European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 Contents lists available at ScienceDirect

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4 European Journal of Pharmacology
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journal homepage: www.elsevier.com/locate/ejphar
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Title: Phytoestrogens and their effects
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14 Alexander V Sirotkin
15 Constantine the Philosopher University, Nitra and Research Institute of Animal Production, Lužianky, Slovak Republic
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18 art ic l e i nf o a b s t r a c t
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20 Article history: The chemical structure, classification, source, metabolism, physiological and health effects of plant
21 Received 23 February 2014 phytoestrogens and mechanisms of their action are reviewed. The available knowledge suggests that
22 Received in revised form phytoestrogens can affect a number of physiological and pathological processes related to reproduction,
23 July 2014
23 bone remodeling, skin, cardiovascular, nervous, immune systems and metabolism. Due to these effects,
Accepted 27 July 2014
24 phytoestrogens and phytoestrogen-containing diet can be useful for the prevention and treatment of
25 menopausal symptoms, skin aging, osteoporosis, cancer, cardiovascular, neurodegenerative, immune and
Keywords: metabolic diseases. Possible problems in understanding and application of phytoestrogens (multiple
26 Phytoestrogens targets and multiple estrogen receptor –dependent and –independent mechanisms of action, the
27 Reproduction
discrepancy between the results of experimental and clinical studies, adequate source of phytoestrogen)
28 Bone remodeling
have been discussed.
29 Skin
Cardiovascular system & 2014 Published by Elsevier B.V.
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Nervous system
31 Immune system
32 Metabolism
33 Cancer
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36 Contents
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38 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
39 2. Phytoestrogen classification and structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
40 3. Phytoestrogen source and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
41 4. Phytoestrogen mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
42 5. Phytoestrogens and reproduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
6. Phytoestrogen and skin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
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7. Phytoestrogen and bone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
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8. Phytoestrogen and cardiovascular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
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9. Phytoestrogens and metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
46 10. Phytoestrogens and nervous system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
47 11. Phytoestrogen and immune system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
48 12. Phytoestrogens and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
49 13. Conclusions and possible directions of further studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
50 Uncited reference . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
51 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
52 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
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57 1. Introduction application of plant bioactive compounds has increased dramati-
58 cally over the last decade. Of particular interest in relation to
59 Interest of both public and specialists in medicine and func- human health are the class of compounds known as the phytoes-
60 tional food production in the physiological role and practical trogens, which includes several groups of non-steroidal estrogens
61 that are widely distributed within the plant kingdom. There is a
62 growing body of evidence, that consumption of some these plants
63 E-mail addresses: sirotkin@cvzv.sk, asirotkin@ukf.sk or their molecules could be an additive efficient tool to prevent
64 http://dx.doi.org/10.1016/j.ejphar.2014.07.057
65 0014-2999/& 2014 Published by Elsevier B.V.
66

Please cite this article as: Alexander V, S., Title: Phytoestrogens and their effects. Eur J Pharmacol (2014), http://dx.doi.org/10.1016/j.
ejphar.2014.07.057i
 2 S. Alexander V / European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 and to treat several dysfunctions and diseases related to aging, (Zhengkang et al., 2006). For instance, the effects of daidzein is
2 mental processes, metabolism, malignant transformation, cardio- variable depending on individuals and to their ability to convert
3 vascular diseases and reproduction - breast and prostate cancers, daidzein to more active equol that seems to be restricted to
4 menopausal symptoms, osteoporosis, atherosclerosis and stroke, approximately 1/3 of the population (Gil-Izquierdo et al., 2012).
5 and neurodegeneration (see Cassidy, 2003; Tuohy, 2003; Branca Bioavailability of isoflavones requires an initial hydrolysis of the
6 and Lorenzetti, 2005 for review). Some aspects of phytoestrogen sugar moiety by intestinal beta-glucosidases to allow the following
7 structure, source, metabolism, physiological action, its mechan- uptake by enterocytes and the flow through the peripheral
8 isms and interrelationships with some disorders are reviewed circulation. Following absorption, isoflavones are then reconju-
9 below. gated mainly to glucuronic and sulfuric acids (Cassidy, 2003;
