European Journal of Pharmacology 741 (2014) 230–236
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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Phytoestrogens and their effects Alexander V. Sirotkin a,b,n, Abdel Halim Harrath b a b
Constantine the Philosopher University, Nitra and Research Institute of Animal Production, Lužianky, Slovak Republic Dept. of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
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, classification, 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 classification 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
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Corresponding author. E-mail addresses: [email protected], [email protected] (A.V. Sirotkin).
http://dx.doi.org/10.1016/j.ejphar.2014.07.057 0014-2999/& 2014 Elsevier B.V. All rights reserved.
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application of plant bioactive compounds has increased dramatically over the last decade. Of particular interest in relation to 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 efficient tool to prevent and to treat several dysfunctions and diseases related to aging,
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mental processes, metabolism, malignant transformation, cardiovascular diseases and reproduction - breast and prostate cancers, menopausal symptoms, osteoporosis, atherosclerosis and stroke, 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.
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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). Bioavailability of isoflavones requires an initial hydrolysis of the sugar moiety by intestinal beta-glucosidases to allow the following uptake by enterocytes and the flow through the peripheral circulation. Following absorption, isoflavones are then reconjugated mainly to glucuronic and sulfuric acids (Cassidy, 2003; Chiang and Pan, 2013; Vitale et al., 2013).
2. Phytoestrogen classification and structure On the basis of their chemical structure and in respect to biosynthesis patterns, phytoestrogens may be divided in chalcones, flavonoids (flavones, flavonols, flavanones, isoflavonoids), lignans, stilbenoids, and miscellaneous classes. Particular attention should be given to isoflavonoids, the subgroup of flavonoids which includes amongst others the chemical groups of isoflavones, isoflavanones, 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). Isoflavones are found in legumes—mainly soybeans, flaxseed is a major source of lignans, and coumestans are significantly present in clover, alfalfa and soybean sprouts. 8-Prenyl flavonoids 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 microflora (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
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 specific 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 hypothalamo–hypophysial axis), gonads, reproductive tract, placenta, mammary gland, bones, gastrointestinal tract, lung a.o. This suggests that phytoestrogens may exert tissue specific hormonal effects (Cassidy, 2003; Younes and Honma, 2011; Böttner et al., 2013). The estrogen receptor-specific 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
Fig.1. Molecular structure of the most ubiquitous phytoestrogens (from Michel et al., 2013)
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factors NF-kappaB and DNA topoisomerase activities (Vina et al., 2011; Ming et al., 2013), histone modification, RNA expression (Rietjens et al., 2013) and other intracellular regulators of cell cycle 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 difficult to discriminate due to multiple signaling pathways mediating phytoestrogen effects and the insufficient 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, isoflavone 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 isoflavones, 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 isoflavones 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 (isoflavones, lignans, coumestans of different botanical sources) in pre- and postmenopausal period may prevent the menopausal symptoms induced by declined endogenous estrogen production – hot flashes, 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 isoflavone 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 significant reduction of somatic-vegetative and psychological symptoms of menopause under the influence 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 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 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 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 phytoestrogen 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). 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 significantly 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 deficit 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 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 be especially potent enhancer of osteoblastic differentiation and
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maturation and an inhibitor of osteoclast formation and bone resorption through inducing osteoclastogenic inhibitor osteoprotegerin and blocking NF-kappaB signaling, whilst these effects are 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 beneficial 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 profile (reduce levels of LDL cholesterol), angiogenesis, inflammation, 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 isoflavones 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 benefits of phytoestrogens and the data from clinical trials, which failed to demonstrate significant effect of isoflavones 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-inflammatory 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 β cells failure and apoptosis. These two dysfunctions are the fundamental defects that precede type 2 diabetes. An isoflavone genistein can exert the suppressive effect on obesity and type 2 diabetes via inhibition the adipocyte life-cycle, obesity-related lowgrade inflammation, 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, isoflavones 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 isoflavones failed to influence 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
