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第 12 号（2016 年 12 月）

EFFICACY OF SUPPLEMENT CONTAINING ARGININE AND CITRULLINE
ON MALE SEXUAL FUNCTION IN HEALTHY JAPANESE― A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY ―Masatomo NAJIMA1), Mitsuhiko MUNEKATA2) and Ryo KOHIYAMA3)
1) JACTA (Japan Clinical Trial Association)
2) OZ Clinic3) INSPIRE CO. LTD.

Abstract
Objectives: The objective of this research was to investigate the effectiveness of daily
ingestion of a supplement, which contains arginine and citrulline on the male sexual function
improvement.
Methods: In this randomized, placebo-controlled, double-blind trial, 49 subjects wereenrolled. To evaluate this objective, subjective reporting of sexual function (modified
International Index of Erectile Function), blood flow velocity, and Profile of Mood States
were measured as the primary outcome.
Results: 5 subjects were withdrawn. The withdrawal was due to personal reasons (4;occupational conﬂict, 1; a cold) .With 44 subjects, changes in scores of modiﬁed IIEF weresignificant in intergroup comparison after 12-week ingestion. Moreover, in the Vigor andFatigue questionnaire, the magnitude of change from baseline was significantly different
between the two groups after 12-week ingestion.
Conclusion: We found out that the ingestion of the supplement containing arginine andcitrulline by healthy Japanese people for 12 weeks contributed to the improvement of themale sexual function. In addition, no safety-related matter occurred during 12-week test
period.
Key words: arginine, citrulline, male sexual function, erectile dysfunction

1. INTRODUCTION
Currently in Japan, there are several countermeasures tothe falling birth rate. Although it is diﬃcult to indicate a
speciﬁc cause of the falling birth rate since it involves a
mix of factors, the infertility attributable to the decline inmale sexual function is considered as one of the reasons.
Now in Japan one out of six couples undergo some sort oftreatment for infertility 1), and the survey conducted by
WHO says that a half of reasons of the infertility relate to
the male sexual function. The major reasons of the maleinfertility are such as Varicocele or Obstructive
azoospermia: at the same time, Erectile Dysfunction (ED)is also considered as one of main reasons 2), and according
to the statistics its frequency is reported as 15 to 30%
which is deﬁnitely not low. Erectile Dysfunction (ED) isdeﬁned as a condition in which a man is unable to get or
keep an erection firm enough for sexual intercourse 3)(National Institute of Health (NIH), 1993), and the same
deﬁnition is applied in our country. In an epidemiologicalsurvey conducted in Japan in 1998, about 8.7 million
people were estimated to suffer from moderate ED (acondition in which a man can sometimes get or keep an
erection firm enough for sexual intercourse), whereas
about 2.6 million were estimated to be suffered fromcomplete ED (a condition in which a man is always unable
to get or keep an erection firm enough for sexualintercourse): those add up to about 11.3 million people,
which means that one in four men aged 25 years old orolder were reported to have an erectile dysfunction
problem 4), and the number is expected to increase due tothe country s aging population. It is commonly known
that ED is brought on by various factors such as aging,
psychological factors, adult lifestyle-related diseases and/or a medicinal agent 5).
In Japan the use of Viagra became operational in 1999
and now three kinds of phos-phodiesterase 5 inhibitor(PDE5I) are widely being used 6). However, it is reported
that their use may cause adverse events such as
headache, variability in blood pressure or palpitation, andthere are some medicines that should not be administered
together with them 7). In addition, since they are only
available on prescription, purchasing them is somewhat ahurdle for the male who does not suffer from a serious
symptom of ED. This fact accelerates the needs among
men to improve their sexual function by taking the foods
they eat regularly or the supplements. Based on theseneeds, many kinds of supplement are recently sold formen who want to improve their sexual function, and forthese supplements, amino acids and/or herbs are診療と新薬・第 53 巻

Table 1

第 12 号（2016 年 12 月）

51（1137）

Schedule for the study
Term

Item
Informed consent
Questionnaire on the treatment of sexual function
Selection and/or allocation
Modiﬁed IIEF
Blood ﬂow velocity
POMS
Biochemical analysis of the blood
Urine analysis
Ingestion of test foods
Log

Screening

Pretrial

Test period (12 w)

Test

Week 6

Week 12

●
●
●
●
●

●
●
●
●
●

●
●
●
●
●

●
●
●

● : Implementation↔ : Daily practice during the test period

commonly contained as their main ingredients.
Especially, amino acids have functions different fromthose of PDE5I, and they are popularly used since they
are contained in the natural foods and therefore tend to
be regarded as safe . The types of amino acids widelyused for these supplements are arginine, ornithine and/or
citrulline. Arginine is a kind of non-essential amino acidcontained in chicken, soybean or Koya-dofu (freeze-driedbean curd) 8)9), and it is reported to have functions such asincreasing the production of growth hormones andimproving blood ﬂow by causing blood vessels to dilate10).
Ornithine is reported to be eﬀective for fatigue recovery
and growth promotion11). Citrulline, on the other hand, isthe free amino acid discovered from watermelon, and it isreported to have functions such as improving the functionof blood vessels and recovering from fatigue12)13).
We previously studied the functions of arginine andornithine to the male sexual function by using the
supplement containing these two amino acids14). On theother hand, although there are some reports that
citrulline, which is said to have functionalities moresimilar to those of arginine compared to ornithine, isassociated with the treatment of ED, there are only a few
reports that scrutinize the relationship between theingestion of citrulline and/or arginine, and its eﬀects on
the sexual function of Japanese male.
I n t h i s s t u d y, w e e x a m i n e d t h e e f f e c t o f t h e
combination of arginine and citrulline for the male sexualfunction and the safeness of the combined use of them,excluding any deliberate effect of increasing vitality
achieved by medicine. The test targets were healthy
Japanese men, and the test method was a randomized,
placebo-controlled, double-blind study using the
supplement containing arginine and citrulline.

