Original Article

54 巻
診療と新薬 2017;診療と新薬・第54: 37‑45

第 1 号（2017 年 1 月）

Eﬃcacy on Menopausal Discomfort of
the Supplement Containing Pueraria Miriﬁca
in Healthy Japanese Females:37

診療と新薬 WebA Randomized, Double-blind, Placebo-controlled Study

Masatomo NAJIMA1）／ Mitsuhiko MUNEKATA2）／ Hiroyuki SASAGAWA3）● Abstract
Objective: The objective of this study is to verify the improvement of womenʼs menopausal discomfort byingesting food containing Pueraria miriﬁca .
Methods: A randomized, placebo-controlled, double-blind study was conducted to evaluate various conditions
related to menopausal discomfort. The study used the method of subjective reporting (questionnaire) for
evaluating the above conditions.
Results: From all of 89 applicants, 63 were eliminated due to not meeting the inclusion criteria. Among 26
subjects, 1 was withdrawn due to personal reasons and the remaining 25 subjects completed the study (Test;
13, Placebo; 12). After 12 weeks of ingestion, the study showed signiﬁcant diﬀerence in the items related tonight sweating, diﬃculty sleeping and unstable feeling. These results suggest that the ingestion of the test
product contributed to improving parts of symptoms concerning menopausal discomfort. No adverse eﬀects
were observed after the ingestion of the test product.
Conclusion: We found out that the ingestion of the test product containing Pueraria miriﬁca for 12 weeks
contributed to the improvement of symptoms of menopausal discomfort (night sweating, urination, discomfort
of skin, unstable feeling, and loss of interest in sex). In addition, no safety-related matter occurred during the
12-week test period.
Key Words: Pueraria miriﬁca , menopause, climacteric age, menopausal discomfort, estrogen

1. INTRODUCTION
Generally, climacteric age refers to the 5 years before
and 5 years after menopause in the life cycle of women.
Since the median age of menopause of Japanese women isaround 50 years old, the age-group between 45 and 55
years old is described as the climacteric age. During theclimacteric age, about 80% of women suffer fromsymptoms such as emotional stress, hot flushes,
palpitations, or perspiration (sweating) due to a decreaseof estrogen, a type of female hormone. Among these
symptoms (menopausal discomfort), the clinicalconditions that hinder womenʼs our daily lives are deﬁned
as postmenopausal syndrome 1). Pueraria mirifica is a
Thai plant with a very large tuber. The dried powder ofthe root has traditionally been used as a folk remedy formenopause-related disorders for centuries 2) . Also,
Pueraria miriﬁca contains the ﬂavonoids such as daidzin,puerarin or genistein 3) and the phytoestrogens such as
miroestrol 4).
1) JACTA (Japan Clinical Trial Association)
2) OZ Clinic3) Hoshi corporation

The decrease in the amount of estrogen with aging isregarded as one of the causes of menopausal discomfort.
It is reported that the phytoestrogen shows an estrogenlike effect when ingested internally 5), therefore it isconsidered to be effective for menopausal discomfort.
There is also a report that verifies the efficacy of thephytoestrogen for menopausal discomfort 6). Furthermore,
a lot of supplement-foods containing Pueraria miriﬁca arebeing sold recently. However, there are few studies
which actually examine how the ingestion of Pueraria
miriﬁca aﬀects the condition of menopausal discomfort ofJapanese people. Therefore in this study, we conducted arandomized, placebo-controlled, double-blind study toverify the efficacy of Pueraria mirifica for menopausal
discomfort of healthy Japanese and its safeness.

2. METHODS
2.1. Trial design
A randomized, placebo-controlled, double-blind study was
conducted with the aid of a fund from Hoshi corporation(Tokyo) at JACTA (Tokyo). The study period was 12
weeks, from April 8th, to July 1st, 2016. This study was
conducted in accordance with the ethical principles of thedeclaration of Helsinki. The study protocol was approved38 （38）

