Menopause: The Journal of The North American Menopause Society

Vol. 21, No. 9, pp. 990/996

DOI: 10.1097/gme.0000000000000200
* 2014 by The North American Menopause Society

Effects of grape seed proanthocyanidin extract on menopausal

symptoms, body composition, and cardiovascular parameters in
middle-aged women: a randomized, double-blind, placebo-controlled
pilot study
Masakazu Terauchi, MD, PhD, NCMP,1 Noe Horiguchi, BS,2 Asuka Kajiyama, MD,2
Mihoko Akiyoshi, PhD,2 Yoko Owa, BS,2 Kiyoko Kato, BS,2 and Toshiro Kubota, MD, PhD2
Abstract
Objective: This study aims to assess the effects of proanthocyanidinVa class of polyphenol antioxidants extracted
from grape seedsVon menopausal symptoms, body composition, and cardiovascular parameters in middle-aged women.
Methods: We conducted a randomized, double-blind, placebo-controlled study in 96 women aged 40 to 60 years
who had at least one menopausal symptom. The study participants were randomized to receive grape seed extract
tablets containing either low-dose (100 mg/d) or high-dose (200 mg/d) proanthocyanidin, or placebo, for 8 weeks.
Their menopausal symptoms were evaluated using the Menopausal HealthYRelated Quality of Life Questionnaire,
Hospital Anxiety and Depression Scale, and Athens Insomnia Scale before and after 4 and 8 weeks of treatment.
Body composition and cardiovascular parameters were also measured.
Results: A total of 91 women (95%) completed the study. Background characteristics, including age, menopause
status, subjective symptom scores, body composition, and cardiovascular parameters, were similar among the
groups. The following significant changes were observed during the course of the study: (1) physical symptom score,
hot flash score, and (2) Athens Insomnia Scale score decreased in the high-dose group after 8 weeks of treatment; (3)
Hospital Anxiety and Depression Scale Anxiety score and (4) systolic and diastolic blood pressure decreased in the
low-dose and high-dose groups after 4 weeks; and, (5) lastly, muscle mass increased in the low-dose and high-dose
groups after 8 weeks of treatment.
Conclusions: Grape seed proanthocyanidin extract is effective in improving the physical and psychological
symptoms of menopause while increasing muscle mass and reducing blood pressure in middle-aged women.
Key Words: Antioxidants Y Polyphenols Y Flavonoids Y Catechin Y Hot flashes Y Anxiety Y Insomnia Y
Sarcopenia Y Hypertension.

omen in the menopausal transition and postmenopausal period are affected by vasomotor symptoms,
urogenital atrophy, sexual dysfunction, somatic
symptoms, cognitive difficulty, sleep disturbance, and psychological problems. Some of these effects (particularly vasomotor
symptoms and vaginal atrophy) are closely associated with estrogen deficiency, but the exact mechanisms underlying the
other symptoms are not fully understood.1 Postmenopausal
women are also at increased risk for cardiovascular morbidity2
as a net effect of central obesity,3 dyslipidemia,4 hypertension,5
and diabetes6 partly induced by estrogen deficiency.
Received November 6, 2013; revised and accepted December 4, 2013.
From the Departments of 1Womens Health and 2Obstetrics and Gynecology, Tokyo Medical and Dental University, Tokyo, Japan.
Funding/support: This study was supported by Kikkoman Corp.
Financial disclosure/conflicts of interest: M.T. received a research grant
from Kikkoman Corp.
Address correspondence to: Masakazu Terauchi, MD, PhD, NCMP,
Department of Womens Health, Tokyo Medical and Dental University,
Yushima 1-5-45, Bunkyo, Tokyo 113-8510, Japan. E-mail: teragyne@tmd.ac.jp

990

Estrogen therapy remains one of the most effective therapies for vasomotor symptoms and vaginal atrophy, and it
could be beneficial for young and recently postmenopausal
women in relation to improvements in cardiovascular health.7
However, estrogen use has been on the decline since the
publication of the Womens Health Initiative reports on the
negative aspects of hormone therapy.8
Complementary and alternative medicine is widely used
worldwide, especially by women, middle-aged individuals,
and individuals with higher levels of education and higher
incomes.9 In the early 2000s, complementary and alternative
medicine was reported to be used by almost 50% of middleaged women in Western countries to alleviate menopausal
symptoms,9,10 and this value may currently be even higher
given the decline in hormone use.
Proanthocyanidin, a class of polyphenol antioxidants, is an
oligomer of flavan-3-ol (mainly [+]-catechin and [j]-epicatechin)
found in the fruits, bark, leaves, and seeds of many plants.
Proanthocyanidin and flavan-3-ol monomers are known to possess
various biological properties and show anticancer, antioxidant,

