European Journal of Pharmacology 741 (2014) 230236

Contents lists available at ScienceDirect

European Journal of Pharmacology

journal homepage: www.elsevier.com/locate/ejphar

Phytoestrogens and their effects

Alexander V Sirotkin
Constantine the Philosopher University, Nitra and Research Institute of Animal Production, Luianky, Slovak Republic

art ic l e i nf o

a b s t r a c t

Article history:
Received 23 February 2014
Received in revised form
23 July 2014
Accepted 27 July 2014
Available online 23 August 2014

The chemical structure, classication, source, metabolism, physiological and health effects of plant
phytoestrogens and mechanisms of their action are reviewed. The available knowledge suggests that
phytoestrogens can affect a number of physiological and pathological processes related to reproduction,
bone remodeling, skin, cardiovascular, nervous, immune systems and metabolism. Due to these effects,
phytoestrogens and phytoestrogen-containing diet can be useful for the prevention and treatment of
menopausal symptoms, skin aging, osteoporosis, cancer, cardiovascular, neurodegenerative, immune and
metabolic diseases. Possible problems in understanding and application of phytoestrogens (multiple
targets and multiple estrogen receptor dependent and independent mechanisms of action, the
discrepancy between the results of experimental and clinical studies, adequate source of phytoestrogen)
have been discussed.
& 2014 Elsevier B.V. All rights reserved.

Keywords:
Phytoestrogen
Reproduction
Bone
Cardiovascular
Nervous system
Immune system

Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Phytoestrogen classication and structure . . . . . . . . . .
3. Phytoestrogen source and metabolism . . . . . . . . . . . . .
4. Phytoestrogen mechanisms of action . . . . . . . . . . . . . .
5. Phytoestrogens and reproduction . . . . . . . . . . . . . . . . .
6. Phytoestrogen and skin . . . . . . . . . . . . . . . . . . . . . . . . .
7. Phytoestrogen and bone . . . . . . . . . . . . . . . . . . . . . . . .
8. Phytoestrogen and cardiovascular system . . . . . . . . . .
9. Phytoestrogens and metabolism . . . . . . . . . . . . . . . . . .
10. Phytoestrogens and nervous system. . . . . . . . . . . . . . .
11. Phytoestrogen and immune system . . . . . . . . . . . . . . .
12. Phytoestrogens and cancer . . . . . . . . . . . . . . . . . . . . . .
13. Conclusions and possible directions of further studies
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction
Interest of both public and specialists in medicine and functional food production in the physiological role and practical
application of plant bioactive compounds has increased dramatically over the last decade. Of particular interest in relation to

E-mail addresses: sirotkin@cvzv.sk, asirotkin@ukf.sk

http://dx.doi.org/10.1016/j.ejphar.2014.07.057
0014-2999/& 2014 Elsevier B.V. All rights reserved.

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230
231
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human health are the class of compounds known as the phytoestrogens, which includes several groups of non-steroidal estrogens
that are widely distributed within the plant kingdom. There is a
growing body of evidence, that consumption of some these plants
or their molecules could be an additive efcient tool to prevent
and to treat several dysfunctions and diseases related to aging,
mental processes, metabolism, malignant transformation, cardiovascular diseases and reproduction - breast and prostate cancers,
menopausal symptoms, osteoporosis, atherosclerosis and stroke,

S. Alexander V / European Journal of Pharmacology 741 (2014) 230236

and neurodegeneration (see Cassidy, 2003; Tuohy, 2003; Branca

and Lorenzetti, 2005 for review). Some aspects of phytoestrogen
structure, source, metabolism, physiological action, its mechanisms and interrelationships with some disorders are reviewed
below.

231

Bioavailability of isoavones requires an initial hydrolysis of the

sugar moiety by intestinal beta-glucosidases to allow the following
uptake by enterocytes and the ow through the peripheral
circulation. Following absorption, isoavones are then reconjugated mainly to glucuronic and sulfuric acids (Cassidy, 2003;
Chiang and Pan, 2013; Vitale et al., 2013).