診療と新薬・第 54 巻

by the Institutional Review Board of Pharmaceutical Law
Wisdoms (Tokyo). Written informed consent was
obtained from all subjects.
The allocation of the test product to the subjects was
carried out by the person in charge of allocation. The
allocation list was sealed by the person in charge ofallocation and strictly controlled in a safe deposit box of
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),recruited from February through March, 2016.
2.2.1. Inclusion criteria(1) Healthy females aged between 45 and 55 years;(2) Individuals concerned by menopausal discomfort;(3) Non-smoker.
2.2.2. Exclusion criteria(1) Individuals undergoing treatment of chronic diseases
such as atrial fibrillation, arrhythmia, rheumatism,
diabetes, high blood pressure, lipid metabolism, anddiseases of the liver, kidney, central nervous system, andcirculatory system;(2) Individuals on medication, including herbal medicines;(3) Individuals with a pollen or food allergy;(4) Individuals who are pregnant, nursing, or likely to
become pregnant during the trial;(5) Individuals judged to be ill by the principle
investigator.
2.3. Randomization
From all of 89 applicants, 63 were eliminated according to
the exclusion criteria. The inclusion criteria was judged
by the principle investigator. All subjects weresequentially allocated to group A (n = 13) and group B(n = 13) using a random number table. In the process ofsubject assignment, background factors such as age weretaken into consideration to avoid biased distribution.
Subjects in Group A ingested the placebo, and subjects inGroup B ingested the test sample for 12 weeks.
2.4. Description of test foods and blinding
The test product was prepared by Hoshi corporation. The
amount of daily intake was 4 capsules (1 capsule weighs
230 mg, therefore 4 capsules weigh 920 mg). The
composition of the test product was Pueraria mirifica ,collagen, hyaluronan etc., while the placebo product was
mainly consisted of indigestible dextrin and did notinclude Pueraria mirifica . Both tablets wereindistinguishable in shape, color, or taste, and weremanaged by an identification symbol. All involved wereblinded.
2.5. Experimental procedures
2.5.1. Experimental protocol
Subjects consumed 4 capsules of the supplement with hotor cold water every day for 12 weeks. Subjects were
instructed as follows: to take the assigned foods as
indicated; to maintain their usual lifestyles and habits; to

第 1 号（2017 年 1 月）

avoid excessive amounts of food, drink, or alcohol; tomaintain a daily record of lifestyle factors such as amountof food, exercise, and sleep for the day during the test
period.
2.5.2. Outcome
The objective of this study was to verify the improvementof womenʼs menopausal discomfort by ingesting foodcontaining Pueraria miriﬁca . To evaluate this objective,
subjective reporting of menopausal discomfort wasobserved as the primary outcome. The questionnaire (45items) is designed by the conducting doctor. The details
are illustrated in Appendix 1.
To evaluate the safety of the test foods, adverse eventswere collected by means of a written questionnaireduring the study. According to the schedule shown in
Table 1, we measured parameters on eﬃcacy and safety.
These assessments were conducted upon preintervention and post-intervention.
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).
With respect to scores of subjective reporting, changes
from baseline in the same group were assessed using thepaired t-test. Studentʼs t-test was used for intergroupcomparisons of changes from baseline. Studentʼs 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 4(Yanai, 2015). The results were considered signiﬁcant at
the < 5% level in the two-sided test.

3. RESULTS
3.1. Participant demographics
The 26 subjects were randomly assigned to intervention
groups and made a start with ingestion. 1 was withdrawn
due to personal reasons, and the remaining 25 subjects
completed the study. Thus, data obtained with 25
subjects (Test; 13, Placebo; 12) was used for the analysis
of eﬃcacy (Fig. 1). There was no signiﬁcant diﬀerence inage between groups (Table 2).
3.2. Subjective condition assessments
The result of subjective condition assessments are shownin Table 3. The intergroup comparison of 6 weeks
illustrated a significant difference regarding questions;#35 (feeling tingly skin), #38 (feeling virginal dryness),#41 (feeling sexual disinterest), #42 (uncontrolled
urination), #43 (frequent urination), and #45 (anxious
about urination). In addition, in the between-groupcomparison there was a significant difference after
12-weeks of ingestion, in #3 (sudden sweating at night),#8 (nervousness), #9 (feeling isolated), #12 (feeling
unstable), #13 (weeping), #14 (sleeping light), #15(diﬃculty falling asleep), #29 (becoming cold waist), #35

診療と新薬・第 54 巻

Table 1Term
Item
Informed consent
Selection and/or allocation
Subjective reporting
Ingestion of test foods
Log

第 1 号（2017 年 1 月）

39 （39）

Schedule for the study.
Test period

Pretrial

Screening

test

6w

12 w

●

●

●

●
●

● : Implementation↔ : Daily practice during the test period

Enrollment

Assessed for eligibility (n = 89)

Excluded (n = 63)¨Did not meet inclusion criteria (n = 63)¨Declined to participate (n = 0)
¨Other reasons (n = 0)

Randomized (n = 26)
Group AGroup B

Allocation
Allocated to Placebo (n = 13)¨Received allocated intervention (n = 13)¨Did not receive allocated intervention (n = 0)

Allocated to Test sample (n = 13)¨Received allocated intervention (n = 13)¨Did not receive allocated intervention (n = 0)

Follow-Up
Lost to follow-up (n = 0)
Discontinued intervention (n = 1)

Lost to follow-up (n = 0)
Discontinued intervention (n = 0)

¨Personal reasons (n = 1)

AnalysisAnalysed (n = 13)

Analysed (n = 12)¨Excluded from analysis (n = 0)

¨Excluded from analysis (n = 0)

Fig. 1 Flow diagram of subject disposition(feeling tingly skin), #41 (feeling sexual disinterest), #42(uncontrolled urination), and #45 (anxious about
urination).
3.3. Safety
No adverse eﬀects associated with the test product wereobserved in the course of the reporting.

