PHYTOTHERAPY RESEARCH

Phytother. Res. 26: 204–207 (2012)

Published online 27 May 2011 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/ptr.3462

Clinical Assessment of a Supplement of

Pycnogenol® and L‐arginine in Japanese Patients
with Mild to Moderate Erectile Dysfunction

Hiromitsu Aoki,1 Junji Nagao,1 Taro Ueda,1 Jeffry M. Strong,2 Frank Schonlau,2* Song Yu‐Jing,3
Yan Lu3 and Shigeo Horie3
1
Central Laboratories, Kobayashi Pharmaceutical Co., Ltd., 4‐4‐10 Doshomachi, Chuo‐ku, Osaka, Japan
2
Horphag Research (UK) Ltd., London, UK
3
Department of Urology, Teikyo University School of Medicine, 2‐11‐1 Kaga, Itabashi‐ku, Tokyo, Japan

A double‐blind parallel group comparison design clinical study was conducted in Japanese patients with mild to
moderate erectile dysfunction to investigate the efficacy of a supplement containing Pycnogenol® and L‐arginine.
Subjects were instructed to take a supplement (Pycnogenol® 60 mg/day, L‐arginine 690 mg/day and aspartic
acid 552 mg/day) or an identical placebo for 8 weeks, and the results were assessed using the five‐item erectile
domain (IIEF‐5) of the International Index of Erectile Function. Additionally, blood biochemistry, urinalysis and
salivary testosterone were measured. Eight weeks of supplement intake improved the total score of the IIEF‐5. In
particular, a marked improvement was observed in ‘hardness of erection’ and ‘satisfaction with sexual intercourse’.
A decrease in blood pressure, aspartate transaminase and γ‐glutamyl transpeptidase (γ‐GTP), and a slight
increase in salivary testosterone were observed in the supplement group. No adverse reactions were observed
during the study period. In conclusion, Pycnogenol® in combination with L‐arginine as a dietary supplement is
effective and safe in Japanese patients with mild to moderate erectile dysfunction. Copyright © 2011 John Wiley &
Sons, Ltd.
Keywords: erectile dysfunction; edicare; pycnogenol; L‐arginine; Japanese; testosterone.