2. METHOD
2.1. Trial design
A randomized, placebo-controlled, double-blind study was
conducted with the aid of a fund from INSPIRE CO. LTD.
(Tokyo) at two centers (OZ clinic, Tokyo and JACTA,Tokyo). The study period was 12 weeks, from October
31 st, 2015 to January 23 rd, 2016.
This study was conducted in accordance with the
ethical principles of the declaration of Helsinki. The study
protocol was approved by the Institutional Review Boardof Pharmaceutical Law Wisdoms (Tokyo). Written
informed consent was obtained from all subjects. The
allocation of the test product to the subjects was carriedout by the person in charge of allocation. The allocation
list was sealed and strictly controlled in a safe deposit boxof JACTA until the end of the study.
2.2. Subjects
Healthy subjects participated in the present study. All of
the subjects in this study were public volunteers who had
enrolled in the monitor bank of CROee Inc. (Tokyo) andRabbits-coco (Tokyo).
2.2.1. Inclusion criteria(1) Healthy males aged between 20 and 69 years;(2) Males who have a sexual decline;(3) Males who have a sexual partner.
(4) Males who suitable for the sexual function questionnaire(Appendix 1).
2.2.2. Exclusion criteria(1) Subjects who are allergic to food related to the test
material of this trial;(2) Subjects who have previous medical history of theserious diseases (heart, liver, kidney, blood, digestivesystem, metabolism system);(3) Subjects who are under treatment for hypertension,or who untreated hypertension (not less than level 2);(4) Subjects who are under treatment for diabetes;52 （1138）

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第 12 号（2016 年 12 月）

Recruited (n ＝ 68)
Excluded (n ＝ 19)<Questionnaire for screening>
Randomized (n ＝ 49)

GOLD (n ＝ 25)

Placebo (n ＝ 24)

Withdraw (n ＝ 3)
<business conﬂict: 2, a cold: 1>

Withdraw (n ＝ 2)
<business conﬂict: 2>

Full analysis set

GOLD (n ＝ 22)

Placebo (n ＝ 22)

Fig. 1 Flow diagram of subject disposition(5) Subjects who contract, or are under treatment for
diseases of prostatic;(6) Subjects who are judged as inappropriate for thisstudy by the principle investigator.
2.3. Randomization
Recruited subjects were 68 persons. Subjects who
fulﬁlled eligibility criteria were 49 persons. The inclusion
criteria were judged by the principle investigator. All
subjects were sequentially allocated to group T (Testsample: 25) and group P (Placebo: 24) using arandomized number table. In the process of subject
assignment, background factors such as age were taken
into consideration to avoid biased distribution.
2.4. Description of test foods and blinding
The test food, The Gold Premium ( GOLD ) andplacebo were prepared by INSPIRE CO. LTD. The
amount of daily intake is 12 tablets (1 tablet weighs 330
mg, therefore 12 tablets weigh 3,960 mg). The
compositions of GOLD were arginine, citrulline, etc.,
while Placebo was mainly consisted of cellulose. Bothtablets were indistinguishable in shape, color or taste.
Tablets were managed by the identification symbol. All
involved were blinded.
2.5. Experimental procedures
2.5.1. Experimental protocol
Subjects consumed 12 tablets of the supplement with hotor cold water every day for 12 weeks. Subjects were
instructed as follows: to take the assigned foods as

Table 2 Subject demographics
Item

Unit

GOLD

Placebo

Subjects
Age*

numbersyears

22
44.5 ± 9.1

2244.5 ± 9.1

mean ± SD* No signiﬁcant diﬀerenceindicated; to maintain their usual lifestyles and habits; toavoid excessive amounts of food, drink or alcohol; tomaintain a daily record of lifestyle factors such as all thefood items or number of steps they took for the day
during the test period.
2.5.2. Outcome
The objective of this study is to verify the male sexualfunction improvement of ingesting food containing
arginine and citrulline. To evaluate this objective,
subjective reporting of sexual function was observed as
the primary outcome. The questionnaire is based up on
International Index of Erectile Function (IIEF) 15). Somequestions are eliminated or modiﬁed because they are thecriteria of Erectile Dysfunction (ED). This study isintended to exclude ED patients. The details areillustrated in Appendix 2.
Furthermore the blood ﬂow velocity, testosterone level
and Profile of Mood States ( POMS ) 16) were measured
as the secondary outcome. The blood flow velocity was

診療と新薬・第 53 巻

第 12 号（2016 年 12 月）

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Table 3 Modiﬁed IIEF (questionnaire of sexual function)
Questionnaire

1

2

4

5

6

7

8

9

10

P-value 2)

pointsGOLD (n ＝ 22) 1)

Placebo (n=22) 1)

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

1.6 ± 1.0
2.1 ± 1.0 **0.5 ± 0.6
2.4 ± 0.7 **0.8 ± 0.8

1.8 ± 1.0
1.4 ± 0.9
− 0.4 ± 1.0
1.5 ± 1.0
− 0.3 ± 1.1

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

2.3 ± 1.0
2.7 ± 0.8 **0.5 ± 0.7
3.2 ± 0.8 **1.0 ± 1.0

3.1 ± 1.0
3.0 ± 1.2
− 0.1 ± 1.0
2.7 ± 1.4
− 0.4 ± 1.4

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

2.3 ± 0.7
2.3 ± 1.0
0.0 ± 1.4
2.9 ± 0.6 **0.6 ± 0.7

2.6 ± 0.9
2.6 ± 0.7
0.0 ± 0.8
2.6 ± 1.1
0.0 ± 1.0

0.892

Over the past 6 weeks, when
you had sexual stimulation orintercourse how often did you
ejaculate?

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

3.4 ± 1.5
3.9 ± 1.3 †0.5 ± 1.5
4.2 ± 0.9 **0.8 ± 1.0

4.0 ± 1.0
4.0 ± 1.2
0.0 ± 0.8
3.7 ± 1.5
− 0.2 ± 1.5

0.167

Over the past 6 weeks, when
you had sexual stimulation orintercourse how often did you
have the feeling of orgasm or
climax?

