**5.1 Effects on serum lipid levels**

Obesity is associated with disruption in lipid and sugar metabolism, and is a principal cause of chronic diseases, namely cardiovascular diseases, hypertension, atherosclerosis and type II diabetes mellitus. This makes obesity a major health problem, which has reached pandemic proportions. The treatment for obesity is lifestyle change, including diet restriction and exercise. However, pharmacological treatment is often necessary. Isoflavones are of particular interest as an alternative to statins or fibrates in potential lowering of serum lipid levels.

Epidemiologic studies demonstrated a reduced rate of mortality due to coronary hearth disease in Japanese postmenopausal women populations consuming a traditional Japanese diet. On the other side expatriate Japanese living in the US had higher blood pressure and cholesterol levels than the Japanese still living in Japan. Some authors proposed that detected differences are not of genetic origin but are due to diet rich in soy products, fish and fiber (Adlercreutz et al., 1998).

Anderson et al. (1995) published a meta-analysis that attracted widespread attention, demonstrating that intake of at least 25g of soy protein per day lowered total and low density lipoprotein (LDL) cholesterol. Lipid lowering potential of soy protein was also demonstrated in various animal studies (Greaves, et al., 1999; Potter, et al., 1995). This led to U.S. Food and Drug Administration (FDA) issuing a health claim for soy protein and coronary hearth disease (1999). FDA also claimed that the evidence did not support significant role of isoflavones in lipid-lowering effects of soy protein. Some more recent reports also demonstrated a significant reduction in plasma concentrations of total and LDL cholesterol in humans exposed to soy proteins (Greany et al., 2004; Teixeira et al., 2000).

Due to their estrogenic activity, isoflavones may be the bioactive component attributed to soy protein. This possibility was examined using different experimental approaches and

Marcelet al., 2001). In vitro tests also showed that soy isoflavone genistein induced apoptosis and inhibited growth of both androgen-sensitive and androgen-independent prostate cancer

Wuttke et al. (2010) in a recent review provided detailed analysis of both in vitro and animal experimental data and concluded that isoflavones may protect the prostate to make it less

In conclusion, based on inconsistent evidence, it is apparent that the use of phytoestrogens as chemopreventive agents is still in its infancy, justifying a need for further research. Experimental studies based on nutritionally relevant doses are needed to clarify potential health benefits, as well as estrogenic, antiandrogenic and/or nonestrogenic isoflavone

**5. Soybean phytoestrogens in prevention and therapy of cardiovascular** 

Soy protein and isoflavones received great attention and provoked heated discussions due to their potential role in reducing risks of cardiovascular diseases. Following is a historical overview of the most relevant results and announcements related to clinical trials, as well as of animal and in vitro research, providing insight into potential mechanisms of isoflavone

Obesity is associated with disruption in lipid and sugar metabolism, and is a principal cause of chronic diseases, namely cardiovascular diseases, hypertension, atherosclerosis and type II diabetes mellitus. This makes obesity a major health problem, which has reached pandemic proportions. The treatment for obesity is lifestyle change, including diet restriction and exercise. However, pharmacological treatment is often necessary. Isoflavones are of particular interest as an alternative to statins or fibrates in potential lowering of serum

Epidemiologic studies demonstrated a reduced rate of mortality due to coronary hearth disease in Japanese postmenopausal women populations consuming a traditional Japanese diet. On the other side expatriate Japanese living in the US had higher blood pressure and cholesterol levels than the Japanese still living in Japan. Some authors proposed that detected differences are not of genetic origin but are due to diet rich in soy products, fish

Anderson et al. (1995) published a meta-analysis that attracted widespread attention, demonstrating that intake of at least 25g of soy protein per day lowered total and low density lipoprotein (LDL) cholesterol. Lipid lowering potential of soy protein was also demonstrated in various animal studies (Greaves, et al., 1999; Potter, et al., 1995). This led to U.S. Food and Drug Administration (FDA) issuing a health claim for soy protein and coronary hearth disease (1999). FDA also claimed that the evidence did not support significant role of isoflavones in lipid-lowering effects of soy protein. Some more recent reports also demonstrated a significant reduction in plasma concentrations of total and LDL cholesterol in humans exposed to soy proteins (Greany et al., 2004; Teixeira et al., 2000). Due to their estrogenic activity, isoflavones may be the bioactive component attributed to soy protein. This possibility was examined using different experimental approaches and

cells (Hussain et al., 2003).

prone to develop cancer.