which is suggested to be a physiologic response secondary

INTRODUCTION
The incidence of erectile dysfunction (ED) is high in Japan
and is reported to occur in 25% of adult males (Demir
et al., 2006; Shirai, 2002). The relationship between ED
and diseases influenced by lifestyle (diabetes mellitus,
hypertension, and hypercholesterolemia) has been re-
cently attracting attention (Lamm, 2009; Thompson et al.,
2005). Clinical studies conducted in Europeans and
Americans have confirmed that the proprietary, patented
combination of L‐arginine aspartate and French maritime
pine bark extract Pycnogenol®, Prelox® (both trade-
marks of Horphag Research Ltd.,) can improve mild to
moderate ED (Stanislavov et al., 2008). Pycnogenol® is a
specific pine bark extract consisting of a concentrate of
polyphenols, mainly procyanidins, and is listed in the
United States Pharmacopoeia 30 as Maritime Pine Bark
(United States Pharmacopeial Convention, Inc., 2007).
Pycnogenol® demonstrates its action to improve ED by
activating endothelial nitric oxide synthase (e‐NOS),
thereby increasing nitric oxide production and promoting
vasodilation (Rohdewald, 2002). A synergistic effect in
nitric oxide production is achieved when Pycnogenol®
is administered in combination with L‐arginine, the
substrate for e‐NOS (Stanislavov and Nikolova, 2003). It
has been reported that the combination of Pycnogenol®
and L‐arginine may increase testosterone concentration,
* Correspondence to: Dr Frank Schonlau, Horphag Research (UK)
Limited, Suite 39328, Old Brompton Road, London SW7 3SS, UK.
E‐mail: Frank@horphag.com
Copyright © 2011 John Wiley & Sons, Ltd.
to increased sexual activity (Lamm, 2009). However,
there has been no report on the clinical assessment of a
Pycnogenol® and L‐arginine supplement for ED in
Asians in general, or in Japanese patients specifically.
Therefore, this study in Japanese patients with ED was
undertaken using a health food supplement containing
Pycnogenol®, L‐arginine and aspartic acid. The primary
objective of this study was to assess potential ED‐
improving action of 8 weeks of ingestion of a Pycnogenol®
and L‐arginine supplement in Japanese men with mild
to moderate ED using the 5‐item version of the Inter-
national Index of Erectile Function (IIEF‐5). The sec-
ondary objective was to assess salivary testosterone
concentration changes due to ingestion of the Pycnogenol®
and L‐arginine supplement.
MATERIALS AND METHODS
Subjects. This study was conducted in compliance with
the Helsinki Declaration after obtaining the approval of
the Ethics Committee of Akihabara Medical Clinic.
Subjects were selected from 24 outpatients with mild to
moderate ED who had given written informed consent.
Subjects who did not meet the following 12 exclusion
criteria were selected (Table 1): habitual consumption of
medication and/or a food supplement intended for ED
improvement; habitual consumption of medication and/
or food supplement that contained either L‐arginine,
aspartic acid, or maritime pine bark extract; allergy to
the substances investigated in this study; participation in
Received 29 November 2010
Revised 08 February 2011
Accepted 08 February 2011
 PYCNOGENOL® AND L‐ARGININE SUPPLEMENT FOR ERECTILE DYSFUNCTION
Table 1. Background of subjects included in analysis
Measured baseline
values(mean ± standard deviation)
Placebo group Supplement group
Age (years) 50.6 ± 7.5 51.4 ± 9.0
Height (cm) 169.3 ± 3.8 169.2 ± 5.8
Body weight (kg) 67.1 ± 9.2 69.8 ± 6.1
BMI (kg/m2) 23.4 ± 2.9 24.4 ± 2.0
Systolic blood 128.4 ± 12.9 125.7 ± 13.9
pressure (mmHg)
Diastolic blood 80.8 ± 10.0 76.6 ± 10.2
pressure (mmHg)
Pulse rate (beats/min) 69.4 ± 8.5 76.6 ± 10.2
Total IIEF‐5 score 17.5 ± 0.5 16.0 ± 0.9
Salivary testosterone 53.5 ± 8.4 53.5 ± 10.0
(pg/ml)
Placebo group n = 11; Supplement group n = 12.
another clinical study at the start of the study; existence
of diabetes mellitus, heart disease, renal disease, hepatic
disease, moderate or severe hypertension; habitual
consumption of any food supplement to improve the
circulation; body mass index (BMI) ≥ 35 kgm‐2; receiving
concurrent dental treatment; reported smoking 20 or
more cigarettes a day; morning erection achieved most
days; and those judged by the investigator (on the basis of
laboratory test value or other reasons) as inappropriate
for participation in this study. The subjects were divided
by BMI into the study drug group and placebo group,