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

2.9 ± 1.3
3.3 ± 0.9 *0.4 ± 0.7
3.5 ± 0.9 **0.6 ± 0.7

2.9 ± 1.1
3.1 ± 1.1
0.2 ± 0.9
2.9 ± 1.2
0.0 ± 1.4

0.575

Over the past 6 weeks, howoften have you felt sexualdesire?

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

2.7 ± 1.0
3.0 ± 0.9
0.2 ± 0.8
3.1 ± 0.8 †0.4 ± 0.8

2.9 ± 1.0
3.1 ± 0.8
0.2 ± 0.8
3.3 ± 1.0
0.4 ± 1.0

Over the past 6 weeks, howwould you rate your level ofsexual desire?

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

2.6 ± 0.5
2.8 ± 0.7
0.1 ± 0.8
2.9 ± 0.5 †0.3 ± 0.7

2.6 ± 0.7
2.9 ± 0.5 †0.3 ± 0.7
2.9 ± 0.7 †Over the past 6 weeks, howmany times have you attempted
sexual intercourse?

Over the past 6 weeks, when
you attempted sexualintercourse, how often was it
satisfactory for you?

3

ScoresTime

Over the past 6 weeks, howmuch have you enjoyed sexualintercourse?

0.2 ± 0.6

0.001 ##
< 0.001 ##0.030 #
< 0.001 ##0.028 #

0.011 #

0.067 ‡

1.000
1.000

0.561
0.820

Baseline

2.6 ± 0.7

2.7 ± 0.8

Over the past 6 weeks, howsatisﬁed have you been with you

Week 6⊿ 0‑6 w

3.0 ± 0.7*
0.3 ± 0.6

3.0 ± 0.9
0.3 ± 0.8

0.833

overall sex life?

Week 12⊿ 0‑12 w

3.2 ± 0.8 **0.6 ± 0.8

3.1 ± 0.7 *0.4 ± 0.9

0.484Over the past 6 weeks, howsatisﬁed have you been withyour sexual relationship withyour partner?

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

3.0 ± 0.6
2.9 ± 0.7
− 0.1 ± 0.9
3.4 ± 0.7 †0.4 ± 1.0

2.7 ± 0.8
3.0 ± 0.8 †Over the past 6 weeks how
often have you experienced
nocturnal penile tumescence?

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

2.2 ± 0.7
2.4 ± 0.6
0.2 ± 0.8
2.7 ± 0.5 *0.5 ± 0.9

2.3 ± 0.8
2.3 ± 0.8
0.0 ± 0.8
2.5 ± 0.9 †0.3 ± 0.6

0.4 ± 0.9
3.2 ± 0.7 *0.5 ± 0.9

Scores are expressed as the mean ± SD.
1) † p < 0.1, * p < 0.05, ** p < 0.01 against baseline.
2) ‡ p < 0.1, # p < 0.05, ## p < 0.01 between-group diﬀerences in change from baseline.

0.071 ‡
0.742

0.584
0.323

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診療と新薬・第 53 巻

Table 4Item

Time points

Blood ﬂow
velocity（cm/s, KHz）

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

Testosterone(ng/mL)

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

第 12 号（2016 年 12 月）

Blood ﬂow velocity
ValuesP-value 2)

GOLD (n ＝ 22) 1)

Placebo (n ＝ 22) 1)

4.9 ± 3.0
7.2 ± 3.9 **2.3 ± 2.2
7.4 ± 3.8 **2.5 ± 3.1

6.8 ± 3.6
5.8 ± 3.1
− 1.0 ± 2.8
4.5 ± 3.6 *− 2.2 ± 3.9< 0.001 ##4.89 ± 1.52
4.97 ± 1.50
0.08 ± 1.23
4.70 ± 1.68
− 0.19 ± 1.29

0.976

4.94 ± 1.56
5.01 ± 1.48
0.07 ± 1.21
4.78 ± 1.67
− 0.16 ± 0.95

< 0.001 ##0.926

Values are expressed as the mean ± SD.
1) † p < 0.1, * p < 0.05, ** p < 0.01 against baseline.
2) ‡ p < 0.1, # p < 0.05, ## p < 0.01 between-group diﬀerences in change from baseline.

tested by Bi- directional Doppler ES-100V3 (Hadeco,
Inc., Tokyo). For POMS, Vigor and Fatigue werequestioned. The details of questionnaire are listed inAppendix 3. Blood biochemical and urine parameters
were recorded to evaluate the safety of the test foods as
the secondary outcome.
These assessments were conducted upon entry into thestudy (pre-intervention), 6 weeks and 12 weeks (postintervention). To evaluate the safety of the test foods,
adverse events were collected by means of a written
questionnaire during the study. According to theschedule shown Table 1, we measured parameters on
eﬃcacy and safety.
2.6. Data analysis
A full analysis set was adopted in the present study andno sample size design was used. All statistics wereexpressed as mean ± standard deviation (SD). For themodified IIEF, blood flow velocity, testosterone, thePOMS, and biochemical analyses of blood and urine,changes from the baseline in the same group wereassessed using the paired t-test. Student s t-test was used
for intergroup comparisons of changes from the baseline.
Student s t-test was used to compare subject backgrounds
between groups. Multiplicity according to the occasions
was not adjusted. Any subjects with missing values were
eliminated from the analysis. Statistical analyses were
performed using Statcel 3 (Yanai, 2011). The results
were considered signiﬁcant at the < 5% level in the twosided test.