Table 2 Subject demographics
Item

Unit

Test

Placebo

Subjects
Age ＊numbersyears

13
50.9 ± 2.4

1251.8 ± 2.5

mean ± SD＊

No signiﬁcant diﬀerence40 （40）

診療と新薬・第 54 巻

Table 3

第 1 号（2017 年 1 月）

Results of questionnaire analyses (1)ScoresTest (n = 13)1）
Placebo (n = 12)1）
Baseline
2.5 ± 1.4
2.2 ± 1.2
6‑week
1.4 ± 1.2 ＊2.0 ± 1.4
⊿ 0‑6 w
− 1.1 ± 1.3− 0.2 ± 1.3#1
12‑week
1.5 ± 1.5 ＊1.3 ± 1.2 †⊿ 0‑12 w− 1.0 ± 1.3− 0.9 ± 1.4
Baseline
2.1 ± 1.6
2.3 ± 1.6
6‑week
1.4 ± 1.4
2.0 ± 1.3
⊿ 0‑6 w
− 0.7 ± 1.7− 0.3 ± 1.0#2
12‑week
1.5 ± 1.5
2.4 ± 1.4
⊿ 0‑12 w− 0.6 ± 1.3
0.1 ± 0.7
Baseline
1.9 ± 1.6
1.3 ± 1.5
6‑week
0.8 ± 1.2 †1.2 ± 1.3
⊿ 0‑6 w
− 1.2 ± 2.0− 0.2 ± 0.7#3＊12‑week
0.6 ± 1.3
1.5 ± 1.4
⊿ 0‑12 w− 1.3 ± 1.6
0.2 ± 0.6
Baseline
1.1 ± 1.0
1.8 ± 1.3†
6‑week
0.5 ± 0.8
1.3 ± 1.2 ＊⊿ 0‑6 w
− 0.5 ± 1.1− 0.5 ± 0.7#412‑week
0.8 ± 1.2
1.8 ± 1.2
⊿ 0‑12 w− 0.2 ± 1.4− 0.1 ± 0.3
Baseline
1.2 ± 1.2
1.2 ± 1.3
6‑week
0.9 ± 1.2
1.1 ± 1.1
⊿ 0‑6 w
− 0.2 ± 1.0− 0.1 ± 0.5#512‑week
1.1 ± 1.0
1.3 ± 1.3
⊿ 0‑12 w− 0.1 ± 1.0
0.1 ± 0.3
Baseline
0.5 ± 1.2
1.3 ± 1.3
6‑week
0.4 ± 1.0
1.6 ± 1.4
⊿ 0‑6 w
− 0.2 ± 1.3
0.3 ± 0.9
#612‑week
0.3 ± 0.9
1.7 ± 1.4 ＊⊿ 0‑12 w− 0.2 ± 1.5
0.3 ± 0.5
Baseline
2.1 ± 1.2
2.3 ± 1.2
6‑week
1.9 ± 1.3
2.2 ± 1.1
⊿ 0‑6 w
− 0.2 ± 1.2− 0.1 ± 1.0#7
12‑week
2.0 ± 1.0
2.3 ± 1.0
⊿ 0‑12 w− 0.1 ± 1.0
0.0 ± 0.7
1.8 ± 1.4
Baseline
2.8 ± 1.2
1.8 ± 1.4
6‑week
1.8 ± 1.3 ＊0.1 ± 1.4
⊿ 0‑6 w
− 0.9 ± 1.3#8＊＊
12‑week
1.6 ± 1.2
2.1 ± 1.2
⊿ 0‑12 w− 1.2 ± 1.2
0.3 ± 0.7
1.2 ± 1.2
Baseline
1.9 ± 1.4
1.3 ± 1.2
6‑week
1.6 ± 1.3
0.2 ± 0.7
− 0.3 ± 0.9⊿ 0‑6 w
#9
12‑week
1.0 ± 1.2 ＊1.6 ± 1.3 †⊿ 0‑12 w− 0.9 ± 1.2
0.4 ± 0.8
1.6 ± 1.1
Baseline
1.6 ± 1.4
1.8 ± 1.2
6‑week
1.3 ± 1.2
0.3 ± 1.1
− 0.3 ± 0.6⊿ 0‑6 w
#10
12‑week
1.2 ± 1.1
2.0 ± 1.2
⊿ 0‑12 w− 0.5 ± 1.5
0.4 ± 0.9
2.1 ± 1.2
1.8 ± 1.0
Baseline
2.2 ± 1.3
1.7 ± 1.4
6‑week
0.1 ± 0.8
− 0.1 ± 0.9⊿ 0‑6 w
#11
12‑week
1.2 ± 0.9
2.3 ± 1.2
⊿ 0‑12 w− 0.5 ± 1.2
0.3 ± 0.6
1.1 ± 0.7
1.6 ± 1.0
Baseline
1.3 ± 0.8
1.5 ± 1.1
6‑week
0.3 ± 0.8
− 0.1 ± 0.6⊿ 0‑6 w
#12
12‑week
0.8 ± 1.0 ＊1.4 ± 0.7
⊿ 0‑12 w− 0.8 ± 0.9
0.3 ± 0.7
Baseline
1.4 ± 1.0
1.4 ± 1.1
6‑week
1.2 ± 1.3
1.6 ± 1.4
⊿ 0‑6 w
− 0.2 ± 1.4
0.2 ± 0.8
#13
12‑week
0.8 ± 1.2 ＊2.0 ± 1.3 ＊⊿ 0‑12 w− 0.6 ± 1.0
0.6 ± 0.8
1.8 ± 1.3
2.5 ± 1.5
Baseline
1.8 ± 1.5
2.0 ± 1.3
6‑week
0.0 ± 1.0
− 0.5 ± 1.1⊿ 0‑6 w
#14＊＊
12‑week
1.3 ± 1.5
2.3 ± 1.4
⊿ 0‑12 w− 1.2 ± 1.2
0.5 ± 1.0
Baseline
2.1 ± 1.5
1.3 ± 1.1
6‑week
1.7 ± 1.3
1.3 ± 1.2
⊿ 0‑6 w
− 0.4 ± 1.6
0.1 ± 1.2
#15
12‑week
1.1 ± 1.3 ＊＊1.8 ± 1.1 †⊿ 0‑12 w− 1.0 ± 0.8
0.6 ± 1.1
Scores are expressed as the mean ± SD.
1）† p < 0.1, ＊ p < 0.05, ＊＊ p < 0.01 against baseline.
2）‡ p < 0.1, ＃＃ p < 0.01 between-group diﬀerence in change from baseline.
No.