each consisting of 12 subjects.
Supplement use. The commercialized food supplement
Edicare (manufactured by Kobayashi Pharmaceutical
Co., Ltd., which contains 10 mg of Pycnogenol®, 115 mg
of L‐arginine and 92 mg of aspartic acid per tablet, was
used in the present study. The placebo was a tablet
(manufactured by Kobayashi Pharmaceutical Co., Ltd.)
whose appearance and weight were equivalent to
those of the study supplement but that did not contain
Pycnogenol®, L‐arginine nor aspartic acid. The placebo
contained the same excipients as the study supplement
with the addition of 6.0 mg per tablet of red rice malt
powder for coloring. The subjects were asked to take six
tablets of either the supplement or placebo each day
and to record their supplement intake in a diary. The
IIEF‐5, translated into Japanese, was provided to the
subjects for assessment before the start of the study, at
4 weeks and again at 8 weeks.
Biochemical analyses and physical examination. Subjects
had blood, urine and saliva samples collected, were
asked about their general health condition and examined
by a physician before the start of the study, and again at
4 and 8 weeks after the start of the study. In combination
with the questioning by the physician, height, body
weight, BMI, blood pressure and pulse rate were also
recorded. Blood test parameters consisted of red
blood cell count, white blood cell count, hemoglobin,
hematocrit, platelet count, total protein, albumin, LDH
(Lactate Dehydrogenase), ALP (Alkaline Phosphatase),
AST (Aspartate Amino Transferase), ALT (Alanine
transaminase), γ‐GTP (γ‐glutamyl transpeptidase), total
bilirubin, creatinine, urea nitrogen, hemoglobin Alc,
Copyright © 2011 John Wiley & Sons, Ltd.
205
triglycerides, total cholesterol, HDL cholesterol, LDL
cholesterol, sodium, potassium and chlorine. The pH,
qualitative protein, qualitative glucose and occult blood
were investigated by urinalysis. Blood biochemistry
analysis and urinalysis was consigned with BML
Inc. Salivary testosterone was analyzed by ELISA
(Demeditec Diagnostics, Germany) at the Department
of Urology, Teikyo University School of Medicine.
Statistical analysis. The student’s t‐test was employed
for inter‐group comparison of the change in IIEF‐5
scores, blood biochemistry and salivary testosterone.
Wilcoxon’s signed rank sum test was used for intra‐
group comparisons, and differences in mean values
were assayed. In each case, the level of statistical
significance was set at p < 0.05.
RESULTS
There was no statistical difference in the BMI of either
the placebo (23.4 ± 2.9) or supplement group (24.4 ± 2.0)
before the start of the study.
During the study period, one subject in the placebo
group was unable to continue the study because of his
transfer abroad. Accordingly, he was excluded from
analysis. As a result, the analysis was conducted in
12 subjects in the study drug group and 11 subjects in
the placebo group. No adverse events were reported
during the study period.
Effect on erectile function according to IIEF‐5 scores
The total IIEF‐5 score increased in 67% of subjects in
the supplement group (8/12) and in 36% (4/11) of the
placebo group (Table 2). Concerning the intra‐group
change, the scores of question 2 (Q2, “When you had
erections with sexual stimulation, how often were your
erections hard enough for penetration?”) significantly
improved in the supplement group after 8 weeks. A
trend of improved scores was present in the remaining
questions (Table 3) in the supplement group. No
significant improvements in scores or similar trends
were observed in the placebo group. The total IIEF‐5
score tended to increase in the supplement group, but
this change was not significant ( p < 0.1) (Fig. 1).
Significant improvement was observed in the supplement
group compared to placebo group scores in Q2 ( p < 0.05)
and that of question 5 ( p < 0.05) (When you attempted
sexual intercourse, how often was it satisfactory to you?).
The total IIEF‐5 score and mean score of Q2 and Q5
declined in the placebo group, but this change was not
significant (Table 3).
Table 2. Number of subjects with cenesthesia
After 4 weeks After 8 weeks
Placebo group 36.4% (4/11) 36.4% (4/11)
Supplement group 41.7% (5/12) 66.7% (8/12)
An increase of IIEF‐5 score by ≥ 1 point is regarded as cenesthesia.
Placebo group n = 11; Supplement group n = 12.
Phytother. Res. 26: 204–207 (2012)
206 H. AOKI ET AL.

