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PHYTOTHERAPY RESEARCH

Phytother. Res. (2017)


Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/ptr.5841

Phytoestrogen-Rich Natural Preparation for


Treatment of Climacteric Syndrome and
Atherosclerosis Prevention in Perimenopausal
Women

T. V. Kirichenko,1† V. A. Myasoedova,2,3*† V. A. Orekhova,1,4 A. L. Ravani,2 N. A. Nikitina,4


A. V. Grechko,5 I. A. Sobenin4 and A. N. Orekhov1,3
1
Institute for Atherosclerosis Research, Skolkovo Innovative Center, 143025, Moscow, Russia
2
Centro Cardiologico Monzino, IRCCS, 20138, Milan, Italy
3
Institute of General Pathology and Pathophysiology, 125315, Moscow, Russia
4
Russian Cardiology Research and Production Complex, Moscow, Russia
5
Federal Scientific Clinical Center for Resuscitation and Rehabilitation, 109240, Moscow, Russia

The present study evaluated the risks and benefits of phytoestrogen treatment in healthy perimenopausal women
in relation to the dynamics of climacteric syndrome and progression of atherosclerosis. Study participants were
treated with placebo or phytoestrogen-rich natural preparation Karinat based on grape (Vitis vinifera) seeds,
green tea (Camellia sinensis) leaves, hop (Hunulus lupulus) cone powder and garlic (Allium sativum) powder.
The dynamics of climacteric syndrome was evaluated by Kupperman Index and Utian Quality of Life Scale.
Atherosclerosis progression was evaluated by measuring carotid intima-media thickness. Significant changes of
climacteric syndrome’s severity in both Karinat and placebo groups (p = 0.005 and p = 0.001) were obtained after
24 months of follow-up. Detailed analysis of Kupperman Index suggested that Karinat possessed a significant
effect on nervousness (p = 0.010), weakness (p = 0.020) and formication (p = 0.010). A significant improvement
of medical (p = 0.070) and emotional (p = 0.060) components of Kupperman Index and Utian Quality of Life
Scale was also observed in Karinat group. However, difference in carotid intima-media thickness between the
two groups was not statistically significant at follow-up. A slight positive effect of phytoestrogens on climacteric
syndrome manifestations was demonstrated in this study. Karinat can be used for alleviation of climacteric
syndrome and cardiovascular disease prevention in perimenopausal women. Copyright © 2017 John Wiley &
Sons, Ltd.
Keywords: perimenopause; atherosclerosis; climacteric syndrome; phytoestrogens; phytoestrogen-rich natural preparation; carotid
intima-media thickness.

bioflavonoids that have a structure similar to endogenous


INTRODUCTION
oestrogens. Several classes of phytoestrogens have need
described, including isoflavones (Gaspard et al., 1999;
A sharp decline of oestrogen level in the postmenopausal Glazier and Bowman, 2001).
period is associated with increased risk of cardiovascular Isoflavone-rich plant foods include legumes (of which
disease (CVD; Colditz et al., 1987). Numerous studies soybeans are the most studied), pomegranates, figs,
have demonstrated that oestrogens have an indirect sunflower seeds, cabbages and red clovers. Favourable
protective effect on lipid and glycaemic profiles, as effect of phytoestrogens on CVD dynamics has been
well as the endothelial function (Rossi et al., 2002; Rossi demonstrated in several epidemiological and clinical
et al., 2005). Oestrogen replacement therapy is commonly studies (Lamartiniere et al., 1995; Colacurci et al.,
recommended in early postmenopause for climacteric 2005). According to the current knowledge, incidence
symptoms reduction and for CVD and osteoporosis of coronary heart disease in Asia is lower than in other
prevention. However, long-term use of oestrogen parts of the world, and that is probably associated with
and progestin hormone therapy (HT) not only was a higher consumption of products containing
associated with increased risk of malignant hormone- phytoestrogens. One small sample study failed to
dependent tumours but also lacked a beneficial effect demonstrate a positive influence of soy isoflavones on
on cardiovascular risk (Krieger et al., 2005; Koh et al., blood lipid levels in healthy women (Lamartiniere
2004). Plant-derived estrogens, also known as et al., 1995). On the other hand, soybeans and
phytoestrogens, can be considered an alternative strategy isoflavone genistein had a positive influence on
for CVD prevention. Phytoestrogens are represented by endothelial function due to a regulatory effect on
endothelial proliferation, apoptosis and leukocyte
adhesion (Sandoval et al., 2010). In the previous studies,
* Correspondence to: Veronika A. Myasoedova, Unit of Atherosclerosis we have investigated the possible antiatherosclerotic
Prevention, Centro Cardiologico Monzino, IRCCS, Via Carlo Parea 4,
20138 Milan, Italy.
effect of phytoestrogens in an ex vivo model (Nikitina
E-mail: veronika.myasoedova@gmail.com; veronika.myasoedova@ccfm.it et al., 2006). We have demonstrated the benefits of