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promise to improve cognitive brain function. Some evidence, that phytoestrogens may affect congitive functions, and that these effect may be sex-specific have been published, but due to discrepancy among the published studies and their results, no definitive 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 isoflavones 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 flavonoids expressed various pharmacological potentials and mechanisms of action on the catecholamine system in adrenal medullary cells and sympathetic neurons. For example, both soy isoflavone daidzein and cytrus isoflavone nobiletin can stimulate catecholamine synthesis via plasma membrane estrogen receptor and Ser19 and Ser40 of tyrosine hydroxylase and Ca2þ influx respectively. In addition, soy isoflavone 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 (Viña 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 (Viña 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 influence 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 inflammation and immune response (Vina et al., 2011; Chiang and Pan, 2013; Ming et al., 2013) suggest potential influence of phytoestrogens on immune system. Genistein can suppresses antigen-specific 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 inflammatory responses (Sakai and Kogiso, 2008). Several epidemiological studies suggest that consumption of traditional soy food containing isoflavones is associated with reduced prevalence of chronic health disorders. Nevertheless, the potential therapeutic action of isoflavones 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,
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tissue vascularization, decreased apoptosis, immune response and other processes whose can be under control of estrogens (Rietjens et al., 2013; Viedma-Rodríguez 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 isoflavone 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 benefit of soy isoflavones for prevention of colon (Branca and Lorenzetti, 2005), endometrial and ovarian cancer (Eden, 2012). On the contrary, the breast cancer studies generated conflicting and even negative evidence from epidemiological, intervention and experimental animal studies regarding the chemopreventing effects of soy isoflavones 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 isoflawones 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 isoflavones to prevent breast cancer. Men may benefit from the intake of soy isoflavones with regard to reducing the risk of prostate cancer (Andres et al., 2011). Metaanalyses of the two studies including men with identified risk of prostate cancer found a significant reduction in prostate cancer diagnosis following administration of soy/soy isoflavones (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 significantly 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 flaxseed 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, finally, the epidemiological studies have proved the anticarcinogenic activity of the components of the flaxseed 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
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.
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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 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 benefits 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 first 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 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 production, 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 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.
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Contents lists available at ScienceDirect
European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar
Phytoestrogens and their effects Alexander V. Sirotkin a,b,n, Abdel Halim Harrath b a b
Constantine the Philosopher University, Nitra and Research Institute of Animal Production, Lužianky, Slovak Republic Dept. of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
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, classification, 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 classification 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
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Corresponding author. E-mail addresses: [email protected], [email protected] (A.V. Sirotkin).
http://dx.doi.org/10.1016/j.ejphar.2014.07.057 0014-2999/& 2014 Elsevier B.V. All rights reserved.
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application of plant bioactive compounds has increased dramatically over the last decade. Of particular interest in relation to 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 efficient tool to prevent and to treat several dysfunctions and diseases related to aging,
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mental processes, metabolism, malignant transformation, cardiovascular diseases and reproduction - breast and prostate cancers, menopausal symptoms, osteoporosis, atherosclerosis and stroke, 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.
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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). Bioavailability of isoflavones requires an initial hydrolysis of the sugar moiety by intestinal beta-glucosidases to allow the following uptake by enterocytes and the flow through the peripheral circulation. Following absorption, isoflavones are then reconjugated mainly to glucuronic and sulfuric acids (Cassidy, 2003; Chiang and Pan, 2013; Vitale et al., 2013).