Table 3. Changes in IIEF‐5 scores

Total score

Change in score
Before study After 4 weeks After 8 weeks

Placebo 17.5 ± 0.5 17.0 ± 0.8 17.1 ± 1.1

Supplement 16.0 ± 0.9 16.9 ± 1.1 17.1 ± 1.1
Q1
Placebo 2.8 ± 0.1 2.9 ± 0.1 2.8 ± 0.1
Supplement 2.6 ± 0.2 2.8 ± 0.2 2.6 ± 0.2
Q2
Before ingestion After 4 weeks After 8 weeks
Placebo 3.7 ± 0.2 3.3 ± 0.2 3.5 ± 0.3
Supplement 3.3 ± 0.2 3.4 ± 0.3 3.6 ± 0.2a Placebo group Study drug group

Q3
Placebo 3.4 ± 0.2 3.1 ± 0.3 3.5 ± 0.2 Figure 1. Based on the pre‐ingestion level, the change is calculated
Supplement 2.9 ± 0.3 3.1 ± 0.3 3.2 ± 0.3 from the score obtained after ingestion, and the result is indicated
in mean ± standard deviation. Placebo group: n = 11; Study drug
Q4
group: n = 12; Student’s t‐test: *p < 0.05, **p < 0.01
Placebo 3.8 ± 0.2 4.3 ± 0.2 3.9 ± 0.3
Supplement 3.9 ± 0.1 4.1 ± 0.3 4.0 ± 0.3
Q5

Change in testosterone (pg/ml)

Placebo 3.8 ± 0.1 3.5 ± 0.2 3.5 ± 0.2 70.00
Supplement 3.3 ± 0.3 3.6 ± 0.3 3.8 ± 0.2a 60.00
50.00
Mean ± standard error. Placebo group n = 11; Supplement group 40.00
n = 12. Wilcoxon signed rank sum test: a p < 0.05.
30.00
20.00

Salivary testosterone 10.00

0.00
Before ingestion After 4 weeks After 8 weeks
The mean salivary testosterone concentrations increased -10.00

in the supplement group at 4 and 8 weeks (mean increase Placebo group Study supplement group

28 pg/ml). When salivary testosterone concentrations

before the start of the study were compared to
concentrations after 4 weeks of supplement intake, a
trend of increase (p < 0.1) was observed in the supplement
group. No changes in salivary testosterone were observed
in the placebo group during the study period (Fig. 2).
Figure 2. In total IIEF‐5 score and salivary testosterone concen-
tration. Based on pre‐study salivary testosterone concentrations,
the change was calculated from the score obtained after the study,
and the result is indicated as mean ± standard deviation. Placebo
group: n = 11, Supplement group: n = 12. Student’s t‐test:
*p < 0.05, **p < 0.01