**diseases** 

action.

lipid levels.

activities in the breast and prostate tumors.

**5.1 Effects on serum lipid levels** 

and fiber (Adlercreutz et al., 1998).

animal models. Some research studies highlighted a favorable hypolipidemic effect related to isoflavones, at least when consumed in combination with soy proteins. Removal of the isoflavone-containing fraction from soy protein resulted in a loss of its beneficial effect on the serum lipid profile and atherosclerosis progression in mice (Kirk et al., 1998), in golden Syrian hamsters (Lucas, et al., 2001), and in rhesus monkeys (Anthony et al. 1996). High isoflavone, combined with high soy protein intake leads to significantly decreased serum total and LDL cholesterol compared to low isoflavone intake. Some authors reported that ingested purified isoflavones exert lipid-lowering effects (Ae Park et al. 2006; Kojima et al. 2002; Sosić-Jurjević et al., 2007). However, others showed minimal or no effects of isolated isoflavones on blood lipid levels (Greaves et al., 1999; Molsiri et al., 2004).

Clinical trials also show diverse beneficial effects of isoflavone supplements on cardiovascular system. These discrepancies may be a result of different intestinal bacterial flora and hence bioavailability of soy isoflavone metabolites. Other reasons might be differences in dose–response effects (Hooper et al., 2008), sex and length of isoflavone supplementation (Zhan & Ho, 2005), limited number of subjects, or pre-existing metabolic status of subjects included in supplement trials (Villa et al., 2009).

In contrast to previously mentioned data, in 22 random trials, isolated soy protein combined with isoflavones, compared with milk or other proteins, decreased LDL cholesterol by approximately 3%. This reduction was small in comparison to amount of soy protein (average 50g per day) intake (Sacks et al., 2006). There was no detected benefit on level of HDL cholesterol, triglycerides or blood pressure. These authors concluded that soy food may be beneficial to cardiovascular health because of their high content of fiber, vitamins, high content of polyunsaturated fat, rather than and its isoflavone content. Recent review of the animal models used to investigate the health benefits of soy isoflavones also concluded that the efficiency of isoflavones in improving lipid profile is less than earlier research suggested (Cooke, 2006).

For this reason, American Hearth Association issued a discoursing statement, and warned that earlier research indicating clinically important favorable effects of soy products on low density lipoprotein (LDL) is not confirmed by most studies during the past 10 years. U.S. FDA announced its intent to reevaluate the data related to cardio protective effects of soy (2007).

More recent research demonstrated that the combined intervention of genistein and lcarnitine act synergistically in reducing serum lipid and LDL levels, as well as reducing body weight in mice and rats (Che et al., 2011; Yang et al., 2006). In addition, synergy portfolio diet, containing plant sterols, viscous fibers and soy protein reduced serum LDL cholesterol similar to traditional statin drugs (Jenkins et al., 2003). Therefore, soybean isoflavones, either as natural components of food or as nutritional supplements, in combination with other functional food may favorably alter indicators of cardiovascular disease risk.

Though positive effects on metabolism in humans have been widely debated, studies in rodents should help in identifying and evaluating the biologically relevant mechanisms involved in isoflavone actions.