3. RESULTS
3.1. Participant demographics
The 49 subjects were randomly assigned to intervention
groups and made a start with ingestion. 5 werewithdrawn due to personal reasons (4; occupational
conﬂict, 1; a cold). Thus, data obtained with 44 subjects(GOLD; 22, Placebo; 22) was used for the analysis ofeﬃcacy (Fig. l). There was no signiﬁcant diﬀerence in themean age between the groups (Table 2).
3.2. Modiﬁed IIEF (questionnaire of sexual function)
Data obtained with respect to the scores of the modiﬁed
IIEF are summarized in Table 3. Changes in values of
the questionnaire were detected as follows: The intake ofGOLD resulted in a significant increase in the score of#1, #2, #3, #4, #5, #8, and #10 after 12-weekingestion. For intergroup comparison, the score of #1
and #2 showed significant increase after 6-weekingestion, and the score of #19, #2, #3 and #4 showedsigniﬁcant increase after 12-week ingestion.
3.3. Blood ﬂow velocity and Testosterone
Table 4 depicts changes in the blood flow velocity,
testosterone level. In the blood ﬂow velocity, signiﬁcant
upward changes were seen in the GOLD compared to thePlacebo after 6-week and 12-week ingestion. There wasno signiﬁcant diﬀerence in testosterone.
3.4. POMS (vigor and fatigue)
Changes of scores were also evaluated in POMS
(subscales of vigor and fatigue). The signiﬁcant diﬀerence
was found in the intragroup comparison with the GOLDof 1 item after 6-week ingestion, also 9 items after 12week ingestion (Table 5). For the intergroupcomparison, 1 item after 6-week ingestion and 3 items
after 12-week ingestion revealed the significant
diﬀerence.
3.5. Blood and urine test
Table 6 and 7 show the blood biochemical and urine
parameters. A signiﬁcant diﬀerence was observed in thechanges of AST and LD (LDH) of the GOLD after 6
weeks of ingestion. There was no signiﬁcant diﬀerence of
the GOLD after 12 weeks of ingestion. In addition, no
signiﬁcant change or diﬀerence was shown in urine test.
However, the investigator judged it as the range of診療と新薬・第 53 巻

第 12 号（2016 年 12 月）

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Table 5 POMS (vigor and fatigue)
Questionnaire

Time points

ScoresGOLD (n ＝ 22) 1)
Placebo (n=22) 1)
2.1 ± 0.9
1.5 ± 0.9
2.2 ± 0.9
2.0 ± 0.7 *0.1 ± 0.8
0.5 ± 0.9
2.0 ± 0.8
2.0 ± 0.7 *0.0 ± 0.7
0.5 ± 0.9
1.9 ± 0.8
2.4 ± 0.5
2.1 ± 0.9
2.1 ± 0.8
0.2 ± 0.9
− 0.3 ± 0.9
2.6 ± 0.7 **2.0 ± 0.8 *0.7 ± 0.6
− 0.5 ± 0.9
1.8 ± 0.7
1.5 ± 0.5
1.5 ± 0.7
1.8 ± 0.7 †− 0.3 ± 0.9
0.3 ± 0.7
1.8 ± 0.7
1.9 ± 0.6 **0.0 ± 0.8
0.5 ± 0.7
2.1 ± 0.9
1.6 ± 0.9
2.3 ± 0.8
2.0 ± 0.7 *0.2 ± 0.8
0.5 ± 0.8
2.2 ± 0.8
2.2 ± 0.9 *0.1 ± 0.7
0.6 ± 1.1
1.2 ± 0.8
2.0 ± 0.7
1.7 ± 0.8 **2.3 ± 0.8
0.5 ± 0.6
0.3 ± 0.8†
2.0 ± 0.8 **2.3 ± 0.8
0.7 ± 0.8
0.3 ± 0.8
2.0 ± 0.8
1.9 ± 0.7
2.2 ± 0.9
1.9 ± 0.6
0.2 ± 0.8
0.0 ± 0.9
2.4 ± 0.9 **1.8 ± 0.6
0.4 ± 0.7
− 0.1 ± 0.9
1.4 ± 0.8
1.6 ± 0.8
1.9 ± 1.0 †1.9 ± 1.1
0.5 ± 1.1
0.3 ± 0.8
1.9 ± 0.9 *1.9 ± 0.7 †0.5 ± 1.0
0.2 ± 0.5
1.7 ± 0.8
1.9 ± 0.8
1.8 ± 0.6
2.1 ± 0.9 †0.1 ± 0.7
0.2 ± 0.6†
1.9 ± 0.8
2.1 ± 0.8
0.2 ± 1.0
0.3 ± 0.6
1.8 ± 1.1
2.1 ± 1.0
1.5 ± 1.1
1.9 ± 0.8 †− 0.3 ± 0.9− 0.2 ± 0.8
1.4 ± 1.0
1.5 ± 1.1 **− 0.4 ± 1.2− 0.6 ± 0.8
1.5 ± 1.1
1.6 ± 0.9
1.4 ± 0.9
1.3 ± 0.9 †− 0.1 ± 0.7− 0.4 ± 0.8
1.3 ± 1.1 †1.3 ± 0.9
− 0.4 ± 0.8− 0.1 ± 0.8
2.2 ± 1.0
2.4 ± 1.0
2.0 ± 0.8
2.0 ± 0.8 †− 0.2 ± 1.1− 0.3 ± 0.9
1.8 ± 1.1 †1.7 ± 0.9 **− 0.4 ± 1.0− 0.7 ± 1.0
1.5 ± 1.2
1.7 ± 1.2
1.4 ± 0.9
1.5 ± 1.0 †− 0.1 ± 1.1− 0.3 ± 0.8
1.2 ± 1.1
1.1 ± 0.9 **− 0.4 ± 1.0− 0.6 ± 0.8
2.0 ± 1.0
1.8 ± 1.1
1.5 ± 1.0 *1.6 ± 0.9
− 0.5 ± 0.9− 0.2 ± 1.0
1.2 ± 0.9 **1.3 ± 1.1 †− 0.7 ± 0.9− 0.5 ± 1.1
1.5 ± 1.2
1.5 ± 1.2
1.3 ± 0.8
1.1 ± 1.0 †− 0.3 ± 1.0− 0.3 ± 1.0
1.1 ± 1.0 †1.0 ± 1.0 *− 0.5 ± 1.1− 0.4 ± 1.1
1.6 ± 1.2
1.5 ± 1.2
1.3 ± 1.1
1.1 ± 1.1
− 0.3 ± 0.9− 0.4 ± 1.2
1.2 ± 1.0 *1.0 ± 1.1 †− 0.4 ± 1.1− 0.5 ± 1.2