Time point

P-value2）

0.092 ‡
0.880

0.521
0.114

0.126
0.006 ＃＃

0.915
0.717

0.655
0.611

0.386
0.222

0.876
0.825
0.075 ‡
< 0.001 ＃＃0.148
0.003 ＃＃

0.119
0.085 ‡

0.634
0.053 ‡

0.253
0.002 ＃＃

0.408
0.003 ＃＃

0.282
0.001 ＃＃

0.407
< 0.001 ＃＃診療と新薬・第 54 巻

Table 3

第 1 号（2017 年 1 月）

Results of questionnaire analyses (2)ScoresTest (n = 13)1）
Placebo (n = 12)1）
Baseline
2.6 ± 1.3
2.3 ± 1.4
6‑week
2.2 ± 1.1
2.3 ± 1.4
⊿ 0‑6 w
− 0.5 ± 1.1− 0.1 ± 1.2#16
12‑week
2.3 ± 1.3
2.8 ± 1.3
⊿ 0‑12 w− 0.3 ± 1.0
0.4 ± 1.1
Baseline
2.6 ± 1.4
2.3 ± 1.7＊＊
6‑week
1.8 ± 1.3
2.3 ± 1.3
⊿ 0‑6 w
− 0.8 ± 0.6
0.0 ± 1.3
#17
12‑week
2.2 ± 1.2
2.2 ± 1.6
⊿ 0‑12 w− 0.5 ± 1.0− 0.1 ± 1.1
Baseline
2.0 ± 1.2
2.3 ± 1.3
6‑week
1.5 ± 1.0
2.3 ± 1.4
⊿ 0‑6 w
− 0.5 ± 1.0− 0.1 ± 0.8#1812‑week
1.5 ± 1.3
2.6 ± 1.4 †⊿ 0‑12 w− 0.5 ± 1.3
0.3 ± 0.5
Baseline
2.0 ± 1.4
2.2 ± 1.2
6‑week
1.7 ± 1.1
2.3 ± 1.5
⊿ 0‑6 w
− 0.3 ± 0.9
0.1 ± 0.8
#19
12‑week
1.8 ± 1.4
2.5 ± 1.3
⊿ 0‑12 w− 0.2 ± 1.3
0.3 ± 0.9
2.3 ± 1.1
2.0 ± 1.2
Baseline
2.3 ± 1.1
1.7 ± 1.0
6‑week
0.1 ± 0.7
− 0.3 ± 1.1⊿ 0‑6 w
#20
12‑week
1.7 ± 1.2
2.2 ± 1.4
⊿ 0‑12 w− 0.3 ± 1.8− 0.1 ± 1.0
1.5 ± 1.2
0.9 ± 1.3
Baseline
1.4 ± 1.2
1.2 ± 1.4
6‑week
− 0.1 ± 0.8
0.3 ± 1.0
⊿ 0‑6 w
#21
12‑week
1.2 ± 1.7
1.7 ± 1.2
⊿ 0‑12 w
0.2 ± 1.1
0.2 ± 1.2
Baseline
1.3 ± 1.5
2.3 ± 1.4
6‑week
1.2 ± 1.5
1.9 ± 1.2
⊿ 0‑6 w
− 0.1 ± 1.0− 0.4 ± 1.4#22
12‑week
1.4 ± 1.7
2.5 ± 1.2
⊿ 0‑12 w
0.1 ± 1.2
0.2 ± 0.6
Baseline
2.1 ± 1.6
2.1 ± 1.2
6‑week
2.0 ± 1.3
1.9 ± 1.2
⊿ 0‑6 w
− 0.1 ± 0.9− 0.2 ± 1.3#23
12‑week
1.6 ± 1.6
2.3 ± 1.2
⊿ 0‑12 w− 0.5 ± 1.4
0.3 ± 1.1
Baseline
0.6 ± 1.2
1.6 ± 1.5
6‑week
0.5 ± 0.8
1.4 ± 1.4
⊿ 0‑6 w
− 0.2 ± 0.8− 0.2 ± 1.0#24
12‑week
0.4 ± 0.7
1.9 ± 1.6
⊿ 0‑12 w− 0.2 ± 0.9
0.3 ± 0.8
1.3 ± 1.4
0.5 ± 1.0
Baseline
1.1 ± 1.4
0.3 ± 0.9
6‑week
− 0.2 ± 0.6− 0.2 ± 1.0⊿ 0‑6 w
#25
12‑week
0.2 ± 0.6
1.6 ± 1.5
⊿ 0‑12 w− 0.3 ± 0.9
0.3 ± 0.8
2.0 ± 1.6
Baseline
3.3 ± 1.0
2.1 ± 1.8
6‑week
3.2 ± 1.3
⊿ 0‑6 w
0.1 ± 1.4
− 0.1 ± 0.9#2612‑week
1.8 ± 1.6
3.2 ± 1.1
⊿ 0‑12 w− 0.2 ± 1.3− 0.1 ± 1.0
Baseline
2.2 ± 1.5
1.9 ± 1.4
6‑week
1.8 ± 1.3
1.6 ± 1.6
⊿ 0‑6 w
− 0.4 ± 1.4− 0.3 ± 0.7#27
12‑week
1.1 ± 1.3 ＊1.8 ± 1.5
⊿ 0‑12 w− 1.1 ± 1.6− 0.2 ± 0.4
Baseline
2.2 ± 1.5
2.5 ± 1.3
6‑week
1.8 ± 1.5
2.2 ± 1.9
⊿ 0‑6 w
− 0.3 ± 1.3− 0.3 ± 0.8#28
12‑week
1.4 ± 1.5 †2.4 ± 1.4
⊿ 0‑12 w− 0.8 ± 1.5− 0.1 ± 0.3
Baseline
1.5 ± 1.6
2.2 ± 1.3
6‑week
1.5 ± 1.5
1.9 ± 1.5
⊿ 0‑6 w
0.0 ± 1.6
− 0.3 ± 0.6#29†2.4 ± 1.1
12‑week
0.8 ± 1.3
0.3 ± 0.6
⊿ 0‑12 w− 0.7 ± 1.3
Baseline
0.5 ± 1.0
1.3 ± 1.1
6‑week
0.7 ± 1.2
1.2 ± 1.3
⊿ 0‑6 w
0.2 ± 0.9
− 0.1 ± 0.7#30
12‑week
0.8 ± 1.2
1.3 ± 1.1 †⊿ 0‑12 w
0.3 ± 0.9
0.1 ± 0.3
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 between-group diﬀerence in change from baseline.
No.