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PROANTHOCYANIDIN FOR MIDDLE-AGED WOMEN

analgesic, anti-inflammatory, and antiatherosclerotic activities.11

Furthermore, a proanthocyanidin-rich French maritime pine bark
extract (Pycnogenol) was recently found to alleviate menopausal
symptoms in Taiwanese,12 Italian,13 and Japanese women.14 In a
previous study, gel permeation chromatography analysis showed
that proanthocyanidins extracted from grape seeds generally
have higher molecular weights than those extracted from pine
bark,15 suggesting that biological activities of both extracts could
be different.
In the present study, we examined the effects of grape seed
proanthocyanidin extract (GSPE) on menopausal symptoms,
body composition, and cardiovascular parameters in middleaged women.
METHODS
We conducted a randomized, double-blind, placebocontrolled study at the Menopause Clinic of the Tokyo Medical and Dental University to assess the effects of GSPE.
Japanese women aged 40 to 60 years with at least one
menopausal symptom were eligible for the study. Those who
had already been treated with estrogen, herbal medicine, or
psychotropic agents were excluded.
The participants were randomized to receive grape seed extract tablets that contained either low-dose (100 mg/d; n = 33)
or high-dose (200 mg/d; n = 32) proanthocyanidin, or placebo
(n = 31), for 8 weeks. The grape seed extract with concentrated (85%) proanthocyanidin (Gravinol) is a product of
Kikkoman Biochemifa Company (Tokyo, Japan). The remaining
approximately 15% of the extract mainly consists of falvan-3-ol
monomers such as catechin, epicatechin, and epicatechin gallate.
The low-dose and high-dose GSPE and placebo tablets, indistinguishable in shape, weight, and color, were manufactured and
packaged by Kikkoman Biochemifa Company. The women were
instructed to take four tablets per day at any time of the day; each
tablet contained 50, 25, or 0 mg of GSPE.
The participants were classified as follows: premenopausal
(regular menstrual cycles in the past 3 mo), in the menopausal
transition (a menstrual period within the past 12 mo but a
missed period or irregular cycles in the past 3 mo), postmenopausal (no menstrual period in the past 12 mo), or had surgical menopause (hysterectomy).
The menopausal symptoms of the participants were evaluated using the Menopausal HealthYRelated Quality of Life
(MHR-QOL) Questionnaire, Hospital Anxiety and Depression Scale (HADS), and Athens Insomnia Scale (AIS) before
and after 4 and 8 weeks of treatment.
The MHR-QOL Questionnaire, developed and validated in
our clinic,16<21 is a modification of the Womens Health
Questionnaire22,23 and contains 38 items scored on a fourpoint or binary scale covering four major domains (physical
health, mental health, life satisfaction, and social involvement)
of a womans health during menopause. The physical health
domain consists of nine items that assess somatic (nausea,
dizziness, numbness, muscle and joint pains, tiredness, and
headaches), urinary (frequent urination), and vasomotor (hot
flashes and night sweats) symptoms. Higher scores on the