Dr Kirichenko and Dr Myasoedova contributed equally to this work. phytoestrogen therapy in relation to atherosclerosis
Received 12 January 2017
Revised 05 May 2017
Copyright © 2017 John Wiley & Sons, Ltd. Accepted 06 May 2017
T.V. KIRICHENKO ET AL.

progression in healthy postmenopausal women Kupperman Index was carried out by filling a patient
(Myasoedova et al., 2016). The aim of the present study questionnaire containing 11 questions characterizing
was to test the hypothesis that phytoestrogens may the different groups of symptoms. The original index
provide dual beneficial effect both on the development value equal to 1–6 score corresponds to a mild degree
of atherosclerosis and manifestations of climacteric of climacteric syndrome, equal to 7–11 points (moderate
syndrome in perimenopausal women. Therefore, the severity), from 12 to 16 points (severe). Quality-of-life
primary outcome was carotid intima-media thickness assessment on the UQOLS was carried out by filling in
(c-IMT) progression rate used as a quantitative the patient questionnaire consisting of 23 questions.
measure of carotid atherosclerosis. The secondary Finally, five values of quality of life were formed
outcome was the change of climacteric syndrome according to the answers in the questionnaire,
severity. describing the overall quality of life and the four
constituent components: emotional, sexual, social and
medical.
Carotid intima-media thickness was detected by high-
METHODS resolution B-mode ultrasound using a SSI-1000 scanner
(SonoScape, China) equipped with a 7.5-MHz linear
Study subjects. A total of 238 perimenopausal women array probe. Carotid ultrasound has been carried out
were enrolled in the Outpatient Clinics No 202 at by one researcher throughout the study. The far walls
Moscow State University. All study participants were of the right and left common carotids, the bifurcation
asymptomatic for CVD and aged between 40 and and the internal and the external carotid arteries were
55 years. The inclusion criteria were absence of visualized. The c-IMT measurements of the first
menstruation for at least 6 months and no more than centimetre of the common carotid artery, in three
24 months, last spontaneous menses occurring after different projections (anterior, lateral and posterior),
age 40, good general health, plasma follicle-stimulating were performed by using a dedicated software M’ATH
hormone level > 35 Ui/L, mammography without nodal (Metris, SRL France). The average of these measures
form of mastopathy or breast cancer signs and absence was considered as an integral indicator of intima-media
of hypolipidaemic therapy or HT within last 6 months. thickness.
Subjects with personal history or diagnostic of nodal
form of mastopathy or breast cancer, coronary heart
disease or stroke, chronic kidney disease, liver Preparation and distribution of phytomedicines.
dysfunction, untreated high BP, type 2 diabetes, obesity Phytoestrogen-rich natural preparation used in this
(BMI > 30 kg/m2), cigarette smoking, deep vein study was officially registered as a dietary supplement
thrombosis or pulmonary embolism were excluded from ‘Karinat’ and manufactured by INAT-Farma (Moscow,
the study. The study protocol has been approved by the Russia). The phytopreparation Karinat was presented
Ethics Community of Outpatient Clinics no 202, as 500-mg capsules containing 100 mg of garlic
Moscow State University, and all subjects gave written (A. sativum), 40 mg of grape (V. vinifera) seed extract
informed consent upon enrolment. The work was (water ethanol extract), HPLC identification of the
conducted in accordance with the Declaration of authenticity of the extract, UV measurement of
Helsinki. proanthocyanidins (>95%), 115 mg of green tea
(C. sinensis) leaves, 160 mg of hop (H. lupulus) cones
and 85 mg of excipient (Nikitina et al., 2006; Sobenin
Study design. This was a randomized double-blind et al., 2016). The same capsule size and colour were used
placebo-controlled study of healthy perimenopausal for placebo, implemented with excipient only. Three
women aimed to provide prospective data on the risks capsules a day for each participant were given
and benefits of phytoestrogen therapy on the dynamics independently of meal.
of climacteric syndrome and atherosclerosis
progression. The subjects were randomly assigned to
receive Karinat (n = 124) capsules containing 500 mg
of grape (Vitis vinifera) seeds, green tea (Camellia Statistical analysis. Results were expressed in terms of
sinensis) leaves, hop (Hunulus lupulus) cone powder means and standard deviation. Statistical significance
and garlic (Allium sativum) powder or placebo was evaluated by using SPSS 10.1.7 statistical program
(n = 114). The study participants were instructed to take package (SPSS Inc., USA). Significance was defined at
three capsules per day for 24 months. According to the the 0.05 level of confidence. The ultrasound data and
schedule of the study, all participants had the following the changes from baseline to the mean of follow-up
visits: at baseline, after 1 year and a final visit after visits were analyzed by a two-way ANCOVA and paired
2 years. The endpoints of the study were dynamics of two-tailed t-test.
the climacteric syndrome and annual rate of
atherosclerosis progression estimated by the changes in
c-IMT. Furthermore, blood lipid profile, body mass
index and blood pressure were measured. RESULTS