Time point

41 （41）

P-value2）

0.418
0.100
0.074 ‡
0.366

0.299
0.092 ‡

0.277
0.222

0.302
0.701

0.302
0.890

0.478
0.815

0.837
0.177

0.972
0.115

0.849
0.063 ‡

0.744
0.884

0.908
0.069 ‡

0.952
0.142

0.614
0.034 ＃

0.465
0.440

42 （42）

診療と新薬・第 54 巻

Table 3

第 1 号（2017 年 1 月）

Results of questionnaire analyses (3)ScoresP-value2）
Test (n = 13)1）
Placebo (n = 12)1）
Baseline
1.1 ± 1.2
1.0 ± 1.1
6‑week
1.2 ± 1.1
0.9 ± 0.9
⊿ 0‑6 w
0.2 ± 1.2
− 0.1 ± 0.5
0.538
#31
12‑week
0.6 ± 1.0
1.3 ± 1.1
⊿ 0‑12 w− 0.5 ± 1.3
0.3 ± 0.7
0.064 ‡
Baseline
0.2 ± 0.4
0.4 ± 0.9
6‑week
0.2 ± 0.4
0.3 ± 0.5
⊿ 0‑6 w
− 0.1 ± 0.5− 0.2 ± 0.7
0.717
#32
12‑week
0.1 ± 0.3
0.2 ± 0.4
⊿ 0‑12 w− 0.2 ± 0.4− 0.3 ± 0.9
0.718
Baseline
1.8 ± 1.4
2.8 ± 0.8
6‑week
1.2 ± 1.0 ＊2.4 ± 1.0 †⊿ 0‑6 w
− 0.6 ± 1.0− 0.4 ± 0.8
0.580
#33
12‑week
1.2 ± 1.0 †2.8 ± 0.8
⊿ 0‑12 w− 0.7 ± 1.3
0.0 ± 0.0
0.082 ‡
Baseline
1.3 ± 1.2
2.6 ± 1.2
6‑week
0.5 ± 0.8 †2.4 ± 1.2
⊿ 0‑6 w
− 0.8 ± 1.3− 0.2 ± 0.7
0.170
#34
12‑week
0.8 ± 1.1
2.7 ± 1.2
⊿ 0‑12 w− 0.5 ± 1.5
0.1 ± 0.3
0.215
0.8 ± 1.2
Baseline
1.5 ± 1.6＊
0.2 ± 0.4
6‑week
1.9 ± 1.2
− 0.7 ± 1.1⊿ 0‑6 w
0.4 ± 0.9
0.012 ＃
#35＊
12‑week
0.3 ± 0.6
1.9 ± 1.4 †⊿ 0‑12 w− 0.5 ± 0.8
0.4 ± 0.8
0.006 ＃＃
Baseline
1.1 ± 1.3
1.4 ± 1.0
6‑week
0.4 ± 0.9
1.3 ± 1.0
⊿ 0‑6 w
− 0.7 ± 1.4− 0.2 ± 0.6
0.250
#36
12‑week
0.8 ± 1.2
1.1 ± 1.2
⊿ 0‑12 w− 0.3 ± 1.4− 0.3 ± 0.9
0.958
Baseline
1.5 ± 1.3
1.8 ± 1.8
6‑week
1.0 ± 1.5
1.9 ± 1.6
⊿ 0‑6 w
− 0.5 ± 1.2
0.2 ± 0.8
0.145
#37
12‑week
0.9 ± 1.2