10 Chiang and Pan, 2013; Vitale et al., 2013).
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12 2. Phytoestrogen classification and structure
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On the basis of their chemical structure and in respect to 4. Phytoestrogen mechanisms of action
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15 biosynthesis patterns, phytoestrogens may be divided in chal-
cones, flavonoids (flavones, flavonols, flavanones, isoflavonoids), Phytoestrogens are strikingly similar in chemical structure to
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lignans, stilbenoids, and miscellaneous classes. Particular attention the mammalian estrogen, estradiol, and bind to estrogen receptors
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should be given to isoflavonoids, the subgroup of flavonoids which alpha and beta with a preference for the more recently described
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includes amongst others the chemical groups of isoflavones, estrogen receptor beta (Younes and Honma, 2011; Rietjens et al.,
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isoflavanones, pterocarpanes, and coumestans (Dixon, 2004; 2013; Paterni et al., 2014). These receptors after binding with
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Michel et al., 2013). The molecular structures of some selected ligand are able to move from cytoplasm to the nucleus, bind and
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phytoestrogens are present in Fig.1. affect the transcription-control regions of DNA or small RNAs and
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therefore the expression of specific genes. Furthermore, steroids
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are able to bind to receptors of cell surface, promote formation of
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3. Phytoestrogen source and metabolism cytoplasmic cyclic nucleotides and related protein kinases, which
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in turn via transcription factors control the expression of target
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Phytoestrogens are known to be present in fruits, vegetables, genes (Sirotkin, 2014; Yanagihara et al., 2014). Therefore, phytoes-
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and whole grains commonly consumed by humans. They are trogens can potentially affect all the processes regulated by
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abundant in several edible and/or medicinal plants, belonging estrogens including induction sex hormone binding globulin and
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mostly to the Leguminosae family (Dixon, 2004; Michel et al., inhibition aromatase (Wang, 2002). Estrogen receptors are present
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2013). Plant extracts with potential estrogenic activities include in different tissues – central nervous system (including hypotha-
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soy, red clover, kudzu, hops, licorice, rhubarb, yam, and chaste- lamo–hypophysial axis), gonads, reproductive tract, placenta,
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berry (Hajirahimkhan et al., 2013). Isoflavones are found in mammary gland, bones, gastrointestinal tract, lung a.o. This
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legumes—mainly soybeans, flaxseed is a major source of lignans, suggests that phytoestrogens may exert tissue specific hormonal
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and coumestans are significantly present in clover, alfalfa and effects (Cassidy, 2003; Younes and Honma, 2011; Böttner et al.,
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soybean sprouts. 8-Prenyl flavonoids are common in vegetables, 2013). The estrogen receptor-specific effects may occur too. For
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hop and beer. Dietary phytoestrogens are metabolized by intest- example, estrogen receptors alpha are considered as promoters of
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inal bacteria, absorbed, conjugated in the liver, circulated in cell proliferation, whilst estrogen receptors beta are in charge for
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plasma and excreted in urine (Cassidy, 2003). Gut metabolism promoting mainly cellular apoptosis (Rietjens et al., 2013).
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seems key to the determination of the potency of action; some- Phytoestrogens besides their ability to bind to estrogen recep-
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times the biological effect of dietary phytoestrogens is due to tors, have other biological effects, which are not mediated with
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mainly with their metabolites generated by gut microflora (Wang, these receptors – activation of serotoninergic receptors
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2002; Branca and Lorenzetti, 2005). For example, the mammalian (Hajirahimkhan et al., 2013), IGF-1 receptors (Bourque et al.,
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phytoestrogens enterodiol and enterolactone are produced in the 2012), binding of free radicals (Wang, 2002; Cassidy, 2003;
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colon by the action of bacteria on the plant precursors matair- McKay and Blumberg, 2007; Vina et al., 2011; Martinchik and
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esinol, secoisolariciresinol, their glycosides, and other precursors Zubtsov, 2012), inducting DNA methylation (Lim and Song, 2012;
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in the diet (Wang, 2002). The estrogenic activity of plant phytoes- Rietjens et al., 2013), affecting tyrosine kinase, cAMP/protein
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trogens can be enhanced after metabolization to more active kinase A, cGMP/NO, phosphatidylinositol-3 kinase/Akt and
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compounds such as genistein and daidzein by gut microorganisms MAP (ERK1,2, p38) kinases (Vina et al., 2012; Bourque et al., Q3
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66 Fig.1. Molecular structure of the most ubiquitous phytoestrogens (from Michel et al., 2013)

Please cite this article as: Alexander V, S., Title: Phytoestrogens and their effects. Eur J Pharmacol (2014), http://dx.doi.org/10.1016/j.