No significant differences between groups in baseline


Measurements. The dynamics of climacteric syndrome parameters such as age, BMI, blood pressure, serum
was evaluated by using Kupperman Index and Utian lipids, mean c-IMT and the characteristics of
Quality of Life Scale (UQOLS) (Baird et al., 1995). climacteric syndrome were observed during treatment.
The evaluation of complaints of menopausal disorder The duration of amenorrhea period of women
Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
PHYTOESTROGENS AND ATHEROSCLEROSIS IN PERIMENOPAUSE

participating in the study was 6–24 months, and the Kupperman Index: vasomotor reactions, paresthesias,
follicle-stimulating hormone level was 91.3 (±SD insomnia, nervousness, melancholia, vertigo, weakness,
11.4) Ui/L in the Karinat group and 91.8 (±SD arthralgia, myalgia, headache, palpitations and
9.3) Ui/L in the placebo group. The mean c-IMT was formication (Table 3). The index was determined after
0.993 (±SD 0.172) mm in the Karinat group and a detailed examination of each symptom: The placebo
0.984 (±SD 0.178) mm in the placebo group at the first had no effect on the severity of nervousness
examination. Baseline characteristics are shown in (p = 0.160), feelings of formication (p = 0.230) and
Table 1. feelings of weakness and fatigue (p = 0.860).
The assessment of menopausal symptom severity of The Utian Quality of Life Scale has not changed
life quality revealed that, at baseline, the original significantly in both Karinat and placebo groups after
Kupperman Index was 11.4 (±SD 1.7) scores in the the follow-up period (p = 0.364 and p = 0.672
Karinat group and 11.9 (±SD 1.6) scores in the placebo respectively). The analysis of the components (social,
group, corresponding to a moderate severity of medical, emotional and sexual) of the UQOL score
climacteric syndrome. The UQOLS of quality of life in was conducted. There was a trend towards improvement
the Karinat and placebo groups were 45.9 (±SD 1.7) in medical and emotional components of UQOLS in the
and 45.6 (±SD 1.9) scores respectively, suggesting a very Karinat group in contrast to the placebo (Table 4), but
low quality of patients’ life. the differences did not reach statistical significance
The study participants underwent re-examination (p = 0.070 and p = 0.060 respectively).
after 1 and 2 years of follow-up. There were no
significant changes in lipid parameters, BMI and blood
pressure. The ultrasonographic examination of the
carotid arteries was performed at baseline and after 1 DISCUSSION
and 2 years of follow-up. The c-IMT at baseline was
not different between the two groups. After 1 year, a In this randomized double-blinded placebo-controlled
slight increase of atherosclerosis progression was controlled trial, the beneficial effect of phytoestrogen-