2. Phytoestrogen classication and structure

On the basis of their chemical structure and in respect to
biosynthesis patterns, phytoestrogens may be divided in chalcones, avonoids (avones, avonols, avanones, isoavonoids),
lignans, stilbenoids, and miscellaneous classes. Particular attention
should be given to isoavonoids, the subgroup of avonoids which
includes amongst others the chemical groups of isoavones,
isoavanones, pterocarpanes, and coumestans (Dixon, 2004;
Michel et al., 2013). The molecular structures of some selected
phytoestrogens are present in Fig.1.

3. Phytoestrogen source and metabolism

Phytoestrogens are known to be present in fruits, vegetables,
and whole grains commonly consumed by humans. They are
abundant in several edible and/or medicinal plants, belonging
mostly to the Leguminosae family (Dixon, 2004; Michel et al.,
2013). Plant extracts with potential estrogenic activities include
soy, red clover, kudzu, hops, licorice, rhubarb, yam, and chasteberry (Hajirahimkhan et al., 2013). Isoavones are found in
legumesmainly soybeans, axseed is a major source of lignans,
and coumestans are signicantly present in clover, alfalfa and
soybean sprouts. 8-Prenyl avonoids are common in vegetables,
hop and beer. Dietary phytoestrogens are metabolized by intestinal bacteria, absorbed, conjugated in the liver, circulated in
plasma and excreted in urine (Cassidy, 2003). Gut metabolism
seems key to the determination of the potency of action; sometimes the biological effect of dietary phytoestrogens is due to
mainly with their metabolites generated by gut microora (Wang,
2002; Branca and Lorenzetti, 2005). For example, the mammalian
phytoestrogens enterodiol and enterolactone are produced in the
colon by the action of bacteria on the plant precursors matairesinol, secoisolariciresinol, their glycosides, and other precursors
in the diet (Wang, 2002). The estrogenic activity of plant phytoestrogens can be enhanced after metabolization to more active
compounds such as genistein and daidzein by gut microorganisms
(Zhengkang et al., 2006). For instance, the effects of daidzein is
variable depending on individuals and to their ability to convert
daidzein to more active equol that seems to be restricted to
approximately 1/3 of the population (Gil-Izquierdo et al., 2012).

4. Phytoestrogen mechanisms of action

Phytoestrogens are strikingly similar in chemical structure to
the mammalian estrogen, estradiol, and bind to estrogen receptors
alpha and beta with a preference for the more recently described
estrogen receptor beta (Younes and Honma, 2011; Rietjens et al.,
2013; Paterni et al., 2014). These receptors after binding with
ligand are able to move from cytoplasm to the nucleus, bind and
affect the transcription-control regions of DNA or small RNAs and
therefore the expression of specic genes. Furthermore, steroids
are able to bind to receptors of cell surface, promote formation of
cytoplasmic cyclic nucleotides and related protein kinases, which
in turn via transcription factors control the expression of target
genes (Sirotkin, 2014; Yanagihara et al., 2014). Therefore, phytoestrogens can potentially affect all the processes regulated by
estrogens including induction sex hormone binding globulin and
inhibition aromatase (Wang, 2002). Estrogen receptors are present
in different tissues central nervous system (including hypothalamohypophysial axis), gonads, reproductive tract, placenta,
mammary gland, bones, gastrointestinal tract, lung a.o. This
suggests that phytoestrogens may exert tissue specic hormonal
effects (Cassidy, 2003; Younes and Honma, 2011; Bttner et al.,
2013). The estrogen receptor-specic effects may occur too. For
example, estrogen receptors alpha are considered as promoters of
cell proliferation, whilst estrogen receptors beta are in charge for
promoting mainly cellular apoptosis (Rietjens et al., 2013).
Phytoestrogens besides their ability to bind to estrogen receptors, have other biological effects, which are not mediated with
these receptors activation of serotoninergic receptors
(Hajirahimkhan et al., 2013), IGF-1 receptors (Bourque et al.,
2012), binding of free radicals (Wang, 2002; Cassidy, 2003;
McKay and Blumberg, 2007; Vina et al., 2011; Martinchik and
Zubtsov, 2012), inducting DNA methylation (Lim and Song, 2012;
Rietjens et al., 2013), affecting tyrosine kinase, cAMP/protein
kinase A, cGMP/NO, phosphatidylinositol-3 kinase/Akt and
MAP (ERK1,2, p38) kinases (Vina et al., 2011; Bourque et al.,
2012; Ming et al., 2013; Yanagihara et al., 2014), transcription
factors NF-kappaB and DNA topoisomerase activities (Vina et al.,
2011; Ming et al., 2013), histone modication, RNA expression
(Rietjens et al., 2013) and other intracellular regulators of cell cycle