P-value 2)

Baseline
Week 61
Vigor Lively⊿ 0‑6 w
0.204
Week 12⊿ 0‑12 w
0.046 #
Baseline
Week 6
2
Active⊿ 0‑6 w
0.053 ‡
Week 12< 0.001 ##⊿ 0‑12 w
Baseline
Week 6
3
Energetic⊿ 0‑6 w
0.023 #
Week 120.082 ‡
⊿ 0‑12 w
Baseline
Week 6
4
Cheerful⊿ 0‑6 w
0.337
Week 12⊿ 0‑12 w
0.077 ‡
Baseline
Week 65
Alert⊿ 0‑6 w
0.390
Week 12⊿ 0‑12 w
0.087 ‡
Baseline
Week 6
6
Full of pep⊿ 0‑6 w
0.489
Week 12⊿ 0‑12 w
0.045 #
Baseline
Week 6
7
Carefree⊿ 0‑6 w
0.517
Week 120.251⊿ 0‑12 w
Baseline
Week 68
Vigorous⊿ 0‑6 w
0.490
Week 12⊿ 0‑12 w
0.855
Baseline
Week 6
9
Fatigue worn out
0.860⊿ 0‑6 w
Week 120.383⊿ 0‑12 w
Baseline
Week 60.247
10 Listless⊿ 0‑6 w
Week 120.358⊿ 0‑12 w
Baseline
Week 6
0.771
11 Fatigued⊿ 0‑6 w
Week 120.285⊿ 0‑12 w
Baseline
Week 6
12 Exhausted⊿ 0‑6 w
0.641
Week 12⊿ 0‑12 w
0.410
Baseline
Week 6
0.339
13 Sluggish⊿ 0‑6 w
Week 120.381⊿ 0‑12 w
Baseline
Week 60.880
14 Weary⊿ 0‑6 w
Week 120.889⊿ 0‑12 w
Baseline
Week 6
0.673
15 Bushed⊿ 0‑6 w
Week 120.789⊿ 0‑12 w
Scores are expressed as the mean ± SD.
1) † p < 0.1, * p < 0.05, ** p < 0.01 against baseline.
2) ‡ p < 0.1, # p < 0.05, ## p < 0.01 between-group diﬀerences in change from baseline.

56 （1142）

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Table 6
Item

Total Bilirubin

Total Protein

Albumin

AST (GOT)

ALT (GPT)ALP

LD (LDH)

γ-GT (γGTP)CK (CPK)

Total Cholesterol

Unit

mg/dL

g/dL

g/dl

U/L

U/L

U/L

U/L

U/L

U/L

mg/dL

第 12 号（2016 年 12 月）

Changes in biochemical blood test (1)Std. Value

Time points

GOLD (n ＝ 22)

Placebo (n=22)0.2-1.2

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

0.65 ± 0.28
0.72 ± 0.29
0.07 ± 0.27
0.69 ± 0.31
0.04 ± 0.18

0.66 ± 0.25
0.65 ± 0.21
0.00 ± 0.22
0.67 ± 0.27
0.01 ± 0.23

6.5-8.3

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

7.5 ± 0.3
7.4 ± 0.2
− 0.1 ± 0.2
7.4 ± 0.3
− 0.0 ± 0.2

7.3 ± 0.4
7.3 ± 0.4
0.0 ± 0.3
7.3 ± 0.3
0.0 ± 0.3

4.7 ± 0.3
4.7 ± 0.2
− 0.1 ± 0.2
4.7 ± 0.3 †− 0.1 ± 0.2

4.7 ± 0.3

3.8-5.3

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

22.1 ± 6.1
24.5 ± 5.9 *2.4 ± 4.3
22.8 ± 5.4
0.7 ± 5.2

22.0 ± 5.6
23.1 ± 6.0

8-38

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

4-43

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

24.8 ± 14.3
27.6 ± 11.3 †2.8 ± 7.6
25.5 ± 9.1
0.7 ± 9.3

23.0 ± 13.4
22.6 ± 11.9
− 0.4 ± 5.2
24.5 ± 14.9
1.5 ± 7.9

Baseline
Week 6⊿ 0‑6 w

196.2 ± 31.3
189.0 ± 25.8
− 7.2 ± 21.6

Week 12⊿ 0‑12 w

197.1 ± 30.2
0.9 ± 25.4

239.9 ± 46.9
226.6 ± 43.1**− 13.3 ± 20.0
243.6 ± 56.6
3.7 ± 39.4

121-245

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

180.7 ± 29.9
192.8 ± 25.1 *12.1 ± 23.5
178.4 ± 27.3
− 2.3 ± 21.9

175.2 ± 27.9
181.8 ± 27.4
6.5 ± 18.9
176.5 ± 26.8
1.3 ± 17.1

86 andunder

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

48.8 ± 49.0
49.0 ± 49.2
0.1 ± 10.9
47.0 ± 40.9
− 1.8 ± 21.2

31.1 ± 17.4
29.8 ± 13.9
− 1.3 ± 7.2
30.7 ± 14.8
− 0.4 ± 12.4

38-196

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

144.6 ± 100.0
129.1 ± 70.3
− 15.5 ± 49.5
134.4 ± 80.6
− 10.3 ± 49.1

133.7 ± 62.7
140.9 ± 74.2
7.2 ± 40.7
139.5 ± 72.3
5.8 ± 40.0

Baseline
Week 6⊿ 0‑6 w
Week 12207.0 ± 31.1
204.6 ± 41.7
− 2.4 ± 32.4
201.0 ± 37.8

200.8 ± 27.9
199.5 ± 34.0
− 1.3 ± 15.8
200.9 ± 28.3

⊿ 0‑12 w− 6.0 ± 34.7

0.0 ± 18.1

110-354130-219

Values are expressed as the mean ± SD.
†

Values

p < 0.1, * p < 0.05, ** p < 0.01 against baseline.