observed and c-IMT was decreased by 0.004 (±SD rich herbal preparation Karinat was significant for
0.102) mm in the group receiving Karinat and by 0.006 climacteric syndrome in perimenopausal women.
(±SD 0.110) mm in the placebo group; these changes Phytoestrogens, in particular isoflavones, have a similar
were not statistically significant. At the end of the study, chemical structure and similar proprieties to estradiol
there was an increase of c-IMT in both groups, by 0.010 and may play a positive role in the treatment of
(±SD 0.054) in the Karinat group and by 0.011 (±SD climacteric syndrome in perimenopausal women.
0.065) in the placebo group; however, these changes also Climacteric or vasomotor symptoms are prominent
did not reach a statistical significance. The data are features of perimenopausal and early postmenopausal
presented in Table 2. periods, affecting around 70% of women and reducing
After 1 year of follow-up, the Kupperman Index in life quality in more than 20% of them, which may last
the Karinat and placebo groups decreased by 2.7 (±SD from several weeks to many years (Santen et al., 2010;
4.3) and 2.3 (±SD 4.5) scores and amounted to 8.7 Gass et al., 2012). In our study, we found that after 12
(±SD 4.7) and 8.9 (±SD 4.3) scores respectively. After and 24 months of Karinat or placebo administration,
2 years, the same index decreased by 3.2 (±SD 2.3) Blatt–Kupperman menopausal index, parameters of
and 3.1 (±SD 1.5) scores and amounted to 8.2 (±SD climacteric syndrome evaluation were significantly
2.7) and 8.1 (±SD 2.3) scores respectively. Therefore, decreased in both groups. Significant involution of some
statistically significant changes of the severity of climacteric symptoms in the placebo group can be
climacteric syndrome were detected in both Karinat explained as patient’s compliance in healthy lifestyle
and placebo groups, p = 0.005 and p = 0.001 respectively. and diet. A more detailed analysis of Kupperman Index
The severity of climacteric syndrome and its dynamics components suggests that Karinat supplementation has
was assessed by the following parameters of a significant effect on nervousness, weakness and

Table 1. Baseline characteristics of study participants

Characteristics Karinat Placebo Difference between groups, p

Age, years 52.2 (±SD 2.2) 52.5 (±SD 1.2) 0.940


2
BMI, kg/m 27.2 (±SD 2.4) 27.6 (±SD 1.1) 0.721
SBP, mm Hg 120 (±SD 3) 119 (±SD 7) 0.887
DBP, mm Hg 77 (±SD 6) 78 (±SD 3) 0.781
Follicle-stimulating hormone, Ui/L 91.3 (±SD 11.4) 91.8 (±SD 9.3) 0.840
Total cholesterol, mmol/L 5.8 (±SD 0.7) 5.6 (±SD 1.1) 0.231
Triglycerides, mmol/L 1.4 (±SD 0.7) 1.3 (±SD 0.6) 0.121
HDL, mmol/L 2.5 (±SD 0.7) 2.8 (±SD 1.1) 0.059
LDL, mmol/L 2.4 (±SD 0.6) 2.2 (±SD 1.2) 0.289
c-IMT, mm 0.993 (±SD 0.172) 0.984 (±SD 0.178) 0.697
Kupperman Index, scores 11.4 (±SD 1.7) 11.2 (±SD 1.6) 0.874
UQOLS, scores 45.9 (±SD 1.7) 45.6 (±SD 1.9) 0.930