1.9 ± 1.4
⊿ 0‑12 w− 0.5 ± 1.4
0.2 ± 0.8
0.142
Baseline
1.4 ± 1.0
0.9 ± 0.8
6‑week
0.8 ± 1.0 ＊1.0 ± 0.7
⊿ 0‑6 w
− 0.5 ± 0.9
0.043 ＃
0.1 ± 0.5#38†
12‑week
0.9 ± 1.0
0.8 ± 1.1
⊿ 0‑12 w− 0.5 ± 0.8− 0.2 ± 0.6
0.296
Baseline
0.9 ± 1.0
1.1 ± 1.2
6‑week
0.5 ± 0.8 †1.0 ± 1.2
⊿ 0‑6 w
− 0.5 ± 0.8− 0.1 ± 0.5
0.145
#39
12‑week
0.5 ± 0.8 †0.7 ± 0.0 †⊿ 0‑12 w− 0.5 ± 0.8− 0.4 ± 0.80.802
Baseline
1.4 ± 1.2
1.2 ± 1.1
6‑week
1.0 ± 1.2
1.0 ± 0.7
⊿ 0‑6 w
− 0.4 ± 1.3− 0.2 ± 1.1
0.619
#40
12‑week
0.8 ± 0.9
1.1 ± 0.8 †0.200⊿ 0‑12 w− 0.6 ± 1.2− 0.1 ± 0.9
1.9 ± 1.4
Baseline
3.0 ± 1.2
2.2 ± 1.4
6‑week
1.3 ± 1.3 ＊＊0.3 ± 0.8
< 0.001 ＃＃⊿ 0‑6 w
− 1.7 ± 1.5#41＊＊
12‑week
1.3 ± 1.5
2.1 ± 1.3
⊿ 0‑12 w− 1.7 ± 1.6
0.2 ± 0.6
< 0.001 ＃＃Baseline
1.6 ± 1.3
0.3 ± 0.7
6‑week
0.6 ± 0.9 ＊0.3 ± 0.5
⊿ 0‑6 w
− 1.0 ± 1.2
0.0 ± 0.6
0.014 ＃
#42
12‑week
0.6 ± 1.0 ＊＊0.3 ± 0.7
⊿ 0‑12 w− 1.0 ± 0.9
0.0 ± 0.7
0.005 ＃＃
Baseline
2.0 ± 1.4
1.8 ± 1.7
6‑week
1.2 ± 1.1 ＊＊1.8 ± 1.3
⊿ 0‑6 w
− 0.8 ± 0.9
0.1 ± 1.0
0.018 ＃
#43
12‑week
1.5 ± 1.4
2.0 ± 1.4
⊿ 0‑12 w− 0.5 ± 1.3
0.3 ± 0.9
0.080 ‡
Baseline
0.8 ± 1.1
0.6 ± 0.7
6‑week
0.5 ± 0.9
0.6 ± 0.9
⊿ 0‑6 w
− 0.3 ± 0.6
0.0 ± 0.7
0.253
#44
†
12‑week
0.3 ± 0.6
0.3 ± 0.5 †⊿ 0‑12 w− 0.5 ± 0.8− 0.3 ± 0.5
0.360
Baseline
1.8 ± 1.3
0.8 ± 0.9
6‑week
1.2 ± 1.1 ＊0.9 ± 0.8 †⊿ 0‑6 w
− 0.6 ± 0.9
0.2 ± 0.7
0.020 ＃
#45
12‑week
1.0 ± 1.1 †1.0 ± 1.0
⊿ 0‑12 w− 0.8 ± 1.4
0.3 ± 1.0
0.030 ＃
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 diﬀerence in change from baseline.
No.