4.6 ± 0.3 *− 0.1 ± 0.2
4.6 ± 0.3 †− 0.1 ± 0.2

1.0 ± 3.5
23.1 ± 6.9
1.0 ± 4.3

診療と新薬・第 53 巻

Table 6
Item

Neutral Fat (TG)

SodiumChloride

Potassium

Unit

mg/dL

mEq/L

mEq/L

mEq/L

第 12 号（2016 年 12 月）

Changes in biochemical blood test (2)Std. Value

Time points

Inorganic
Phosphorus

Urea Nitrogen

Creatinine

Blood Sugar(Serum)

mg/dL

mg/dL

mg/dL

mg/dL

mg/dL

Placebo (n ＝ 22)

30-149Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

175.9 ± 141.1
147.5 ± 74.9
− 28.4 ± 107.6
147.0 ± 61.2
− 29.0 ± 115.8

201.6 ± 157.1
190.8 ± 142.7− 10.8 ± 83.1
179.4 ± 139.5− 22.2 ± 102.1

135-150

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

143.1 ± 1.9
143.0 ± 1.7− 0.1 ± 2.1
143.4 ± 1.8
0.2 ± 1.8

142.7 ± 1.6
142.6 ± 1.4− 0.1 ± 1.4
142.6 ± 1.4− 0.1 ± 1.9

98-110Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

102.8 ± 2.1
102.9 ± 1.9
0.1 ± 2.0
103.2 ± 2.4
0.5 ± 2.0

103.0 ± 1.8
103.4 ± 2.0
0.4 ± 1.6
102.7 ± 2.1− 0.3 ± 2.0

3.5-5.3

Baseline
Week 6⊿ 0‑6 w

4.0 ± 0.2
4.2 ± 0.2 †0.2 ± 0.4
4.0 ± 0.2
− 0.1 ± 0.3

8.4-10.2

2.5-4.5

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

3.1 ± 0.4
3.1 ± 0.5
− 0.1 ± 0.5
3.2 ± 0.4
0.1 ± 0.4

3.2 ± 0.6
3.0 ± 0.5 †− 0.2 ± 0.5
3.2 ± 0.6
0.0 ± 0.6

8.0-22.0

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

13.8 ± 2.4
14.0 ± 3.3
0.2 ± 2.2
14.3 ± 2.5
0.5 ± 2.4

14.0 ± 2.9
14.0 ± 2.9
0.0 ± 3.3
13.5 ± 3.2− 0.5 ± 2.9

0.61-1.04

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

0.82 ± 0.13
0.80 ± 0.14
− 0.01 ± 0.07
0.83 ± 0.12
0.01 ± 0.07

0.83 ± 0.12
0.81 ± 0.14
− 0.01 ± 0.06
0.83 ± 0.15
0.00 ± 0.05

60-109Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

68.1 ± 10.9
69.0 ± 16.6
0.9 ± 16.6
66.8 ± 14.9
− 1.3 ± 14.1

67.9 ± 13.4
72.2 ± 19.1
4.4 ± 15.9
67.5 ± 17.5
− 0.3 ± 14.2

p < 0.1, * p < 0.05, ** p < 0.01 against baseline.

9.7 ± 0.3
9.7 ± 0.3
0.0 ± 0.2
9.8 ± 0.3 †0.1 ± 0.2

4.1 ± 0.2
4.3 ± 0.3 **0.2 ± 0.3
4.1 ± 0.3
0.0 ± 0.3

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

Values are expressed as the mean ± SD.
†

ValuesGOLD (n ＝ 22)

Week 12⊿ 0‑12 w

Calcium

57（1143）9.7 ± 0.3
9.6 ± 0.3
0.0 ± 0.3
9.8 ± 0.3 *0.2 ± 0.3

58 （1144）

診療と新薬・第 53 巻

第 12 号（2016 年 12 月）

Table 7 Transition of urinalysis
Item

Speciﬁc Gravity

pH

Unit

−

−

Std. Value

ValuesTimepointsGOLD (n ＝ 22)

Placebo (n ＝ 22)

1.010-1.025

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

1.020 ± 0.007
1.018 ± 0.006− 0.003 ± 0.008
1.021 ± 0.007
0.000 ± 0.008

1.019 ± 0.007
1.018 ± 0.006− 0.001 ± 0.008
1.018 ± 0.007− 0.002 ± 0.007

4.5-8.0

Baseline
Week 6⊿ 0‑6 w
Week 12⊿ 0‑12 w

6.6 ± 0.6
6.7 ± 0.8
0.1 ± 0.8
6.4 ± 0.7
− 0.2 ± 0.8

6.5 ± 0.7
6.3 ± 0.6
− 0.3 ± 0.7
6.4 ± 0.8
− 0.1 ± 0.9

Values are expressed as the mean ± SD.

physiological variation (or clinically safe).
3.6. Adverse events
Any other adverse event was depicted with the test
product in the course of the reporting.