Fig.1. Molecular structure of the most ubiquitous phytoestrogens (from Michel et al., 2013)

232

S. Alexander V / European Journal of Pharmacology 741 (2014) 230236

and apoptosis. These abilities are probably responsible for antioxidant, antiproliferative, antimutagenic and antiangiogenic
effects of phytoestrogens and their ability to promote human
health and longevity (Kurzer and Xu, 1997; Wang, 2002; Cassidy,
2003; Fu et al., 2010; Vina et al., 2011; Lim and Song, 2012;
Hajirahimkhan et al., 2013; Ming et al., 2013). Nevertheless, the
hormonal and non-hormonal mechanisms of phytoestrogen effect
on particular processes listed below are sometimes difcult to
discriminate due to multiple signaling pathways mediating phytoestrogen effects and the insufcient related knowledge. The
current studies and related publications are focused more to
clinical application, than to basic studies of the mechanisms of
phytoestrogen effects.

5. Phytoestrogens and reproduction

The exogenous estrogen-like molecules can both promote and
destroy reproductive processes. For example, isoavone genistein
is able to stimulate animal ovarian progesterone, etradiol and
cAMP production, oocyte maturation and preimplantation zygote
development (Makarevich et al., 1997). Phytoestrogens of green
tea, indian turmeric and other plants inhibited proliferation,
promoted apoptosis and altered the release of steroid hormones
by porcine ovarian cells (Kadasi and Sirotkin, unpublished data).
Consumption of soybean products, which contain high levels of
isoavones, can alter animal sexual development, including
altered pubertal timing, impaired estrous cycling and ovarian
function, and altered hypothalamus and pituitary functions. The
adverse effect of phytoestrogens on human reproduction has not
been reported, but some authors (Vandenplas et al., 2011;
Jefferson and Williams, 2011; Jefferson et al., 2012; Kim and
Park, 2012) donot exclude their existence. For example, the
reproductive consequences of consummation of soybean-based
infant formulas, which increases soy isoavones level in neonate
plasma (Vandenplas et al., 2011), require careful assesment (Tuohy,
2003; Jefferson et al., 2012), although no adverse effect of such
formula on male sexual development has been reported yet
(Cederroth et al., 2010).
On the other hand, exposition of women to phytoestrogens
(isoavones, lignans, coumestans of different botanical sources) in
pre- and postmenopausal period may prevent the menopausal
symptoms induced by declined endogenous estrogen production
hot ashes, vasomotor symptoms, vaginal atrophy a.o., whilst no
negative side-effect of these phytoestrogens on breast and endometrial health have been observed (Kronenberg and Fugh-Berman,
2002; Branca and Lorenzetti, 2005; Bedell et al., 2012). Soy and
black cohosh are reported to be the most promising source of
phytoestrogens, whilst isoavone preparations seem to be less
effective than soy foods (Kronenberg and Fugh-Berman, 2002).
Many post-menopausal women often perceived phytoestrogens in
food supplements as a safer alternative than hormone replacement therapy (Poluzzi et al., 2014). Moreover, unlike hormone
therapy, lignans may not increase clotting risk in postmenopausal
women, thus such supplements may serve as a treatment option
for patients who have contraindications to hormone therapy
(Bedell et al., 2012). Some studies demonstrated a signicant
reduction of somatic-vegetative and psychological symptoms of
menopause under the inuence of soy and Cimicifuga racemosa
phytoestrogens, while urogenital symptomatology was not significantly changed (Wuttke et al., 2002, 2003; Rosic et al., 2013). On
the other hand, other epidemiologic studies failed to detect
signicant effect of red clower on plasma gonadotropin level,
breast density or endometrial thickness (Powles et al., 2008) or
the signicant inuence of either soy or red clower products,
extract of dong quai, ginseng extract, extract and evening primrose