Time point

診療と新薬・第 54 巻

4. DISCUSSION
We conducted a randomized, placebo-controlled, doubleblind study for examining the eﬃcacy of the test productcontaining Pueraria miriﬁca . The objective of this study
was to verify whether the ingestion of the food containing
Pueraria mirifica affects the conditions of menopausal
discomfort.
As the primary outcome, the questionnaire about
menopausal discomfort showed a signiﬁcant diﬀerence in
the items related to functions of skin, vagina andurination, after 6-weeks of ingestion of the test product.
In addition, the results after 12 weeks showed asigniﬁcant diﬀerence in the items related to sweating atnight, difficulty sleeping and unstable feeling. These
results suggest that the ingestion of the test productcontributed to improving some symptoms concerningmenopausal discomfort. In addition, as the secondary
outcome, no adverse effects associated with the test
product were observed in the course of the reporting,and the safety of ingesting the test product wassuggested.
Main Findings
This study showed the improvement of several symptomsof menopausal discomfort, as a result of the ingestion of
the test product containing Pueraria miriﬁca . According
to the result data of the questionnaire, there was asigniﬁcant diﬀerence in the items related to sweating atnight such as #3 (sudden sweating at night) , the items
related to unstableness or nervousness such as #8, #9,#12, and #13, the items related to sleeping such as #14,
and #15, the items related to physical disorder such as#29, #35, and #38, the items related to sexualdisinterest such as #41, and the items related to urinary
function such as #42, #43, and #45, after the ingestionof the test product. On the other hand, we could not ﬁnd
a significant difference in the items related to physicalsymptoms such as dizziness or headache, and the items
related to the cognitive functions such as memory orforgetfulness. The questionnaire used for this test is
prepared by the doctor in charge of carrying out the test,
who consulted several menopausal indexes such as theKupperman (menopausal) index 7)8) or the Greene
Climacteric Scale 9)10) for diagnosing menopausal
discomfort 11). Thanks to this preparation, this test
enabled us to evaluate not only whether the test subjects
suffer from menopausal discomfort or not, but also how
the test product shows an influence against some
symptoms of the menopausal discomfort.
Pueraria mirifica contains, as its active ingredient, five
major isoﬂavonoids (puerarin, daidzin, genistin, daidzein,
and genistein), miroestrol and deoxymiroestrol.
Deoxymiroestrol easily changes to miroestrol when
exposed to the oxygen in the air 12). These ingredients are
phytoestrogens which mimic the biological activity offemale hormone estrogen 13) and are thought as a causal

第 1 号（2017 年 1 月）

43 （43）

substance of the functions of Pueraria mirifica 14). In
womenʼs bodies, gonadotropins are secreted fromhypothalamus at the time of ovulation, and this secretion
stimulates the pituitary to secrete follicle stimulating
hormone (FSH) which encourages the secretion of female
hormones by the ovary. The stimulation of the ovary by
the hormone lets the ovarian follicle start its maturation,and during this maturation, estrogen is secreted 15). Whenan adequate amount of estrogen is secreted, ovulation
occurs with the secretion of the corpus luteum hormone.
On the other hand, once the women face climacteric
symptoms and the secretion of estrogen becomesinadequate, the hypothalamus or the pituitarycontinuously stimulates the ovary in order to activate thesecretion of estrogen (negative feedback). However, theadequate secretion of the estrogen is not achieved due toa decline in the function of the ovary, and as a result the
hypothalamus becomes a continuous hyper-function.
Eventually, since the hypothalamus is the nerve center of
automatic nerves, the function of automatic nerves gets
worse and this disorder has various negative impacts on
the body; this is often regarded as one of the causes ofmenopausal discomfort 16)17). It is thought that since thephytoestrogen contained in Pueraria miriﬁca perform an
estrogen-like effect internally, it inhibits the hyperfunction state of hypothalamus and fixes up thedysfunction of automatic nerve 18). The automatic nerve
controls the functions of organs or blood vessels andprepares the bodyʼs internal environment. Therefore, thesymptoms which showed the tendency of improvement inthis study are all thought to have a relationship with theautomatic nerve functions. The affective disorders suchas difficulty sleeping or unstable feeling may have beencaused by the decrease of estrogen, which causes theinhibition of degradation of monoamine oxidase and thefall in the density of serotonin 19), but is recovered andimproved by the estrogen-like eﬀect of Pueraria miriﬁca .
As for the skin tingle, it is likely that the estrogen-like
effect also brought an improvement of the condition,
since estrogen is equipped with the function of supportingthe collagen formation of dermic layer 20). In addition, thesexual factors such as an interest in sex or virginal
dryness directly involve the estrogen (female hormone),so the improvement tendency has been possibly seen. On
the other hand, the symptoms that did not show
signiﬁcant improvements are thought to be the symptoms
the estrogen does not have a direct involvement in, or
the symptoms which have a strong relationship withsocial or environmental factors of women.
Based on the discussion above, it is suggested that theingestion of the test product containing Pueraria miriﬁca
contributes to improving several disorders of climactericage.
Secondary Findings
In this study, adverse events were collected by means ofa written questionnaire during the study, and no44 （44）