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1 2012; Ming et al., 2013; Yanagihara et al., 2014), transcription
2 factors NF-kappaB and DNA topoisomerase activities (Vina et al.,
3 2012; Ming et al., 2013), histone modification, RNA expression
4 (Rietjens et al., 2013) and other intracellular regulators of cell cycle
5 and apoptosis. These abilities are probably responsible for anti-
6 oxidant, antiproliferative, antimutagenic and antiangiogenic
7 effects of phytoestrogens and their ability to promote human
8 health and longevity (Kurzer and Xu, 1997; Wang, 2002; Cassidy,
9 2003; Fu et al., 2010; Vina et al., 2011; Lim and Song, 2012;
10 Hajirahimkhan et al., 2013; Ming et al., 2013). Nevertheless, the
11 hormonal and non-hormonal mechanisms of phytoestrogen effect
12 on particular processes listed below are sometimes difficult to
13 discriminate due to multiple signaling pathways mediating phy-
14 toestrogen effects and the insufficient related knowledge. The
15 current studies and related publications are focused more to
16 clinical application, than to basic studies of the mechanisms of
17 phytoestrogen effects.
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20 5. Phytoestrogens and reproduction
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22 The exogenous estrogen-like molecules can both promote and
23 destroy reproductive processes. For example, isoflavone genistein
24 is able to stimulate animal ovarian progesterone, etradiol and
25 cAMP production, oocyte maturation and preimplantation zygote
26 development (Makarevich et al., 1997). Phytoestrogens of green
27 tea, indian turmeric and other plants inhibited proliferation,
28 promoted apoptosis and altered the release of steroid hormones
29 Q4 by porcine ovarian cells (Kadasi and Sirotkin, unpublished data).
30 Consumption of soybean products, which contain high levels of
31 isoflavones, can alter animal sexual development, including
32 altered pubertal timing, impaired estrous cycling and ovarian
33 function, and altered hypothalamus and pituitary functions. The
34 adverse effect of phytoestrogens on human reproduction has not
35 been reported, but some authors (Vandenplas et al., 2011;
36 Jefferson and Williams, 2011; Jefferson et al., 2012; Kim and
37 Park, 2012) donot exclude their existence. For example, the
38 reproductive consequences of consummation of soybean-based
39 infant formulas, which increases soy isoflavones level in neonate
40 plasma (Vandenplas et al., 2011), require careful assesment (Tuohy,
41 2003; Jefferson et al., 2012), although no adverse effect of such
42 formula on male sexual development has been reported yet
43 (Cederroth et al., 2010).
44 On the other hand, exposition of women to phytoestrogens
45 (isoflavones, lignans, coumestans of different botanical sources) in
46 pre- and postmenopausal period may prevent the menopausal
47 symptoms induced by declined endogenous estrogen production –
48 hot flashes, vasomotor symptoms, vaginal atrophy a.o., whilst no
49 negative side-effect of these phytoestrogens on breast and endo-
50 metrial health have been observed (Kronenberg and Fugh-Berman,
51 2002; Branca and Lorenzetti, 2005; Bedell et al., 2012). Soy and
52 black cohosh are reported to be the most promising source of
53 phytoestrogens, whilst isoflavone preparations seem to be less
54 effective than soy foods (Kronenberg and Fugh-Berman, 2002).
55 Many post-menopausal women often perceived phytoestrogens in
56 food supplements as a safer alternative than hormone replace-
57 ment therapy (Poluzzi et al., 2014). Moreover, unlike hormone
58 therapy, lignans may not increase clotting risk in postmenopausal
59 women, thus such supplements may serve as a treatment option
60 for patients who have contraindications to hormone therapy
61 Q5 (Bodell et al., 2012). Some studies demonstrated a significant
62 reduction of somatic-vegetative and psychological symptoms of
63 menopause under the influence of soy and Cimicifuga racemosa
64 phytoestrogens, while urogenital symptomatology was not signif-
65 icantly changed (Wuttke et al., 2002, 2003; Rosic et al., 2013). On
66 the other hand, other epidemiologic studies failed to detect
significant effect of red clower on plasma gonadotropin level,
breast density or endometrial thickness (Powles et al., 2008) or
the significant influence 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 flush
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 incon-
clusive 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 significant association
between soy isoflavones 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 phytoestro-
gen on male, in contrast to female, reproductive functions have
been demonstrated yet.