seed oil in ameliorating menopausal symptoms or hot ush

frequency (Wuttke et al., 2003; Krebs et al., 2004; Low Dog,
2005; Eden, 2012). Clinical studies of the effects of hop product
containing phytoestrogens on these parameters provided inconclusive results too (Keiler et al., 2013).
A negative effect of molecules with estrogenic action on male
reproductive hormones, spermatogenesis, sperm capacitation and
fertility has been postulated (Giwercman, 2011; Hess et al., 2011).
There are some reports indicating negative association between
exposure to certain estrogen-like chemical endocrine disrupers
and sperm parameters, but such evidence has not been found
for phytoestrogens (Cederroth et al., 2010; Giwercman, 2011).
Meta-analyses indicated no statistically signicant association
between soy isoavones consummation and men plasma estrogen
and androgen level (van Die et al., 2013). Although the presence of
both types of estrogen receptors seems necessary for maintenance
of ductules and epididymis functions and male fertility (Hess et al.,
2011; Joseph et al., 2011), no positive effect of dietary phytoestrogen on male, in contrast to female, reproductive functions have
been demonstrated yet.

6. Phytoestrogen and skin

Estrogen deciency following menopause results in atrophic
skin changes and acceleration of skin aging. Estrogens signicantly
modulate skin physiology, targeting keratinocytes, broblasts,
melanocytes, hair follicles and sebaceous glands, and improve
angiogenesis, wound healing and immune responses (see below).
Estrogen insufciency decreases defense against oxidative stress;
skin becomes thinner, decreases collagen content, elasticity,
increases wrinkling, dryness and reduces vascularity. Its protective
function becomes compromised and aging is associated with
impaired wound healing, hair loss, pigmentary changes and
increased incidence of skin cancer (Thornton, 2013). Phytoestrogen may have anti-aging effect on the skin via estrogen receptors
(Gopaul et al., 2012) or via increase in hyaluronic acid production
(Patriarca et al., 2013), collagen (Chua et al., 2012), extracellular
matrix proteins (Gopaul et al., 2012) or via promotion of skin
vascularization, cell proliferation, protection against oxidative
stress and apoptosis a.o. (see above). Skin aging can be signicantly delayed by the administration of estrogen, selective estrogen receptor modulators and phytoestrogens (Thornton, 2013).

7. Phytoestrogen and bone

Estrogens are important promoters of bone formation. It is
postulated, that their decit can promote, and the phytoestrogenrich diet can prevent osteoporosis (Wuttke et al., 2002; Cassidy,
2003; Branca and Lorenzetti, 2005). In vitro, phytoestrogens
promote protein synthesis, osteoprotegerin/receptor activation of
nuclear factor-kappa B ligand ratio, and mineralization by
osteoblast-like cells. Administration of phytoestrogens can inhibit
differentiation and activation of osteoclasts, expression of tartrateresistant acid phosphatase, and secretion of pyridinoline compound. Consequently, phytoestrogens enhance bone formation
and increase bone mineral density and levels of alkaline phosphatase, osteocalcin, osteopontin, and 1(I) collagen. Results of
mechanistic studies indicated that phytoestrogens suppress the
rate of bone resorption and enhance the bone formation rate
(Chiang and Pan, 2013). Soy phytoestrogen genistein was shown to
be especially potent enhancer of osteoblastic differentiation and
maturation and an inhibitor of osteoclast formation and bone
resorption through inducing osteoclastogenic inhibitor osteoprotegerin and blocking NF-kappaB signaling, whilst these effects are

