benefit more from treatment with drugs than
those with comparatively mild symptoms. Therefore,
in the next trial design, we will target men with severe
symptoms.
We assessed objective measures including variables
of uroflowmetry, residual volume after voiding and
prostate size in this trial. For measurements of variables of
uroflowmetry, Qmax and mean urinary flow rate had no
significant difference between the G.
lucidum and placebo groups. This lack of correlation between IPSS and
variables of uroflowmetry might be caused by the large
number of our participants with normal findings of
uroflowmetry. Overall, 15 of 41 (37%) and 7 of 41
(17%) in the G. lucidum group, and 15 of 39 (38%) and
9 of 39 (23%) in the placebo group had a baseline
Qmax greater than 15 mL/s, and a baseline mean urinary flow
greater than 10 mL/s, respectively.
In the present study, prostate volume was slightly
reduced in both groups (mean changes of _1.67 mL in
the G. lucidum group and _3.36 mL in the placebo group)
without a significant difference between the groups. This
small reduction in both groups might be caused by an
inadequate measurement of prostate volume using
transabdominal sonography instead of transrectal sonography.
In our previous experiment, we evaluated the effect of
the extract of G. lucidum using rats [11]. After the
extract of G. lucidum was given, the rats were killed and
the weight of prostates was directly measured. The
difference in technical methods or experimental animals
seems to result in a lack of in vivo effect..
Investigation into G. lucidum's mode of action has
shown anti-androgenic and 5α-reductase inhibitory
activities [9]. In the present trial, treatment with
G. lucidum had no effect on serum PSA or testosterone levels. The
absence of any effect of G. lucidum on either PSA or
testosterone suggests that this agent has little or no
effect on other androgen-dependent processes that rely on
the binding of androgens to their receptor. These
observations have important clinical implications for
G. lucidum, if ultimately shown to have tangible clinical
benefits, and it could be used without interfering with
PSA screening or monitoring. The lack of any effect on
prostate volume and PSA for G. lucidum is similar to the
effect seen with other phytotherapeutic agents, such as
Permixon (Pierre Fabre Médicament, Castres, France)
or a saw palmetto extract. Perhaps the mechanism of
action of all plant extracts with 5α-reductase activity is
both similar and different from that of the synthesized
pharmaceuticals.
In conclusion, the use of 6 mg of G.
lucidum for 12 weeks led to a statistically significant decrease in the
IPSS compared with men treated with a placebo. The
peak urinary flow rate and mean urinary flow rate
increased slightly in the G. lucidum group, but no
difference in the degree of improvement was found between
the groups. The mechanism by which G.
lucidum improves LUTS remains unknown. These results
encourage a future, large-scale evaluation of phytotherapy
using G. lucidum for a long duration in men with LUTS.
Acknowledgment
This study was supported in part by the City Area
Program from the Ministry of Education, Science, Sports
and Culture of Japan.
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