ERs are important mediators of the action of estrogen on lipid metabolism both in males and females. Men with mutations in the aromatase gene (enzyme that converts androgens to estrogens) display truncal obesity, insulin resistance and hyperlipidemia (Carani et al., 1997). Due to structural similarities of isoflavones and E2, G and D might also directly influence the regulation of adipogenesis. However, it must be noticed that genistein

Soybean Phytoestrogens – Friends or Foes? 141

(our unpublished data) in comparison to the control values. Therefore, the local production of T3 in liver was increased and the local increase of T3 might contribute to the detected

Atherosclerosis is part of the normal aging process but its progression depends on a wide range of environmental and genetic factors (Davies et al., 2004). Generally, atherosclerosis refers to the formation and hardening of fatty plaques (atheromas) on the inner surface of the arteries. The arteries not only harden, they become narrow. Such narrowed vessels can be easily blocked by constriction or objects in the bloodstream. Atherosclerosis begins with injury to endothelial cells, exposing portions of the artery surface below the endothelium. Free radicals or other irritants could start the process, as well as high blood pressure. Platelets cluster around the injured endothelial cells and release prostaglandins, which cause the endothelial cells to proliferate. LDL-cholesterol particles release their fat into the areas made porous by prostaglandins. Macrophages swell themselves on oxidized LDLcholesterol until they become "foam cells" that invade atheromas. The atheromas are

The atheroprotective effects of soy-based diets have been partly attributed to the associated reduction in cholesterol levels in human studies (Jenkins et al., 2002). Similar findings have also been reported in nonhuman primates fed soy-based diets (Anthony et al., 1997; Register et al., 2005). Animal studies with rabbits and hamsters, which are considered a good nonprimate model for studies of atherosclerosis, demonstrated that soy isoflavones reduce atherosclerotic lesion areas in the aortic arch by means of LDL reduction (Alexandersen et al., 2001; Lucas et al., 2003). In addition, atherosclerotic changes induced by a cholesterol rich diet were prevented by isoflavones in rabbits, hamsters and premenopausal monkeys (Adams, et al. 2005; Lucas et al., 2001). The intake of genistein and daidzein decreases LDL oxidation (Tikkanen, et al., 1998). Both genistein and daidzein have also been shown to protect human umbilical cord endothelial cells and bovine aortic endothelial cells from the

However, numerous animal studies suggest that dietary soy inhibits atherosclerotic lesion

Isoflavones are reported to prevent lipid peroxidation by scavenging lipid-derived peroxyl radicals (Patel et al., 2001) and inhibit copper-dependent LDL oxidation (Kerry & Abbey, 1998). It is well known that oxidized LDL is more prone to induce atherosclerosis than unoxidized form. In addition, proteome analyses revealed protein targets that in response to soy isoflavones increase the anti-inflammatory response in blood mononuclear cells thereby contributing to the atherosclerosis-preventive activities of a soy-rich diet (Wenzel et al., 2008). Studies in apolipoprotein E knock-out mice showed that atherosclerotic lesions are reduced when fed a soy-containing diet despite unchanged serum lipid levels (Adams et al., 2002). Findings from a recent study in aged lipoprotein receptor knock-out mice has underscored the importance of oxidative stress coupled with a failure to up-regulate There is now compelling evidence that isoflavone supplementation have anti-inflammatory functions and hence can represent an effective therapeutic strategy to enhance Nrf2 activity

Vasodilatatory effects of isoflavones may be also related to their estrogenic actions. Both estrogen receptors α and β are expressed in the arteries (Christian et al., 2006). Estrogens have been shown to stimulate inducible NO synthase in endothelial cells and the increased

hardened by fibrin, which forms scar tissue, and finally calcium patches.

atherogenic effect of oxidized LDL (Kapiotis et al., 1997).

development by mechanisms other than lowering serum cholesterol.

to protect the aging vasculature (Adams et al., 2002; Mulvihill & Huff, 2010).

decrease in total cholesterol and LDL levels.

**5.2 Effects on atherosclerosis progression** 

preferably binds to ERβ, while ERα is predominantly found in liver. In ovariectomized mice, estradiol and genistein did not increase estrogen-responsive genes in the liver, and the authors suggested that the cholesterol–lowering ability of estrogen requires estrogen receptors (they postulated crosstalk between ERs and NF κβ) but not estrogen receptordependent gene transcription (Evans et al., 2001).