S. Alexander V / European Journal of Pharmacology 741 (2014) 230236

probably not mediated via estrogen receptors (Ming et al., 2013).

Nevertheless, the published clinical data are inconsistent and do
not support soy's (Lagari and Levis, 2010) or red clover (Powles
et al., 2008) protective effect against bone loss. The antiosteoporotic effects of unknown compounds in Cimicifuga racemosa extracts
have been reported, but it has not been validated by clinical
studies yet (Wuttke et al., 2002, 2003).
8. Phytoestrogen and cardiovascular system
Experimental studies have shown benecial effects of phytoestrogens on endothelial cells, vascular smooth muscle, and extracellular matrix, decreased arterial stiffness and antiatherosclerotic
effects via NO production. Phytoestrogens may also affect other
pathophysiologic vascular processes such as lipid prole (reduce
levels of LDL cholesterol), angiogenesis, inammation, tissue
damage by reactive oxygen species, and these effects could delay
the progression of atherosclerosis. Epidemiological studies suggest
that dietary intake of soy, the richest dietary source of isoavones
phytoestrogens, may contribute to the decreased incidence of
cardiovascular diseases and thromboembolic events and cardiovascular disease mortality rate. However, like in other disfunctions, there is some discrepancy between the experimental studies
demonstrating the vascular benets of phytoestrogens and the
data from clinical trials, which failed to demonstrate signicant
effect of isoavones on arteriosclerosis and other cardiovascular
diseases (Wuttke et al., 2002; Gencel et al., 2012; Gil-Izquierdo
et al., 2012).

9. Phytoestrogens and metabolism

Metabolic syndrome associated with obesity and type 2 diabetes is
a serious public health problem worldwide. The mutual stimulating
intrrelationships between obesity and type 2 diabetes have been
demonstrated. The high levels of pro-inammatory cytokines and
leptin, secreted by the adipose tissue, contribute to the insulin
resistance induction; for instance the high levels of free fatty acids
leads to an overproduction of reactive oxygen species that participate
in pancreatic cells failure and apoptosis. These two dysfunctions are
the fundamental defects that precede type 2 diabetes. An isoavone
genistein can exert the suppressive effect on obesity and type
2 diabetes via inhibition the adipocyte life-cycle, obesity-related lowgrade inammation, oxidative stress and protection of pancreatic beta
cells. (Behloul and Wu, 2013).. The stimulatory effect of genistein on
beta-cell proliferation, which has not been mediated via estrogen
receptor, but via protein kinase A and MAP/ERK1/2 kinase has been
reported too (Fu et al., 2010). In addition, isoavones can increase HDL
and decrease LDL concentrations in human plasma (Wuttke et al.,
2002), increase lean body mass and reduce fat accumulation (Cave
et al., 2007). Therefore soy genistein has been proposed as a promising
compound for the metabolism improvement and treatment of metabolic disorders (Behloul and Wu, 2013). In contrast to soy, red clover
isoavones failed to inuence women serum cholesterol level (Powles
et al., 2008).
10. Phytoestrogens and nervous system
The sex/gender differences in brain cognitive functions may be due
to different level of estrogens in nervous system and its response to
these hormones. Based on epidemiologic evidence comparing Western and Asian populations and clinical studies, phytoestrogens show
promise to improve cognitive brain function. Some evidence, that
phytoestrogens may affect congitive functions, and that these effect
may be sex-specic have been published, but due to discrepancy