診療と新薬・第 54 巻

abnormal change caused by the test product wasobserved during the ingesting period. During the test
period one test subject discontinued the test. The reasonof discontinuance was personal one and it has nothing to
do with the ingestion of the test product. These results
indicated the safety of the ingestion of the test productfor the 12-week test period
General Information
Menopausal discomfort tends to signiﬁcantly deteriorate
the quality of life (QOL) of women, due to its unpleasant
symptom. It is a fact, however, that the appropriate
information or understanding about menopausal
discomfort is not well-known in Japan 21)22). Therefore, a
lot of women are inclined to regard the symptoms as anaturally occurring change caused by aging, and relieve
them. In addition, Japanese women of that age (around 50
years old) often get caught up in businesses such as
nursing care of their parents, which may mean they have
limited time to see doctors 23). For these reasons, it can besaid that almost all Japanese women of climacteric age do
not regularly receive medical support for menopausal
discomfort. It is reported that seeking help to relieve
unpleasant symptoms leads to losing a sense of well-being
and encouraging a negative feeling 24). Based upon theabove discussion, it is contemplated that if the unpleasantfeeling of climacteric symptoms can be alleviated by theingestion of the food of supplement type (which is easily
prepared), it may contribute to improving the QOL of
middle-aged women.
Limitations
Menopausal discomfort is also known as climactericcomplaints . It displays several physical symptoms, eventhough there may not be any organic disease. In otherwords, in many cases we cannot identify a cause of the
discomfort since a medical examination does not show
any numerical anomaly. Therefore, although a variety ofobjective examinations are being used to check up anddiagnose menopausal discomfort 25)26), it is still inevitableto depend on the subjective evaluation such as thequestionnaire for a comprehensive diagnosis 11)27). In
addition, since the onset of the symptom has a strong a
relationship with many factors such as whether they havea job or not, their dietary habits or sports habits 28), andthe type of their job or life style they have 29), the degreeof the symptom diﬀers substantially between individuals,
and this fact makes it diﬃcult to judge whether the test
results are surely yielded by the ingestion of the test
product. Therefore, it is necessary to examine with moret e s t s u b j e c t s . A l s o , e x c e s s i ve i n g e s t i o n o f t h ephytoestrogen in Pueraria mirifica reportedly brings onan endocrine-disrupting eﬀect 5), it is important to ingest amoderate amount of it.

5. CONCLUSION
In conclusion, we found out that the ingestion of the test
product containing Pueraria mirifica for 12 weeks

第 1 号（2017 年 1 月）

contributed to the improvement of symptoms ofmenopausal discomfort (sweating at night, urination,
discomfort of skin, unstable feeling, and loss of interest insex). In addition, no safety-related matter occurred
during the 12-week test period.
CONFLICT OF INTEREST
All parts of this study were funded by Hoshi corporation. Hiroyuki
Sasagawa is a director. All authors state that the study was conducted in
the absence of any other relationships that could be interpreted as a
conﬂict of interest.

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第 1 号（2017 年 1 月）
Appendix 1. Subjective condition assessments
Scale of 0 to 4, with lower scores indicating a better result.
#1 becoming facial redness#2 becoming sweaty#3 sudden sweating at night#4 suddenly becoming heart beating in daily life
#5 feeling dizziness#6 feeling tinnitus#7 feeling anxious#8 nervousness#9 feeling isolated#10 becoming tense#11 feeling maddening#12 feeling unstable#13 weeping#14 sleeping light#15 diﬃculty falling asleep#16 feeling tired#17 feeling malaise#18 lack of concentration#19 diﬃcult to memory#20 becoming forgetful#21 feeling headache#22 feeling lower back discomfort#23 becoming swelling#24 becoming numbness in hand
#25 becoming numbness in foot#26 becoming stiﬀ shoulder#27 becoming cold hand
#28 becoming cold foot#29 becoming cold waist#30 becoming abdominal pain
#31 becoming constipation#32 feeling vomiting#33 becoming dry skin#34 becoming itchy skin
#35 feeling tingly skin
#36 feeling skin eczema#37 feeling hair falling#38 feeling virginal dryness#39 becoming painful sex#40 feeling sexual discomfort#41 feeling sexual disinterest#42 uncontrolled urination#43 frequent urination#44 feeling residual urine#45 anxious about urination

45 （45）