6. Phytoestrogen and skin
Estrogen deficiency following menopause results in atrophic
skin changes and acceleration of skin aging. Estrogens significantly
modulate skin physiology, targeting keratinocytes, fibroblasts,
melanocytes, hair follicles and sebaceous glands, and improve
angiogenesis, wound healing and immune responses (see below).
Estrogen insufficiency 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). Phytoestro-
gen may have anti-aging effect on the skin via estrogen receptors
(Goupal et al., 2012) or via increase in hyaluronic acid production Q6
(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 signifi-
cantly delayed by the administration of estrogen, selective estro-
gen receptor modulators and phytoestrogens (Thornton, 2013).
7. Phytoestrogen and bone
Estrogens are important promoters of bone formation. It is
postulated, that their deficit can promote, and the phytoestrogen-
rich 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 tartrate-
resistant acid phosphatase, and secretion of pyridinoline com-
pound. Consequently, phytoestrogens enhance bone formation
and increase bone mineral density and levels of alkaline phospha-
tase, osteocalcin, osteopontin, and α1(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

Please cite this article as: Alexander V, S., Title: Phytoestrogens and their effects. Eur J Pharmacol (2014), http://dx.doi.org/10.1016/j.
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 4 S. Alexander V / European Journal of Pharmacology ∎ (∎∎∎∎) ∎∎∎–∎∎∎

1 be especially potent enhancer of osteoblastic differentiation and response to these hormones. Based on epidemiologic evidence
2 maturation and an inhibitor of osteoclast formation and bone comparing Western and Asian populations and clinical studies,
3 resorption through inducing osteoclastogenic inhibitor osteopro- phytoestrogens show promise to improve cognitive brain function.
4 tegerin and blocking NF-kappaB signaling, whilst these effects are Some evidence, that phytoestrogens may affect congitive func-
5 probably not mediated via estrogen receptors (Ming et al., 2013). tions, and that these effect may be sex-specific have been
6 Nevertheless, the published clinical data are inconsistent and do published, but due to discrepancy among the published studies
7 not support soy's (Lagari and Levis, 2010) or red clover (Powles and their results, no definitive conclusions concerning the effect of
8 et al., 2008) protective effect against bone loss. The antiosteoporo- phytoestrogens on the cognitive functions of healhy brain may be
9 tic effects of unknown compounds in Cimicifuga racemosa extracts done (Sumien et al., 2013). The ability of some phytoestrogens to
10 have been reported, but it has not been validated by clinical improve not only cognitive functions, but also sleep have been
11 studies yet (Wuttke et al., 2002, 2003). reported (Bedell et al., 2012). Mechanisms of phytoestrogen action
12 on the nervous system requires further studies, although soy
13 isoflavones and phytoestrogens of black cohosh, kudzu, kava,
14 8. Phytoestrogen and cardiovascular system licorice, and dong quai are reported may affect neurons via both
15 steroid receptor and 5-hydroxytryptamine receptor or via promo-
16 Experimental studies have shown beneficial effects of phytoes- tion of serotonin reuptake, i.e. through both estrogenic and
17 trogens on endothelial cells, vascular smooth muscle, and extra- serotonergic activities (Hajirahimkhan et al., 2013). In addition,
18 cellular matrix, decreased arterial stiffness and antiatherosclerotic ability of phytoestrogens to affect catecholamine synthesis and
19 effects via NO production. Phytoestrogens may also affect other uptake has been recently demonstrated. Plant flavonoids
20 pathophysiologic vascular processes such as lipid profile (reduce expressed various pharmacological potentials and mechanisms of
21 levels of LDL cholesterol), angiogenesis, inflammation, tissue action on the catecholamine system in adrenal medullary cells and
22 damage by reactive oxygen species, and these effects could delay sympathetic neurons. For example, both soy isoflavone daidzein
23 the progression of atherosclerosis. Epidemiological studies suggest and cytrus isoflavone nobiletin can stimulate catecholamine
24 that dietary intake of soy, the richest dietary source of isoflavones synthesis via plasma membrane estrogen receptor and Ser19 and
25 phytoestrogens, may contribute to the decreased incidence of Ser40 of tyrosine hydroxylase and Ca2 þ influx respectively. In
26 cardiovascular diseases and thromboembolic events and cardio- addition, soy isoflavone genistein, but not daidzein can enhance
27 vascular disease mortality rate. However, like in other disfunc- noradrenaline uptake by noradrenergic neuroblastoma cells. On
28 tions, there is some discrepancy between the experimental studies the contrary, both daidzein and nobiletin inhibited catecholamine
29 demonstrating the vascular benefits of phytoestrogens and the synthesis and secretion induced by a physiological secretagogue,
30 data from clinical trials, which failed to demonstrate significant acetylcholine (Yanagihara et al., 2014).