233

among the published studies and their results, no denitive conclusions concerning the effect of phytoestrogens on the cognitive functions of healhy brain may be done (Sumien et al., 2013). The ability of
some phytoestrogens to improve not only cognitive functions, but also
sleep have been reported (Bedell et al., 2012). Mechanisms of
phytoestrogen action on the nervous system requires further studies,
although soy isoavones and phytoestrogens of black cohosh, kudzu,
kava, licorice, and dong quai are reported may affect neurons via both
steroid receptor and 5-hydroxytryptamine receptor or via promotion
of serotonin reuptake, i.e. through both estrogenic and serotonergic
activities (Hajirahimkhan et al., 2013). In addition, ability of phytoestrogens to affect catecholamine synthesis and uptake has been
recently demonstrated. Plant avonoids expressed various pharmacological potentials and mechanisms of action on the catecholamine
system in adrenal medullary cells and sympathetic neurons. For
example, both soy isoavone daidzein and cytrus isoavone nobiletin
can stimulate catecholamine synthesis via plasma membrane estrogen
receptor and Ser19 and Ser40 of tyrosine hydroxylase and Ca2 inux
respectively. In addition, soy isoavone genistein, but not daidzein can
enhance noradrenaline uptake by noradrenergic neuroblastoma cells.
On the contrary, both daidzein and nobiletin inhibited catecholamine
synthesis and secretion induced by a physiological secretagogue,
acetylcholine (Yanagihara et al., 2014).
Oxidative stress inducing mitochondrial dysfunction and subsequent apoptosis of nigrastriatal dopaminerghic neurons is considered
as a main cause of both Parkinson's (Bourque et al., 2012; Chao et al.,
2012) and Alzheimer's (Via et al., 2007) diseases. Animal experiments
demonstrated the neuroprotective effect of both estradiol and phytoestrogens, which are able to prevent oxidative stress-induced
degenerative changes in these neurons (Via et al., 2007; Bourque
et al., 2012; Chao et al., 2012). Estrogen therapy can in some cases
reduce risk of women Alzheimer's disease suggesting the potential
suppressive inuence of phytoestrogens on this disease (Henderson,
2009). Nevertheless, clinical and epidemiological evidence for either
curative or preventive action of phytoestrogens on neurodegenerative
diseases remain to be obtained.

11. Phytoestrogen and immune system

The ability of soy phytoestrogens to inhibit the intracellular
signaling pathway related to NF-kappaB transcription factor
activating inammation and immune response (Vina et al., 2011;
Chiang and Pan, 2013; Ming et al., 2013) suggest potential
inuence of phytoestrogens on immune system. Genistein can
suppresses antigen-specic immune response in vivo and lymphocyte proliferation response in vitro. However, genistein can
enhance the cytotoxic response mediated by NK and cytotoxic T
cells and the cytokine production from T cells. Thus, the effect of
genistein on immunity is immune cell-dependent. Due to its effect
on immune function, genistein has been used for the treatment of
the immune diseases in animal models. It has been found that
genistein inhibits allergic inammatory responses (Sakai and
Kogiso, 2008). Several epidemiological studies suggest that consumption of traditional soy food containing isoavones is associated
with reduced prevalence of chronic health disorders. Nevertheless,
the potential therapeutic action of isoavones on human immunodisfunctions require further validation (Masilamani et al., 2012).