Blood chemistry, blood glucose, blood pressure

Slight but significant improvements in diastolic blood
pressure, blood glucose, and the liver enzymes AST and
γ‐GTP were noted in the supplement group. The
general examination revealed a statistically significant
decrease in diastolic blood pressure in the supplement
group at 4 and 8 weeks, but no changes were observed
in any of the other parameters. Diastolic blood pressure
decreased significantly in the supplement group
(from 76.6 ± 10.2 mmHg to 71.4 ± 10.1 mmHg). Blood
biochemistry indicated a moderate decrease in AST,
γ‐GTP and HbA1c in the supplement group (data not
shown). Though changes were also noted in other
parameters, these changes were all within normal limits
(data not shown). Urinalysis remained unchanged in
both groups at 4 and 8 weeks.
DISCUSSION
The results of this double‐blind, parallel group study
confirmed that consumption of a supplement of
Pycnogenol®, L‐arginine and aspartic acid for 8 weeks
significantly improved IIEF‐5 scores related to the
hardness of erection and sexual intercourse satisfaction.
Improvement of sexual intercourse satisfaction is
expected to contribute to the improvement in quality
Copyright © 2011 John Wiley & Sons, Ltd.
of life of subjects, which may in turn positively
contribute to overall health. The improvement in
erectile function in the supplement group was
smaller in this study in comparison with other reports
on the effects of the combination of Pycnogenol® and
L‐arginine. This could be partially attributable to the
smaller dose of Pycnogenol® and L‐arginine used in this
study in comparison with other studies (Stanislavov and
Nikolova, 2003; Stanislavov et al., 2008). The increase in
salivary testosterone in response to Pycnogenol® and
L‐arginine has previously been reported (Lamm, 2009).
Epidemiological surveys have reported on the corre-
lation between testosterone levels and lifestyle diseases.
The trend towards increasing testosterone levels
implies that the supplement may be applicable to the
treatment of lifestyle diseases as well.
The mechanism of how Pycnogenol® and L‐arginine
may increase testosterone is unclear. One potential
mechanism is related to the increase in cGMP as a result
of increased NO production. Continuous administration
of PDE5 (Phosphodiesterase 5) inhibitors have been
suggested to increase testosterone levels by a similar
mechanism of increasing cGMP concentration (Yasuda
et al., 2008). There is also a possibility that testicular
function is improved by increased blood flow in the
testis through dilatation of peripheral vessels. Further-
more, a psychological influence on the improvement of
Phytother. Res. 26: 204–207 (2012)
 PYCNOGENOL® AND L‐ARGININE SUPPLEMENT FOR ERECTILE DYSFUNCTION
erectile dysfunction and an associated increase in sexual
activity also has been shown to increase testosterone
levels by a positive feedback interaction (Lamm, 2009).
Further investigation is necessary to elucidate more
detailed mechanisms of action for these effects.
Erectile dysfunction is a risk factor of cerebrovascular
and coronary events and is also correlated to metabolic
syndrome (Thompson et al., 2005). Recognizing the
relationship of ED to such lifestyle diseases may be
helpful in initiating early interventions to prevent such
diseases. Furthermore, the supplement demonstrated
mild hypertensive action indicated by a statistically
significant decrease in the diastolic blood pressure (from
76.6 ± 10.2 mmHg to 71.4 ± 10.1 mmHg). The results of
this clinical study suggest a supplement of Pycnogenol®
and L‐arginine may be an effective and safe treatment
alternative in mild to moderate ED. It is desirable that a
long‐term and large‐scale clinical study be conducted in
the future to verify the results of this study.
REFERENCES
Demir T, Demir O, Kefi A, Comlekci A, Yesil S, Esen A. 2006.
Prevalence of erectile dysfunction in patients with metabolic
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Lamm S. 2009. Prelox® for Improvement of erectile quality. Eur
Endocrinol 5: 70 –74.
Rohdewald P. 2002. A review of the French maritime pine bark
extract (Pycnogenol), a herbal medication with a diverse clinical
pharmacology. Int J Clin Pharmacol Ther 40: 158 –168.
Shirai M. 2002. The prevalence of ED in Japan: cross‐national
epidemiologic study. Nippon Rinsho 60(Suppl 6): 200–202.
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Stanislavov R, Nikolova V. 2003. Treatment of erectile dysfunc-
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Copyright © 2011 John Wiley & Sons, Ltd.
207
CONCLUSION
Consumption of a supplement of Pycnogenol ® ,
L‐arginine and aspartic acid for 8 weeks demonstrated
a significant improvement of mild to moderate ED
symptoms in Japanese subjects. Especially noteworthy
results were observed in regards hardness of erection
and sexual intercourse satisfaction.
Acknowledgements
The authors report no conflicts of interest in association with this
manuscript.
Conflict of Interest
The authors have declared that there is no conflict of interest.
Stanislavov R, Nikolova V, Rohdewald P. 2008. Improvement of
erectile function with Prelox: a randomized, double‐blind,
placebo‐controlled, crossover trial. Int J Impot Res 20:
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Thompson IM, Tangen CM; Goodman PJ et al. 2005. Erectile
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Yasuda M, Ide H, Furuya K et al. 2008. Salivary 8‐OHdG: a useful
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Phytother. Res. 26: 204–207 (2012)