Isoflavones may have distinct influences on metabolism in males and females. Males have a different number and distribution of ERs compared to females. It is important to realize the impact of other hormones such as androgens and thyroid hormones on liver and other metabolic tissues. Using ovariectomized Wistar rats Molsiri et al. (2004) obtained no significant difference in serum lipid levels after s.c. genistein injections, while we detected lipid lowering effect of both G and D (similar to this obtained for testosterone-treated groups) in orchidectomized young and middle-aged adults, as well as in testis-intact middle-aged male rats (Sosić-Jurjević et al., 2007 and our unpublished data).

Aside from having estrogenic activity (Potter et al., 1995), both G and D exert "phytofibrate" and or "phytoglitazone"аctivity, and activate peroxisome proliferator-activated receptors (PPAR) α and γ (Mezei et al., 2006). PPARs bind a wide number of ligands and directly affect lipid metabolism by enhancing transcription of PPAR-regulated genes (Shen et al., 2006). Generally, PPARα controls the transcription of many genes involved in lipid catabolism, whereas PPARγ controls the expression of genes involved in adipocyte differentiation and insulin sensation. PPARα is important for β-oxidation and is mainly expressed in liver, kidney, heart, and muscle, where lipoprotein metabolism is important. PPARγ is mainly expressed in adipose tissues and is considered the master regulator of adipogenesis (Rosen, 2005; Ørgaard & Jensen, 2008).

Isoflavones may also affect lipid metabolism indirectly, via effect on thyroid function and/or thyroid hormone action in liver. T3 and its receptor (TR) play important role in regulation of energy homeostasis, metabolic processes and body weight. Hypothyroidism causes hypercholesterolaemia characterized by increased levels of LDL (Sasaki, et al., 2006).TRβ1 is the major TR in the liver while T3 action is mediated via TRα1 in the heart. TRβ1 agonist KB-141 lower cholesterol, increases metabolic rate and decreases body weight (Grover et al., 2005). Xiao et al. (2007) described that expression of the rat hepatic thyroid hormone receptor β1 is upregulated by isoflavones. In addition, E interplay with TH in regulation of different physiological functions including effects on growth, bone mass, and triglycerides. E can be viewed as a modulator whose response relies on interplay with T3 signaling mechanisms (DiPippo et al., 1995).

Many researchers have tried to link effects of soy intake on lipid metabolism with modulation of thyroid hormone levels. However, it is still difficult to demonstrate clear-cut effects on thyroid (this topic would be analyzed in more details in a subchapter related to endocrine disruptive potential of isoflavones). On the other hand, most researchers who examined lipid-lowering potential of isoflavones did not include in their research examining of the thyroid status, or deiodinase I enzyme activity in liver. When examining the effects of G and D that should mimic exposure to supplements (10mg/kg) in orchidectomized middle-aged male rats our research team obtained that both G and D decreased the serum total cholesterol and LDL levels similar to control testosterone treatment, and brought about an increase in serum triglycerides similar to that observed after control estradiol treatment (Sosić-Jurjević et al., 2007). Within the same animal model we detected significant decrease of serum thyroid hormones (Sosić-Jurjević et al., 2010). However, when we examined deiodinase I enzyme activity in liver of G and D treated rats, it was significantly increased

preferably binds to ERβ, while ERα is predominantly found in liver. In ovariectomized mice, estradiol and genistein did not increase estrogen-responsive genes in the liver, and the authors suggested that the cholesterol–lowering ability of estrogen requires estrogen receptors (they postulated crosstalk between ERs and NF κβ) but not estrogen receptor-

Isoflavones may have distinct influences on metabolism in males and females. Males have a different number and distribution of ERs compared to females. It is important to realize the impact of other hormones such as androgens and thyroid hormones on liver and other metabolic tissues. Using ovariectomized Wistar rats Molsiri et al. (2004) obtained no significant difference in serum lipid levels after s.c. genistein injections, while we detected lipid lowering effect of both G and D (similar to this obtained for testosterone-treated groups) in orchidectomized young and middle-aged adults, as well as in testis-intact