items indicate worse physical function (0 point, none to once

per month; 1 point, 1-2 times per week; 2 points, 3-4 times per
week; 3 points, almost every day). The total score on the nine
items in the physical health domain was defined as the
Bphysical symptom score.[
HADS is a questionnaire that was developed by Zigmond
and Snaith24 as a reliable instrument for screening clinically
significant anxiety and depression in women visiting a general
medical clinic, and it was translated into Japanese by Zigmond
et al.25 It has seven items (odd items) composing the anxiety
subscale and another seven items (even items) composing the
depression subscale. Women respond to these items using a
four-point Likert scale. Women who received a score of 8 to
10 points were considered likely to be experiencing anxiety or
depression, and those who received a score of 11 to 21 points
were considered to be definitively experiencing anxiety or
depression.
The AIS was developed as a brief and easy-to-administer
self-assessment questionnaire for estimating severity of insomnia defined according to the International Classification
of Diseases Tenth Revision, and its internal consistency and
test-retest reliability have been confirmed.26 The scale consists of eight items: difficulty with sleep induction; awakening
during the night; early morning awakening; total sleep time;
overall quality of sleep; and problems with sense of wellbeing, overall functioning, and sleepiness during the day.
Each item in the AIS can be rated from 0 to 3 (0, no problem at
all; 3, a very serious problem), and a total score of 6 is
regarded as the optimum cutoff for a diagnosis of insomnia.27
The body composition of the participants, including height,
weight, body mass index, fat mass, lean mass, and muscle mass,
was assessed using a body composition analyzer (MC190-EM;
Tanita, Tokyo, Japan). Their cardiovascular parameters, including systolic blood pressure, diastolic blood pressure, heart
rate, and cardioankle vascular index, were measured using
a vascular screening system (VS-1000; Fukuda Denshi,
Tokyo, Japan).
The study protocol was reviewed and approved by the
Tokyo Medical and Dental University Review Board, and a
written informed consent form was obtained from all participants. The study was conducted in accordance with the Declaration of Helsinki.
All statistical analyses were performed with SAS version 9.2
(SAS Institute, Cary, NC) using one-way analysis of variance,
W2 test, Kruskal-Wallis test, Wilcoxon signed rank test, MannWhitney U test, paired t test, and unpaired t test. P G 0.05 was
considered statistically significant.
RESULTS
A total of 96 middle-aged women were enrolled in the
study and randomized to the low-dose group (n = 33), highdose group (n = 32), or placebo group (n = 31); of these, 91
(95%) completed the 8-week study (Fig. 1). Their mean age
was 49 to 50 years; 40% to 48% of the women were
premenopausal, whereas 52% to 60% were in the menopausal
transition, were postmenopausal, or had surgical menopause.
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991

TERAUCHI ET AL

FIG. 1. Participant disposition.

No statistically significant differences in any of the endpoint parameters at baseline were observed among the study
groups (Table).
First, we evaluated the changes in physical symptoms in the
three groups (high-dose, low-dose, and placebo groups). The
mean physical symptom score for the nine items in the physical health domain of the MHR-QOL Questionnaire significantly improved in the high-dose group after 8 weeks of
treatment (Fig. 2A). The mean score for hot flashes similarly
improved in the high-dose group after 8 weeks (Fig. 2B).
Next, we evaluated the changes in psychological symptoms
in the study groups. The mean HADS-Depression subscale
score did not change significantly in any group (Fig. 3A),
whereas the mean HADS-Anxiety subscale score improved
in both low-dose and high-dose groups after 4 weeks of
treatment. The change in HADS-Anxiety subscale score
from baseline to 8 weeks was significantly higher in the highdose group than in the placebo group (Fig. 3B). The mean

AIS score also improved in the high-dose group after 8 weeks

(Fig. 3C).
The mean body weight and fat mass did not change in any
of the study groups (Fig. 4A, B), whereas the mean lean mass
and muscle mass increased significantly in the both low-dose
and high-dose groups after 8 weeks of treatment. The changes
in lean mass and muscle mass from baseline to 8 weeks were
significantly higher in the low-dose and high-dose groups than
in the placebo group (Fig. 4C, D).
Finally, we evaluated the changes in cardiovascular parameters. Although the mean heart rate did not change significantly in any group (data not shown), the mean systolic
and diastolic blood pressure were significantly reduced in both
low-dose and high-dose groups after 4 weeks of treatment.
The change in diastolic blood pressure from baseline to
8 weeks was significantly higher in the low-dose and highdose groups than in the placebo group (Fig. 5A, B).
DISCUSSION
In this randomized, double-blind, placebo-controlled study,
grape seed extract with concentrated amounts of the polyphenol antioxidant proanthocyanidin improved menopausal
symptoms (including hot flashes, anxiety, and insomnia), increased muscle mass, and reduced blood pressure in middleaged women.
In a series of randomized controlled trials evaluating the
effects of the proanthocyanidin-rich French maritime pine
bark extract (Pycnogenol), the product consistently alleviated
menopausal symptoms in middle-aged women.12<14 In the first
report on 155 Taiwanese women who completed a 6-month
study, 200 mg/day of the same pine bark extract alleviated

TABLE. Baseline characteristics of the study participants

Placebo (n = 29)
Age and menopause status
Age, mean (SD), y
Premenopausal/in menopausal transition/postmenopausal/
had surgical menopause, %
Physical symptoms, mean (SD)
Physical symptom score
Hot flash score
Psychological symptoms, mean (SD)
HADS-Depression subscale score
HADS-Anxiety subscale score
Athens Insomnia Scale score
Body composition, mean (SD)
Height, cm
Weight, kg
Body mass index, kg/m2
Fat mass, kg
Lean mass, kg
Muscle mass, kg
Cardiovascular parameters, mean (SD)
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
Heart rate, minj1
Cardioankle vascular index
HADS, Hospital Anxiety and Depression Scale.
a
One-way analysis of variance.
b 2
W test.
c
Kruskal-Wallis test.