2. Phytoestrogen classification and structure On the basis of their chemical structure and in respect to biosynthesis patterns, phytoestrogens may be divided in chalcones, flavonoids (flavones, flavonols, flavanones, isoflavonoids), lignans, stilbenoids, and miscellaneous classes. Particular attention should be given to isoflavonoids, the subgroup of flavonoids which includes amongst others the chemical groups of isoflavones, isoflavanones, 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). Isoflavones are found in legumes—mainly soybeans, flaxseed is a major source of lignans, and coumestans are significantly present in clover, alfalfa and soybean sprouts. 8-Prenyl flavonoids 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 microflora (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
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 specific 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 hypothalamo–hypophysial axis), gonads, reproductive tract, placenta, mammary gland, bones, gastrointestinal tract, lung a.o. This suggests that phytoestrogens may exert tissue specific hormonal effects (Cassidy, 2003; Younes and Honma, 2011; Böttner et al., 2013). The estrogen receptor-specific 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
Fig.1. Molecular structure of the most ubiquitous phytoestrogens (from Michel et al., 2013)
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factors NF-kappaB and DNA topoisomerase activities (Vina et al., 2011; Ming et al., 2013), histone modification, RNA expression (Rietjens et al., 2013) and other intracellular regulators of cell cycle 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 difficult to discriminate due to multiple signaling pathways mediating phytoestrogen effects and the insufficient 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, isoflavone 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 isoflavones, 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 isoflavones 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 (isoflavones, lignans, coumestans of different botanical sources) in pre- and postmenopausal period may prevent the menopausal symptoms induced by declined endogenous estrogen production – hot flashes, 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 isoflavone 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 significant reduction of somatic-vegetative and psychological symptoms of menopause under the influence 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 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 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 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 phytoestrogen 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). 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 significantly 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 deficit 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 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 be especially potent enhancer of osteoblastic differentiation and
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maturation and an inhibitor of osteoclast formation and bone resorption through inducing osteoclastogenic inhibitor osteoprotegerin and blocking NF-kappaB signaling, whilst these effects are 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 beneficial 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 profile (reduce levels of LDL cholesterol), angiogenesis, inflammation, 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 isoflavones 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 benefits of phytoestrogens and the data from clinical trials, which failed to demonstrate significant effect of isoflavones 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-inflammatory 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 β cells failure and apoptosis. These two dysfunctions are the fundamental defects that precede type 2 diabetes. An isoflavone genistein can exert the suppressive effect on obesity and type 2 diabetes via inhibition the adipocyte life-cycle, obesity-related lowgrade inflammation, 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, isoflavones 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 isoflavones failed to influence 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
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promise to improve cognitive brain function. Some evidence, that phytoestrogens may affect congitive functions, and that these effect may be sex-specific have been published, but due to discrepancy among the published studies and their results, no definitive 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 isoflavones 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 flavonoids expressed various pharmacological potentials and mechanisms of action on the catecholamine system in adrenal medullary cells and sympathetic neurons. For example, both soy isoflavone daidzein and cytrus isoflavone nobiletin can stimulate catecholamine synthesis via plasma membrane estrogen receptor and Ser19 and Ser40 of tyrosine hydroxylase and Ca2þ influx respectively. In addition, soy isoflavone 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 (Viña 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 (Viña 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 influence 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 inflammation and immune response (Vina et al., 2011; Chiang and Pan, 2013; Ming et al., 2013) suggest potential influence of phytoestrogens on immune system. Genistein can suppresses antigen-specific 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 inflammatory responses (Sakai and Kogiso, 2008). Several epidemiological studies suggest that consumption of traditional soy food containing isoflavones is associated with reduced prevalence of chronic health disorders. Nevertheless, the potential therapeutic action of isoflavones 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,
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tissue vascularization, decreased apoptosis, immune response and other processes whose can be under control of estrogens (Rietjens et al., 2013; Viedma-Rodríguez 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 isoflavone 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 benefit of soy isoflavones for prevention of colon (Branca and Lorenzetti, 2005), endometrial and ovarian cancer (Eden, 2012). On the contrary, the breast cancer studies generated conflicting and even negative evidence from epidemiological, intervention and experimental animal studies regarding the chemopreventing effects of soy isoflavones 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 isoflawones 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 isoflavones to prevent breast cancer. Men may benefit from the intake of soy isoflavones with regard to reducing the risk of prostate cancer (Andres et al., 2011). Metaanalyses of the two studies including men with identified risk of prostate cancer found a significant reduction in prostate cancer diagnosis following administration of soy/soy isoflavones (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 significantly 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 flaxseed 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, finally, the epidemiological studies have proved the anticarcinogenic activity of the components of the flaxseed 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
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.
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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 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 benefits 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 first 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 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 production, 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 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.
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