4. DISCUSSIONS
We conducted a randomized, placebo-controlled, doubleblind study for examining the efficacy of a supplement(GOLD) containing arginine and citrulline on the
improvement of male sexual function. As the primary
outcome, the study showed the signiﬁcant diﬀerences inthe scores of modified International Index of Erectile
Function (IIEF) on the questionnaire, which is designed
to collect the subjective evaluations for sexual function.
In addition, the signiﬁcant diﬀerences were observed in
the blood ﬂow velocity. Furthermore, several categories
on the questionnaire of Profile of Mood States (POMS)
showed the significant differences, and this result
indicates the improvement of QOL. At the same time, as
the secondary outcome the observation of clinical ﬁndingssuch as medical interview, the blood and urine test
revealed no abnormal change had been triggered by theingestion of GOLD.
Main Findings
In this study we examined the male sexual function by
the questionnaire, designed based upon IIEF which
consists of ten items (the questions which presuppose ED
were excluded by the doctor handling this investigation).
Among the GOLD, the 12-week ingestion of GOLD
resulted in the signiﬁcant diﬀerences in the score of #1,#2, #3, #4, #5, #8 and #10, and for intergroupcomparison, the score of #1, #2 ,#3 and #4 showedsigniﬁcant diﬀerences. IIEF is categorized as intercourse
satisfaction (#1, #2, #3), orgasmic function (#4,#5), sexual desire (#6, #7), overall satisfaction (#8,#9) and erectile function (#10), and the test results
indicate that almost all of the categories of IIEF showed
the significant difference of improvement after the 12-

week ingestion of GOLD. In addition, the comparison
between the GOLD and the Placebo indicates that there
were signiﬁcant diﬀerences in categories of intercourse
satisfaction . Based on the findings illustrated above, it
can be said that from a standpoint of IIEF score, theingestion of GOLD has improved all aspects of malesexual function. Although IIEF was originally developed
to examine a state change associated with treatment of
ED, it has been confirmed that the use of IIEF is alsoavailable for the examination of male sexual function ofhealthy people 17)18). Therefore it should be appropriate asan evaluation criterion for the male sexual function of thisstudy.
The main factor for evaluating the male sexual function
is an erection. It is considered that an erection isachieved based on the following mechanism 19)20); firstly,
sexual stimulation causes agitation on the sexual centerof the cerebrum, and the agitation passes through thepelvic nerve, pelvic plexus and cavernous nerves of thepenis. Then Nitrogen monoxide (NO) is secreted fromnerve terminals and it increases the level of cGMP in the
unstriated muscle of the corpus cavernosum penis. Thenthe unstriated muscle relaxes, and this relaxation lets the
blood ﬂow into the cavernous body. The ﬂow extends thetunica albuginea corporum cavernosorum, then thedraining vein is closed and ﬁnally an erection is achieved.
Arginine and citrulline contained in GOLD produce NO,
and it is reported that when the NO reaches the vascularsmooth muscle, it increases the level of cGMP and causes
dilatation of blood vessels 12)21)22). When ingested, botharginine and citrulline produce NO during theirtransformation and passing through urea cycle 23) .
Therefore it is considered that the simultaneous ingestionof both ingredients activated the urea cycle and increased
the production of NO. The increase of the production of
NO is thought to contribute to the increase of cGMP, thedilatation of blood vessels and the promotion of smootherection (by the blood ﬂow into the cavernous body), and診療と新薬・第 53 巻

it can be said that this mechanism supports the test
results of this study. There is also a report that has
shown a significant subjective improvement in sexualfunction in men with organic ED who have the decreased
production of NO, as a result of the 5g/day ingestion of
L-arginine 8). In addition, since amino acids such asarginine or citrulline are principles of protein, they cancontribute to the improvement of muscle strength andfatigue recovery, and can also affect the function of
unstriated muscle when an erection occurs 24). These
functions are diﬀerent from those of curative medicine for
ED which has functions of inhibiting PDE5 that
biodegrades cGMP and maintaining an erection.
Therefore, GOLD containing both arginine and ornithineis expected to have an improvement eﬀect of male sexualfunction, while excluding any deliberate effect ofincreasing vitality achieved by the medicine.
Secondary Findings
In this study we observed a signiﬁcant diﬀerence of theblood flow velocity in the GOLD compared to thePlacebo, after 6-week and 12-week ingestion. On theother hand, the score of the male hormone testosterone
did not show a signiﬁcant change. These results illustratethat while arginine and citrulline contained in GOLD
contributed to the improvement of the blood flow
velocity, these two ingredients, which function as thesubstances for secreting testosterone 25) , were not
suﬃcient enough to stimulate its secretion. The variationof the blood velocity was within the standard level, anddid not deviate from the usual range. At the same time,for evaluating the QOL of the subjects the doctor
conducted a questionnaire using POMS. For POMS,
vigor and fatigue were questioned. The results showedthat in the GOLD 9 items (of the questionnaire) showed
the significant differences, and the comparison between
the GOLD and the Placebo indicated the significant
diﬀerences on 3 items. Among the category of POMS, we
mainly found the signiﬁcant diﬀerence in vigor-related
categories such as vigor lively and active , and theseresults may indicate that the improvement of sexualfunction brought by the ingestion of GOLD also improved
their level of QOL.
And in this study, it was observed that based uponclinical findings such as blood test and urine test, noabnormal change was triggered by ingestion of GOLD. In
the blood test, although significant difference wasobserved in the changes of AST and LD (LDH), thediﬀerence was a minor one and the investigator judged itas the range of physiological variation. During the test
period ﬁve subjects discontinued the test. Four of them
stopped the test because of their personal reason such as
impossibility of continuing the test due to their business,and the remaining one stopped due to his illness (catchinga cold). Therefore, their discontinuance has nothing to dowith the ingestion of GOLD and we could rule out any
harmful influence against biochemical and/or