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Menopause, Vol. 21, No. 9, 2014

49.8 (5.2)
48.3/20.7/13.8/17.2

Low dose (n = 32)

49.2 (5.3)
43.8/21.9/34.4/0.0

High dose (n = 30)

49.8 (4.7)
40.0/16.7/33.3/10.0

P
0.88a
0.20b

5.3 (3.8)
0.4 (0.9)

5.7 (3.5)
0.5 (0.8)

5.5 (3.0)
0.6 (1.1)

0.76c
0.66c

3.8 (2.9)
4.8 (2.9)
4.2 (3.5)

4.3 (3.7)
5.1 (3.0)
3.5 (2.7)

4.3 (2.3)
6.0 (2.9)
4.0 (2.8)

0.49c
0.30c
0.76c

156.3 (4.7)
52.2 (6.6)
21.4 (2.6)
14.0 (5.0)
38.3 (2.8)
36.1 (2.5)

156.5 (5.8)
52.4 (7.1)
21.4 (3.0)
14.3 (5.4)
38.1 (2.8)
35.9 (2.6)

157.2 (4.3)
52.7 (6.6)
21.3 (2.6)
14.2 (5.0)
38.5 (2.4)
36.3 (2.2)

0.75a
0.96a
0.99a
0.97a
0.79a
0.79a

122.4 (15.9)
75.9 (9.0)
63.8 (11.1)
7.24 (0.77)

122.5 (13.8)
79.9 (9.7)
63.8 (8.5)
7.26 (0.71)

119.4 (14.1)
78.0 (11.7)
63.1 (6.5)
7.15 (0.83)

0.65a
0.31a
0.94a
0.84a

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PROANTHOCYANIDIN FOR MIDDLE-AGED WOMEN

FIG. 2. Physical symptom score (A) and hot flash score (B) before and after
the intervention. Data are presented as mean and standard error. *P G 0.05
versus baseline, Wilcoxon signed rank test.

every symptom listed in the Womens Health Questionnaire,

whereas the placebo improved poor memory alone.12 In the
second report on 65 Italian women who completed an 8-week
study, 100 mg/day of the extract alleviated 28 of 33 symptoms
listed in the Menopause Symptoms Questionnaire, whereas
the placebo did not improve any symptom.13 Sleep disorders
were among the symptoms that the extract failed to alleviate
in the Italian study. In contrast to these previous studies, the
most recent report on 156 Japanese women who completed a
12-week study showed marked placebo effects on menopausal
symptoms14: compared with the placebo, 60 mg/day of French
maritime pine bark extract (Pycnogenol) improved the overall
Kupperman index and the scores on a few Womens Health
Questionnaire items, such as vasomotor symptoms, insomnia,
and tiredness. In line with these reports on pine bark extract,
the present study found that GSPE 200 mg/day improved the
overall physical symptom score, hot flash score, and AIS
score after 8 weeks of treatment (Figs. 2 and 3). A more remarkable improvement was observed in the anxiety domain,
as the HADS-Anxiety subscale score decreased in both the
high-dose and the low-dose GSPE groups as early as 4 weeks
after treatment initiation (Fig. 3B), confirming the beneficial