Aside from having estrogenic activity (Potter et al., 1995), both G and D exert "phytofibrate" and or "phytoglitazone"аctivity, and activate peroxisome proliferator-activated receptors (PPAR) α and γ (Mezei et al., 2006). PPARs bind a wide number of ligands and directly affect lipid metabolism by enhancing transcription of PPAR-regulated genes (Shen et al., 2006). Generally, PPARα controls the transcription of many genes involved in lipid catabolism, whereas PPARγ controls the expression of genes involved in adipocyte differentiation and insulin sensation. PPARα is important for β-oxidation and is mainly expressed in liver, kidney, heart, and muscle, where lipoprotein metabolism is important. PPARγ is mainly expressed in adipose tissues and is considered the master regulator of

Isoflavones may also affect lipid metabolism indirectly, via effect on thyroid function and/or thyroid hormone action in liver. T3 and its receptor (TR) play important role in regulation of energy homeostasis, metabolic processes and body weight. Hypothyroidism causes hypercholesterolaemia characterized by increased levels of LDL (Sasaki, et al., 2006).TRβ1 is the major TR in the liver while T3 action is mediated via TRα1 in the heart. TRβ1 agonist KB-141 lower cholesterol, increases metabolic rate and decreases body weight (Grover et al., 2005). Xiao et al. (2007) described that expression of the rat hepatic thyroid hormone receptor β1 is upregulated by isoflavones. In addition, E interplay with TH in regulation of different physiological functions including effects on growth, bone mass, and triglycerides. E can be viewed as a modulator whose response relies on interplay with T3

Many researchers have tried to link effects of soy intake on lipid metabolism with modulation of thyroid hormone levels. However, it is still difficult to demonstrate clear-cut effects on thyroid (this topic would be analyzed in more details in a subchapter related to endocrine disruptive potential of isoflavones). On the other hand, most researchers who examined lipid-lowering potential of isoflavones did not include in their research examining of the thyroid status, or deiodinase I enzyme activity in liver. When examining the effects of G and D that should mimic exposure to supplements (10mg/kg) in orchidectomized middle-aged male rats our research team obtained that both G and D decreased the serum total cholesterol and LDL levels similar to control testosterone treatment, and brought about an increase in serum triglycerides similar to that observed after control estradiol treatment (Sosić-Jurjević et al., 2007). Within the same animal model we detected significant decrease of serum thyroid hormones (Sosić-Jurjević et al., 2010). However, when we examined deiodinase I enzyme activity in liver of G and D treated rats, it was significantly increased

middle-aged male rats (Sosić-Jurjević et al., 2007 and our unpublished data).

dependent gene transcription (Evans et al., 2001).

adipogenesis (Rosen, 2005; Ørgaard & Jensen, 2008).

signaling mechanisms (DiPippo et al., 1995).

(our unpublished data) in comparison to the control values. Therefore, the local production of T3 in liver was increased and the local increase of T3 might contribute to the detected decrease in total cholesterol and LDL levels.

#### **5.2 Effects on atherosclerosis progression**

Atherosclerosis is part of the normal aging process but its progression depends on a wide range of environmental and genetic factors (Davies et al., 2004). Generally, atherosclerosis refers to the formation and hardening of fatty plaques (atheromas) on the inner surface of the arteries. The arteries not only harden, they become narrow. Such narrowed vessels can be easily blocked by constriction or objects in the bloodstream. Atherosclerosis begins with injury to endothelial cells, exposing portions of the artery surface below the endothelium. Free radicals or other irritants could start the process, as well as high blood pressure. Platelets cluster around the injured endothelial cells and release prostaglandins, which cause the endothelial cells to proliferate. LDL-cholesterol particles release their fat into the areas made porous by prostaglandins. Macrophages swell themselves on oxidized LDLcholesterol until they become "foam cells" that invade atheromas. The atheromas are hardened by fibrin, which forms scar tissue, and finally calcium patches.