第 12 号（2016 年 12 月）

59（1145）

physiological matters of the subjects. These results
indicated the safety of the ingestion of GOLD for the 12week test period.
General Information
There is an opinion that the loss of confidence among
men toward their sexual function tends to decrease thefrequency of sexual intercourse and this tendency is oneof the causes of the decline in the birth rate 26). For men,the matter of the male sexual function (i.e. an erectile
function) not only involves countermeasures to the fallingbirth rate in which the improvement of the male sexualfunction is considered as a key factor, but also relates tothree major desires (food appetite, sleep drive andsexual appetite) . The sexual appetite can be regarded as
one of the important factors for pursuing QOL, since itsigniﬁcantly aﬀects their own conﬁdence and motivation,and their partnership as couples. For men, visiting adoctor for the prescription of the curative medicine for
ED may involve a mental distress, since they have toconfess an actual condition of their sexual function to thedoctor (a third party). If they are able to build conﬁdence
toward their sexual function by simple and convenientmethods without any side effects, such as obtaining
supplements, it should become highly possible tofacilitate the partnership in their daily sex life.
Limitations
In order to evaluate the sexual function it is necessary tohave both an erection (a condition) and sexual intercourse(an action), and for the evaluation of these condition andaction the subjective questionnaire plays an importantrole since they are quite personal matters. Although thisstudy used the questionnaire based on IIEF (which isinternationally recognized), it is inevitable to have someerrors. Although we found an improvement eﬀect of malesexual function attained by the ingestion of arginine andcitrulline, there is also a report that points out arginine is
not functional for the mixed-type impotence 27), and thisindicates that depending on the person the targeted
improvement by the supplement may not be achieved. In
addition, we have not yet discovered the mutual
influences among arginine, citrulline and the otheringredients contained in GOLD, and this point should befurther scrutinized.

5. CONCLUSION
We found out that the ingestion of the supplement GOLD
containing arginine and citrulline by healthy Japanesepeople for 12 weeks contributed to the improvement ofmale sexual function. In addition, no safety-related
matter occurred during the 12-week test period.
CONFLICT OF INTEREST
All parts of this study were funded by INSPIRE CO. LTD. Ryo Kohiyama
is the principal. All authors state that the study was conducted in theabsence of any other relationships that could be interpreted as a conﬂict ofinterest.

60 （1146）

診療と新薬・第 53 巻

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診療と新薬・第 53 巻
Appendix 1 . Questionnaire for screening

61（1147）(4) Most times (more than half the time)(5) Almost always or always
NOTE: similar to IIEF #9

Q1. Over the past 4 weeks, have you taken somemedication for your sexual function improvement?

YES

第 12 号（2016 年 12 月）NOEliminatedQ2. Over the past 4 weeks, have you had a medical
examination for your sexual function improvement?

YES

NO

EliminatedRamdomized

Appendix 2 . Questionnaire of sexual function
Question #1: Over the past 4 weeks, how many times have you attempted
sexual Intercourse?
(0) No attempts(1) 1-2 attempts(2) 3-4 attempts(3) 5-6 attempts(4) 7-8 attempts(5) 11 or more attempts
NOTE: similar to IIEF #6

Question #5: Over the past 4 weeks, when you had sexual stimulation orintercourse how often did you have the feeling of orgasm or climax?
(0) No sexual stimulation or intercourse(1) Almost never or ever(2) A few times (much less than half the time)(3) Sometimes (about half the time)(4) Most times (much more than half the time)(5) Almost always or always
NOTE: similar to IIEF #10
Question #6: Over the past 4 weeks, how often have you felt sexualdesire?
(0) Almost never or never(1) A few times (much less than half the time)(2) Sometimes (about half the time)(3) Most times (much more than half the time)(4) Almost always or always※ Question #6 and #7 ask about sexual desire. Let s deﬁne sexual desire
as a feeling that may include wanting to have a sexual experience (forexample, masturbation or intercourse) thinking about having sex or
feeling frustrated due to a lack of sex.
NOTE: similar to IIEF #11
Question #7: Over the past 4 weeks, how would you rate your level ofsexual desire?
(0) Very low or none at all(1) Low(2) Moderate(3) High(4) Very high
NOTE: similar to IIEF #12
Question #8: Over the past 4weeks, how satisﬁed have you been with you
overall sex life?
(0) Very dissatisﬁed(1) Moderately dissatisﬁed(2) About equally satisﬁed and dissatisﬁed(3) Moderately satisﬁed(4) Very satisﬁed
NOTE: similar to IIEF #13

Question #2: Over the past 4 weeks, when you attempted sexualintercourse, how often was it satisfactory for you?
(0) Did not attempt intercourse(1) Almost never or never(2) A few times (much less than half the time)(3) Sometimes (about half the time)(4) Most times (much more than half the time)(5) Almost always or always
NOTE: similar to IIEF #7

Question #9: Over the past 4 weeks, how satisﬁed have you been withyour sexual relationship with your partner?
(0) Very dissatisﬁed(1) Moderately dissatisﬁed(2) About equally satisﬁed and dissatisﬁed(3) Moderately satisﬁed(4) Very satisﬁed
NOTE: similar to IIEF #14

Question #3: Over the past 4 weeks, how much have you enjoyed sexualintercourse?
(0) No intercourse(1) Not enjoyable(2) Not very enjoyable(3) Fairly enjoyable(4) Highly enjoyable(5) Very highly enjoyable
NOTE: similar to IIEF #8

Question #10: Over the past 4 weeks how often have you experienced
nocturnal penile tumescence?
(0) No attempts(1) 1-2 attempts(2) 3-4 attempts(3) 5-6 attempts(4) 7-8 attempts(5) 11 or more attempts
NOTE: original

Question #4: Over the past 4 weeks, when you had sexual stimulation orintercourse how often did you ejaculate?
(0) Did not attempt intercourse(1) Almost never or never(2) A few times (much less than half the time)(3) Sometimes (about half the time)62 （1148）
Appendix 3 . POMS
Vigor
(1) Lively(2) Active(3) Energetic(4) Cheerful(5) Alert(6) Full of pep(7) Care free(8) Vigorous
Fatigue(1) Worn out(2) Listless(3) Fatigued(4) Exhausted(5) Sluggish

診療と新薬・第 53 巻

第 12 号（2016 年 12 月）(6) Weary(7) Bushed
The scores of answers are as follows:
Vigor(0) Not at all(1) A little(2) Moderate(3) Quite a bit(4) Extremely
Fatigue(0) Extremely(1) Quite a bit(2) Moderate(3) A little(4) Not at all