31 effect of isoflavones on arteriosclerosis and other cardiovascular Oxidative stress inducing mitochondrial dysfunction and sub-
32 diseases (Wuttke et al., 2002; Gencel et al., 2012; Gil-Izquierdo et sequent apoptosis of nigrastriatal dopaminerghic neurons is con-
33 al., 2012). sidered as a main cause of both Parkinson's (Bourque et al., 2012;
34 Chao et al., 2012) and Alzheimer's (Viña et al., 2007) diseases.
35 Animal experiments demonstrated the neuroprotective effect of
36 9. Phytoestrogens and metabolism both estradiol and phytoestrogens, which are able to prevent
37 oxidative stress-induced degenerative changes in these neurons
38 Metabolic syndrome associated with obesity and type 2 dia- (Viña et al., 2007; Bourque et al., 2012; Chao et al., 2012). Estrogen
39 betes is a serious public health problem worldwide. The mutual therapy can in some cases reduce risk of women Alzheimer's
40 stimulating intrrelationships between obesity and type 2 diabetes disease suggesting the potential suppressive influence of phytoes-
41 have been demonstrated. The high levels of pro-inflammatory trogens on this disease (Henderson, 2009). Nevertheless, clinical
42 cytokines and leptin, secreted by the adipose tissue, contribute to and epidemiological evidence for either curative or preventive
43 the insulin resistance induction; for instance the high levels of free action of phytoestrogens on neurodegenerative diseases remain to
44 fatty acids leads to an overproduction of reactive oxygen species be obtained.
45 that participate in pancreatic β cells failure and apoptosis. These
46 two dysfunctions are the fundamental defects that precede type
47 2 diabetes. An isoflavone genistein can exert the suppressive effect 11. Phytoestrogen and immune system
48 on obesity and type 2 diabetes via inhibition the adipocyte life-
49 cycle, obesity-related low-grade inflammation, oxidative stress The ability of soy phytoestrogens to inhibit the intracellular
50 and protection of pancreatic beta cells. (Behloul and Wu, 2013).. signaling pathway related to NF-kappaB – transcription factor
51 The stimulatory effect of genistein on beta-cell proliferation, which activating inflammation and immune response (Vina et al., 2011;
52 has not been mediated via estrogen receptor, but via protein Chiang and Pan, 2013; Ming et al., 2013) suggest potential
53 kinase A and MAP/ERK1/2 kinase has been reported too (Fu et influence of phytoestrogens on immune system. Genistein can
54 al., 2010). In addition, isoflavones can increase HDL and decrease suppresses antigen-specific immune response in vivo and lympho-
55 LDL concentrations in human plasma (Wuttke et al., 2002), cyte proliferation response in vitro. However, genistein can
56 increase lean body mass and reduce fat accumulation (Cave enhance the cytotoxic response mediated by NK and cytotoxic T
57 et al., 2007). Therefore soy genistein has been proposed as a cells and the cytokine production from T cells. Thus, the effect of
58 promising compound for the metabolism improvement and treat- genistein on immunity is immune cell-dependent. Due to its effect
59 ment of metabolic disorders (Behloul and Wu, 2013). In contrast to on immune function, genistein has been used for the treatment of
60 soy, red clover isoflavones failed to influence women serum the immune diseases in animal models. It has been found that
61 cholesterol level (Powles et al., 2008). genistein inhibits allergic inflammatory responses (Sakai and
62 Kogiso, 2008). Several epidemiological studies suggest that con-
63 10. Phytoestrogens and nervous system sumption of traditional soy food containing isoflavones is associated
64 with reduced prevalence of chronic health disorders. Nevertheless,
65 The sex/gender differences in brain cognitive functions may be the potential therapeutic action of isoflavones on human immuno-
66 due to different level of estrogens in nervous system and its disfunctions require further validation (Masilamani et al., 2012).