12. Phytoestrogens and cancer

Malignant transformation of healthy cells and tumorgenesis can
be associated with increased DNA mutagenesis, cell proliferation,
tissue vascularization, decreased apoptosis, immune response and
other processes whose can be under control of estrogens (Rietjens

234

S. Alexander V / European Journal of Pharmacology 741 (2014) 230236

et al., 2013; Viedma-Rodrguez et al., 2014). These processes could

be affected by phytoestrogens via estrogen receptor-dependent
and -independent mechanisms. The antioxidant, antimutagenic,
antiproliferative, antiangiogenic, pro-apoptotic and general anticancer effects of a number of phytoestrogens produced by friuts,
vegetables, soy, green tea, rooibos, honeybush have been reported
(Cassidy, 2003; Branca and Lorenzetti, 2005; McKay and Blumberg,
2007; Rietjens et al., 2013).
Traditional consumption of soy products is considered as a cause of
lower incidence of breast and prostate cancers in China and Japan
versus United States and European countries. The ability of soy
isoavone genistein to inhibit carcinogenesis has been demonstrated
in animal models. There are growing body of experimental evidence
that shows the inhibition of human cancer cells by genistein through
the modulation of genes that are related to the control of cell cycle and
apoptosis. Moreover, it has been shown that genistein inhibits the
activation of NF-kappa B and Akt signaling pathways, both of which
are known to maintain a homeostatic balance between cell survival
and apoptosis and affect immunodeletion of cancer cells. Furthermore,
genistein has been found to have antioxidant property, and shown to
be a potent inhibitor of angiogenesis and metastasis. Both in vivo and
in vitro studies have shown that genistein could be a promising
reagent for cancer chemoprevention and/or treatment (Sarkar and Li,
2003).
Some long-term studies showed reported potential benet of
soy isoavones for prevention of colon (Branca and Lorenzetti,
2005), endometrial and ovarian cancer (Eden, 2012). On the
contrary, the breast cancer studies generated conicting and even
negative evidence from epidemiological, intervention and experimental animal studies regarding the chemopreventing effects of
soy isoavones in breast cancer. Some studies did not show any
association between phytoestrogen intake and breast cancer risk
(Bedell et al., 2012). Moreover, the estrogenic action of soy
isoawones may even promote breast cancer development. Therefore, some specialists (Tomar and Shiao, 2008; Andres et al., 2011)
donot recommend indisputably accept soy or red-clover as a
source of isoavones to prevent breast cancer.

Men may benet from the intake of soy isoavones with regard
to reducing the risk of prostate cancer (Andres et al., 2011). Metaanalyses of the two studies including men with identied risk of
prostate cancer found a signicant reduction in prostate cancer
diagnosis following administration of soy/soy isoavones (van Die
et al., 2013)
Lignans and their derivates phytoestrogens and antioxydants
enterodiol and enterolactone are produced in the colon by the action
of bacteria on the plant precursors in the diet . It has been suggested
that the high production of these antiestrogenic mammalian lignans in
the gut may serve to protect against breast cancer in women and
prostate cancer in men. In vitro experiments suggested that they can
signicantly suppress the growth of human colon tumor cells, and
enterolactone can inhibit the estrogen-induced proliferation of breast
cancer cells (Wang, 2002). There are evidence on high anticancerogenic activity of enterodiol and enterolactone arising from axseed
lignans. The evidence-based biomedical researches on various models
in experimental carcinogenesis, on the tumor cells in vitro, in clinical
trials in patients with hormone-dependent tumors, and, nally, the
epidemiological studies have proved the anticarcinogenic activity of
the components of the axseed antioxidant and validity of recommendations for their both preventive and curative use in hormonedependent tumors (Martinchik and Zubtsov, 2012).

13. Conclusions and possible directions of further studies

The available publications demonstrate the effect of phytoestrogens on a number of physiological and pathological processes
related to reproduction, skin aging, bone, cardiovascular, nervous,
immune systems, metabolism and cancer via various targets and
mechanisms. The available knowledge concerning possible targets
of phytoestrogens are summarized in Fig.2.
In some cases phytoestrogens can support normal physiological
processes (like female reproduction, bone formation etc.) or
they can be safe and easy alternative to hormonal therapy, an
efcient tool to prevent and/or to suppress cancerogenesis and

Phytoestrogens

Estrogen receptors, receptors to other hormones, sex hormone binding

proteins, aromatase, free radicals, DNA methylation, histone modification, RNA
expression, cyclic nucleotides, protein kinases, transcription factors

Suppression of oxidation, proliferation, mutagenesis, angiogenesis, apoptosis

Reproduction, skin, bone, metabolism, cardiovascular, nervous, immune

systems

Menopause, obesity, diabetes, osteoporosis, cardiovascular, neurodegenerative

and immiune disorders, aging, cancer
Fig.2. Summary of possible targets (molecules, processes, functions and dysfunctions) of phytoestrogens. Explanations are in the text.