Significant difference between groups at p < 0.05. SBP, systolic blood pressure; DBP, diastolic blood pressure; UQOLS, Utian Quality of Life
Scale; HDL, high-density lipoprotein; LDL, low-density lipoprotein; c-IMT, carotid intima-media thickness.

Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
T.V. KIRICHENKO ET AL.

Table 2. Intima-media thickness (IMT) dynamics after 1 and 2 years from baseline

Time after inclusion Karinat Placebo

1 year !0.004 (±SD 0.102), p = 0.644 !0.006 (±SD 0.110), p = 0.559


2 year 0.010 (±SD 0.054), p = 0.499 0.011 (±SD 0.065), p = 0.506

IMT changes are presented in mm, significant changes at p < 0.05.

formication compared with placebo. Although there colleagues have shown the antiatherosclerotic effect of
was no difference between groups in Utian Quality of HT on c-IMT progression in women with early
Life Scale, the analysis of components shows postmenopause but not late postmenopause (Hodis
improvement of medical and emotional components et al., 2016). Treatment with oestrogen-containing HT
after 12 and 24 months of Karinat administration. Our in comparison with placebo was associated with a slower
result provides a slight effect on the natural history of progression of c-IMT in women, when administration of
some involution of climacteric symptoms but does not the HT was started within 6 years after menopause but
induce important changes in quality of life. Comparable not more than 10 years. However, in our recently
results were obtained by other randomized clinical trials published study, we have demonstrated a beneficial
showing beneficial effect of phytoestrogen effect of phytoestrogen-rich herbal preparation Karinat
supplementation on Kupperman Index (Lipovac et al., on atherosclerosis progression by using c-IMT in women
2011; Lee et al., 2010). Recently, a systematic review with menopause at least for the last 5 years
and meta-analysis determined the association of (Myasoedova et al., 2016; Sobenin et al., 2016). Despite
phytoestrogens and other plant-based therapies with the fact that increase of c-IMT was observed in both
same menopausal symptoms (Franco et al., 2016). The herbal preparation and placebo groups, in Karinat
results of analysis from 62 studies, including 6653 recipients, the increase of c-IMT was minimal and not
women, identify a strong association of phytoestrogens significant, whereas in the placebo group, the increment
with the decrease of menopausal symptoms such as hot was significantly higher and accounted for 111 μm per
flashed [pooled mean difference of changes, !1.31 year (Myasoedova et al., 2016).
(95% CI, !2.02 to !0.61)] and vaginal dryness score Some studies were dedicated to evaluate the
[pooled mean difference of changes, !0.31 (95% CI, atherosclerosis progression in postmenopausal women
!0.52 to !0.10)] but not the night sweats [pooled mean (Rossi et al., 2011; Hodis et al., 2016; Colacurci et al.,
difference of changes, !2.14 (95% CI, !5.57 to 1.29)]. 2007; Myasoedova et al., 2016), but little is known
Currently, ‘timing hypothesis’ of antiatherosclerotic about atherosclerosis progression in perimenopause.
treatments using HT for CVD prevention in Very interesting data were recently shown in the Los
postmenopausal women is widely discussed in literature. Angeles Atherosclerotic Study. It was confirmed that
Women’s Health Initiative and Heart and perimenopausal period was associated with vascular
Estrogen/Progestin Replacement Study investigators compliance reduction and HT affects arterial
conducted a large number of subgroup analysis and distensibility only taken during transitional period of
identified several characteristics that modify risk for menopause (Shufelt et al., 2016). For determination
CVD events in women with HT (Bassuk and Manson, of atherosclerosis progression estimated by changes
2014). Younger women (<60 years) not more than in c-IMT, in the present study, we have enrolled young
10 years of menopause, absence of metabolic syndrome, perimenopausal women aged from 40 to 55 years.
normal lipids profile and absence of factor V Leiden At baseline, there was no significant difference in
genotype are defined the optimal candidate for HT use clinical and biochemical characteristics between
in postmenopause for CVD prevention. Hodis and phytoestrogen-rich herbal preparation and placebo
groups. After 12 and 24 months of follow-up, we did
not observe significant dynamics in atherosclerosis
Table 3. Involution of climacteric symptoms over observation progression in both groups. Moreover, c-IMT in the
period Karinat group was not significantly decreased after
1 year of administration and not significantly increased
Component Karinat Placebo
after 2 years of administration. Similar results were
Vasomotor 0.001 0.001 obtained in the placebo group. Absence of changes
Paresthesias 0.010 0.010 in c-IMT progression in both groups may be explained
Insomnia 0.002 0.002 by low natural dynamics of atherosclerosis progression
Nervousness* 0.010 0.160
Melancholia 0.010 0.020
Table 4. Dynamics of quality of life over observation period
Vertigo 0.010 0.001
Weakness/fatigue* 0.020 0.860 Component of Utian Quality of Life Scale (UQOLS)KarinatPlacebo
Arthralgia/myalgia 0.001 0.110
Headache 0.003 0.002 Social 0.610 0.290
Palpitations 0.012 0.002 Medical 0.070 0.620
Formication* 0.010 0.230 Emotional 0.060 0.500
Sexual 0.520 0.950
*Changes are significantly different from dynamics in placebo
group at p < 0.05. Significant changes of UQOLS at p < 0.05.

Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)
PHYTOESTROGENS AND ATHEROSCLEROSIS IN PERIMENOPAUSE

in vascular walls because of the young age of our


CONCLUSION
participants. Overall, this study shows results
describing the atherosclerotic profile in
perimenopausal women. Our results suggest that the phytoestrogen-rich natural
One of the main limitations of this study is a preparation Karinat may be employed in
rather small period of observation; 24 months of perimenopausal women because it demonstrated a
follow-up were not enough to observe statically slight positive effect on manifestations of the climacteric
significant changes in atherosclerosis progression in syndrome. Even if the present study, due to the young
perimenopausal women. Taking into account the age of our participants, failed to demonstrate the effect
results from numerous studies that demonstrated the of Karinat on c-IMT progression, our previous study
important increment of risk factors for CVD like has shown the potential effect of this herbal supplement
hypertension, dyslipidaemia, obesity and diabetes on atherosclerosis progression in postmenopausal
(Muka et al., 2016; Modena, 2014; Kacalska-Janssen women. We suggest that the use of phytoestrogen-rich
et al., 2013; Derby et al., 2006) in the perimenopausal natural preparation Karinat may have a beneficial effect
and early postmenopausal women, it is very important for timely CVD prevention not only in postmenopausal
to start with appropriate atherosclerosis prevention. but also in perimenopausal period.
The other limitation is a small sample size, because
of which some of the obtained results did not reach
the statistically significant level. However, preliminary Acknowledgements
data on the variability of the c-IMT progression rate This work was supported by the Russian Science Foundation (grant no
in perimenopausal women of this age in Russian 14-15-00112).
population were not available, and therefore, the
calculation of sample size to reach statistical power
was not feasible. Present data could be useful for a Conflict of Interest
sample size and statistical power calculation for future
studies. The authors declare no conflict of interest.

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Copyright © 2017 John Wiley & Sons, Ltd. Phytother. Res. (2017)