Please cite this article as: Alexander V, S., Title: Phytoestrogens and their effects. Eur J Pharmacol (2014), http://dx.doi.org/10.1016/j.
ejphar.2014.07.057i
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1 12. Phytoestrogens and cancer
2 hormone-dependent tumors (Martinchik and Zubtsov, 2012).
3 Malignant transformation of healthy cells and tumorgenesis can
4 be associated with increased DNA mutagenesis, cell proliferation,
5 tissue vascularization, decreased apoptosis, immune response and
6 other processes whose can be under control of estrogens (Rietjens
7 et al., 2013; Viedma-Rodríguez et al., 2014). These processes could
8 be affected by phytoestrogens via estrogen receptor-dependent and
9 -independent mechanisms. The antioxidant, antimutagenic, anti-
10 proliferative, antiangiogenic, pro-apoptotic and general anti-cancer
11 effects of a number of phytoestrogens produced by friuts, vegeta-
12 bles, soy, green tea, rooibos, honeybush have been reported
13 (Cassidy, 2003; Branca and Lorenzetti, 2005; McKay and
14 Blumberg, 2007; Rietjens et al., 2013).
15 Traditional consumption of soy products is considered as a
16 cause of lower incidence of breast and prostate cancers in China
17 and Japan versus United States and European countries. The ability
18 of soy isoflavone genistein to inhibit carcinogenesis has been
19 demonstrated in animal models. There are growing body of
20 experimental evidence that shows the inhibition of human cancer
21 cells by genistein through the modulation of genes that are related
22 to the control of cell cycle and apoptosis. Moreover, it has been
23 shown that genistein inhibits the activation of NF-kappa B and Akt
24 signaling pathways, both of which are known to maintain a
25 homeostatic balance between cell survival and apoptosis and
26 affect immunodeletion of cancer cells. Furthermore, genistein
27 has been found to have antioxidant property, and shown to be a
28 potent inhibitor of angiogenesis and metastasis. Both in vivo and
29 in vitro studies have shown that genistein could be a promising
30 reagent for cancer chemoprevention and/or treatment (Sarkar and
31 Li, 2003).
32 Some long-term studies showed reported potential benefit of
33 soy isoflavones for prevention of colon (Branca and Lorenzetti,
34 2005), endometrial and ovarian cancer (Eden, 2012). On the
35 contrary, the breast cancer studies generated conflicting and even
36 negative evidence from epidemiological, intervention and experi-
37 mental animal studies regarding the chemopreventing effects of
38 soy isoflavones in breast cancer. Some studies did not show any
39 association between phytoestrogen intake and breast cancer risk
40 (Bedell et al., 2012). Moreover, the estrogenic action of soy
41 isoflawones may even promote breast cancer development. There-
42 fore, some specialists (Tomar and Shiao, 2008; Andres et al., 2011)
43 donot recommend indisputably accept soy or red-clover as a
44 source of isoflavones to prevent breast cancer.