S. Alexander V / European Journal of Pharmacology 741 (2014) 230236

some age-related disfunctions induced by estrogen decit (menopausal syndrom, osteoporosis, neurodegenerative disorders, skin
aging). Benets of estrogens are proposed to be the cause of sex
differences in vitality, longetivity and other phyiological characteristics (Vina et al., 2011). Therefore, some authors recommend the
intake of phytoestrogens for prevention of human diseases and
aging (Branca and Lorenzetti, 2005; Vina et al., 2011) and promotion of farm animal performance (Zhengkang et al., 2006; Balazi
and Sirotkin, unpublished). Nevertheless, recent reviews concerning phytoestrogen benets look less enthusiastic and optimistic,
than the earlier ones. Not only positive (prevention of menopausal
and metabolic syndroms, osteoporosis, neurodegenerative, immunoligical disorders, obesity, type 2 diabetes, cardiovascular diseases, skin aging, some kinds of cancer), but also no or even
negative (induction of breast cancer and may be of reproductive
disorders) actions of phytoestrogens have been proposed. Furthermore, despite large progress in study and application of phytoestrogens, a number of problems in both understanding the
mechanisms of their action and in their practical application are
still retaining. The rst problem is to understand and distinguish
the numerous mechanisms of action on phytoestrogens on physiological and pathological processes and their functional interrelationships. This problem is due to the multiple targets and
mechanisms of phytoestrogens action, the multiple causes and
mechanisms of disorders development and the complexity
of interrelationships between various regulatory systems. For
example, diseases can be induced by oxydative stress-induced
apoptosis, mutagenesis, changes in cell cycle, cholesterol and
carbohydrate metabolism, local vascularization, intracellular
protein kinases, transcription factors a.o., whilst each of this
interlinked processes may be targeted by phytoestrogens. Understanding targets and mechanisms of phytoestrogen action can be
important not only from theoretical, but also from practical viewpoints to predict and to avoid the negative side-effects of phytoestrogen application. The second major problem is the
discrepancy between the results of experimental studies and the
data from clinical trials. This is likely because the phytoestrogens
clinical trials have been limited in many aspects including the
number of participants enrolled, the clinical end points investigated, and the lack of long-term follow-up (Gencel et al., 2012;
Gil-Izquierdo et al., 2012). The third problem is to nd an adequate
source of phytoestrogens for practical application. The majority of
reported studies are focused on soy and red clover isoavones.
Other perspective phytoestrogens and plants (for example, the
molecules of axseed origin) are studied much less despite their
high therapeutic potential. In addition, the general plant-based
approaches are associated with serious disadvantages: the production, isolation and application of plant phytoestrogens are time- and
labour-consuming, whilst their specicity and reproducibility are
sometimes insufcient (Michel et al., 2013). Phytoestrogen spectrum
and content varies between the plant species, sort and origin, and
even the same molecule arising from the different sources can exert
various effect. It may not be excluded, that synthetic phytoestrogens
with desirable structure and activity could be easier and safer
alternative of the traditional plant product of variable origin,
phytoestrogen content and activity.

Acknowledgments
This work was supported by Slovak Agency for Promotion of
Research and Development (APVV, Projects nos. 0137-10 and
0854-11), Operational Program Research and Development funded
from the European Regional Development Fund (Project no.
26220220176) and by the NSTIP strategic technologies programs,
the Kingdom of Saudi Arabia (Project no. 13-ENV1321-02).

235

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