effects of the polyphenol antioxidant on both physical and

psychological symptoms in middle-aged women.
Although the effects of proanthocyanidin (which does not
bind to estrogen receptors) on menopausal symptoms have
generally been attributed to its antioxidant activity,12,13 the
exact mechanism remains to be elucidated. A neurobehavioral
study in rats, for example, showed that the proanthocyanidinrich fraction isolated from the bark of Croton celtidifolius
has hypnosedative and anxiolytic activities, presumably acting through GABAA receptors,28 which might partly explain
the effects of GSPE on improving anxiety in middle-aged
women, as seen in our study.
To our knowledge, ours is the first report, in animals or
humans, to show that proanthocyanidin affects body composition. After 8 weeks of treatment, GSPE 200 and 100 mg/day
both increased muscle mass in the middle-aged women in our
study (Fig. 4). In a pair of animal studies, Pajuelo et al showed
that GSPE stimulates mitochondrial function in skeletal muscle cells specifically by increasing their capacity to oxidize
pyruvate and by reducing muscle reactive oxygen species
generation in normal29 and obese30 rats. This may be the underlying mechanism by which the polyphenol antioxidant affects muscle mass.
The effects of GSPE on blood pressure are well documented.
In an in vitro study investigating the effects of wine and grape
juice on increasing nitric oxide production, Fitzpatrick et al31
showed that the fraction most active in inducing endotheliumdependent vasorelaxation was proanthocyanidin. In a metaanalysis of nine randomized controlled trials focusing on the
effects of grape seed extract on cardiovascular risk markers,
Feringa et al32 estimated the mean decrease in systolic blood
pressure induced by grape seed extract to be j1.54 mm Hg.
They also showed that grape seed extract reduces heart rate by
an average of 1.42 beats/minute but does not affect diastolic
blood pressure significantly. On the other hand, a 12-week
treatment with 200 mg/day of the pine bark extract Flavangenol
failed to reduce systolic blood pressure in 130 men and women
with increased cardiovascular risks.33 The pine bark extract
Pycnogenol in Taiwanese perimenopausal women decreased
systolic blood pressure from 116.4 to 111.9 mm Hg and
diastolic blood pressure from 72.1 to 69.6 mm Hg after
6 months of treatment with 200 mg/day of the product.12 Neither 100 nor 60 mg/day of the product induced any significant
changes in blood pressure in the Italian or Japanese study,
respectively.13,14 Compared with these previous findings, the
observed effects of GSPE on reducing blood pressure in
middle-aged women in the current study are more remarkable.
The mean systolic and diastolic blood pressure decreased by
approximately 5 mm Hg in both the low-dose and the highdose groups after 8 weeks of treatment (Fig. 5). This effective
reduction in blood pressure with GSPE treatment may suggest
the high bioactivity of the polyphenol antioxidant used. In an
animal study, the same GSPE as that used in the current trial was
shown to reduce arterial pressure in ovariectomized spontaneously hypertensive rats, presumably by reducing superoxide
production.34
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993

TERAUCHI ET AL

FIG. 3. Hospital Anxiety and Depression Scale (HADS)-Depression subscale (A), HADS-Anxiety subscale (B), and Athens Insomnia Scale (C) scores
before and after the intervention. Data are presented as mean and standard error. *P G 0.05, **P G 0.01 versus baseline, Wilcoxon signed rank test. #P G 0.05,
change from baseline versus placebo, Mann-Whitney U test.

One of the major limitations of our study was that the participants were administered grape seed extract with concentrated proanthocyanidin, and not the polyphenol antioxidant

itself. We cannot exclude the possibility that some effects on

women in the low-dose or high-dose groups were caused by
coexistent falvan-3-ol monomers or some unknown molecules

FIG. 4. Body weight (A), fat mass (B), lean mass (C), and muscle mass (D) before and after the intervention. Data are presented as mean and standard
error. *P G 0.05 versus baseline, paired t test. #P G 0.05, change from baseline versus placebo, unpaired t test.

994

Menopause, Vol. 21, No. 9, 2014

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PROANTHOCYANIDIN FOR MIDDLE-AGED WOMEN

middle-aged women while increasing muscle mass and reducing blood pressure.

REFERENCES

FIG. 5. Systolic blood pressure (A) and diastolic blood pressure (B)
before and after the intervention. Data are presented as mean and standard
error. *P G 0.05, **P G 0.01, ***P G 0.001 versus baseline, paired t test.
##
P G 0.01, ###P G 0.001, change from baseline versus placebo, unpaired t test.

concurrently extracted from grape seeds. Second, owing to

the small sample size and short duration of the study, some
parameters that showed significant changes within groups from
baseline to 8 weeks failed to show significant differences when
these parameters were compared among the groups. Finally,
the women enrolled in the current study were quite diverse
(premenopausal and postmenopausal women with a variety
of symptoms). This is a symptom-related study not meeting the
necessary criteria for a vasomotor study. Furthermore, the
women were generally in good healthVthe reason that they
could participate in a double-blind, placebo-controlled study of
a dietary supplement. Women with more serious physical or
psychological symptoms, more remarkable sarcopenia, or more
severe hypertension could present magnified effects of GSPE
on menopausal symptoms, muscle mass, or blood pressure.
Further investigation, with all the limitations of this pilot study
considered, is warranted.
CONCLUSIONS
GSPE has been shown to be effective in improving the
physical and psychological symptoms of menopause in

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