45 Men may benefit from the intake of soy isoflavones with regard
46 to reducing the risk of prostate cancer (Andres et al., 2011). Meta-
47 analyses of the two studies including men with identified risk of
48 prostate cancer found a significant reduction in prostate cancer
49 diagnosis following administration of soy/soy isoflavones (van Die
50 et al., 2013)
51 Lignans and their derivates – phytoestrogens and antioxydants
52 enterodiol and enterolactone are produced in the colon by the
53 action of bacteria on the plant precursors in the diet . It has been
54 suggested that the high production of these antiestrogenic mam-
55 malian lignans in the gut may serve to protect against breast
56 cancer in women and prostate cancer in men. In vitro experiments
57 suggested that they can significantly suppress the growth of
58 human colon tumor cells, and enterolactone can inhibit the
59 estrogen-induced proliferation of breast cancer cells (Wang,
60 2002). There are evidence on high anticancerogenic activity of
61 enterodiol and enterolactone arising from flaxseed lignans. The
62 evidence-based biomedical researches on various models in
63 experimental carcinogenesis, on the tumor cells in vitro, in clinical
64 trials in patients with hormone-dependent tumors, and, finally,
65 the epidemiological studies have proved the anticarcinogenic
66 activity of the components of the flaxseed antioxidant and validity
of recommendations for their both preventive and curative use in
13. Conclusions and possible directions of further studies
The available publications demonstrate the effect of phytoes-
trogens 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 efficient
tool to prevent and/or to suppress cancerogenesis and some age-
related disfunctions induced by estrogen deficit (menopausal
syndrom, osteoporosis, neurodegenerative disorders, skin aging).
Benefits of estrogens are proposed to be the cause of sex
differences in vitality, longetivity and other phyiological character-
istics (Vina et al., 2012). Therefore, some authors recommend the
intake of phytoestrogens for prevention of human diseases and
aging (Branca and Lorenzetti, 2005; Vina et al., 2012) and promo-
tion of farm animal performance (Zhengkang et al., 2006; Balazi
and Sirotkin, unpublished). Nevertheless, recent reviews concern-
ing phytoestrogen benefits look less enthusiastic and optimistic,
than the earlier ones. Not only positive (prevention of menopausal
and metabolic syndroms, osteoporosis, neurodegenerative, immu-
noligical disorders, obesity, type 2 diabetes, cardiovascular dis-
eases, 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. Further-
more, despite large progress in study and application of phytoes-
trogens, a number of problems in both understanding the
mechanisms of their action and in their practical application are
still retaining. The first problem is to understand and distinguish
the numerous mechanisms of action on phytoestrogens on phy-
siological and pathological processes and their functional inter-
relationships. 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 exam-
ple, diseases can be induced by oxydative stress-induced apopto-
sis, 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. Under-
standing targets and mechanisms of phytoestrogen action can be
important not only from theoretical, but also from practical view-
points to predict and to avoid the negative side-effects of phy-
toestrogen 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 investi-
gated, and the lack of long-term follow-up (Gencel et al., 2012;
Gil-Izquierdo et al., 2012). The third problem is to find an adequate
source of phytoestrogens for practical application. The majority of
reported studies are focused on soy and red clover isoflavones.
Other perspective phytoestrogens and plants (for example, the
molecules of flaxseed origin) are studied much less despite their
high therapeutic potential. In addition, the general plant-based
approaches are associated with serious disadvantages: the produc-
tion, isolation and application of plant phytoestrogens are time- and
labour-consuming, whilst their specificity and reproducibility are
sometimes insufficient (Michel et al., 2013). Phytoestrogen spectrum

Please cite this article as: Alexander V, S., Title: Phytoestrogens and their effects. Eur J Pharmacol (2014), http://dx.doi.org/10.1016/j.
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1
2 Phytoestrogens
3
4
5
6 Estrogen receptors, receptors to other hormones, sex hormone binding
7 proteins, aromatase, free radicals, DNA methylation, histone modification, RNA
8
9 expression, cyclic nucleotides, protein kinases, transcription factors
10
11
12
13 Suppression of oxidation, proliferation, mutagenesis, angiogenesis, apoptosis
14
15
16
17
18 Reproduction, skin, bone, metabolism, cardiovascular, nervous, immune
19 systems
20
21
22
23
24 Menopause, obesity, diabetes, osteoporosis, cardiovascular, neurodegenerative
25 and immiune disorders, aging, cancer
26
27 Fig.2. Summary of possible targets (molecules, processes, functions and dysfunctions) of phytoestrogens. Explanations are in the text.
28
29 and content varies between the plant species, sort and origin, and Cave, NJ, Backus, RC, Marks, SL, Klasing, KC., 2007. Oestradiol, but not genistein,
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associated with an increase in lean body mass. J. Anim. Physiol. Anim. Nutr.
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41

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