The atheroprotective effects of soy-based diets have been partly attributed to the associated reduction in cholesterol levels in human studies (Jenkins et al., 2002). Similar findings have also been reported in nonhuman primates fed soy-based diets (Anthony et al., 1997; Register et al., 2005). Animal studies with rabbits and hamsters, which are considered a good nonprimate model for studies of atherosclerosis, demonstrated that soy isoflavones reduce atherosclerotic lesion areas in the aortic arch by means of LDL reduction (Alexandersen et al., 2001; Lucas et al., 2003). In addition, atherosclerotic changes induced by a cholesterol rich diet were prevented by isoflavones in rabbits, hamsters and premenopausal monkeys (Adams, et al. 2005; Lucas et al., 2001). The intake of genistein and daidzein decreases LDL oxidation (Tikkanen, et al., 1998). Both genistein and daidzein have also been shown to protect human umbilical cord endothelial cells and bovine aortic endothelial cells from the atherogenic effect of oxidized LDL (Kapiotis et al., 1997).

However, numerous animal studies suggest that dietary soy inhibits atherosclerotic lesion development by mechanisms other than lowering serum cholesterol.

Isoflavones are reported to prevent lipid peroxidation by scavenging lipid-derived peroxyl radicals (Patel et al., 2001) and inhibit copper-dependent LDL oxidation (Kerry & Abbey, 1998). It is well known that oxidized LDL is more prone to induce atherosclerosis than unoxidized form. In addition, proteome analyses revealed protein targets that in response to soy isoflavones increase the anti-inflammatory response in blood mononuclear cells thereby contributing to the atherosclerosis-preventive activities of a soy-rich diet (Wenzel et al., 2008). Studies in apolipoprotein E knock-out mice showed that atherosclerotic lesions are reduced when fed a soy-containing diet despite unchanged serum lipid levels (Adams et al., 2002). Findings from a recent study in aged lipoprotein receptor knock-out mice has underscored the importance of oxidative stress coupled with a failure to up-regulate There is now compelling evidence that isoflavone supplementation have anti-inflammatory functions and hence can represent an effective therapeutic strategy to enhance Nrf2 activity to protect the aging vasculature (Adams et al., 2002; Mulvihill & Huff, 2010).

Vasodilatatory effects of isoflavones may be also related to their estrogenic actions. Both estrogen receptors α and β are expressed in the arteries (Christian et al., 2006). Estrogens have been shown to stimulate inducible NO synthase in endothelial cells and the increased

Soybean Phytoestrogens – Friends or Foes? 143

In addition to effects on osteoblasts, many authors have reported that isoflavones are efficacious in suppressing osteoclast activity in vitro. Genistein completely inhibited bone resorption and osteoclast-like multinucleated cells in culture with bone-resorbing factors (Gao & Yamaguchi, 1999a; Yamaguchi & Gao, 1998a). Also, daidzein inhibited the development of osteoclasts from cultures of porcine bone marrow and reduced bone

While in vitro studies reveal possible actions of isoflavones on individual bone cells, in vivo studies provide insight into the effects of isoflavones on the intact system and coupling effects between osteoblasts and osteoclasts. Most of the animal bone studies investigating isoflavone action have been performed in rodents. Aged ovariectomized female and orchidectomized male rats represent a suitable model for simulating osteoporosis due to estrogen or androgen deficiency (Comelekoglu et al., 2007; Filipović et al., 2007; Pantelić et al., 2010; Turner, 2001; Vanderschueren et al., 1992). Using this animal model, supplementation with isoflavones has been shown to prevent bone loss (Fig. 2) induced by gonadal hormone deficiency (Filipović et al., 2010; Khalil et al., 2005; Lee et al., 2004; Om & Shim, 2007; Ren et al., 2007; Soung et al., 2006). In a randomized placebo controlled trial with estrogen and phytoestrogen on ovariectomized nonhuman primates, Ham et al. (2004) failed to show any efficacy of soy phytoestrogens in decreasing all indices of bone turnover as estrogen does, but soy phytoestrogens were able to increase bone volume, trabecular number and decrease trabecular separation, stressing the importance of phytoestrogens in

Fig. 2. Trabecular bone microarchitecture of the proximal tibia in control orchidectomized (a) and daidzein-treated orchidectomized (b) rat; аzan staining method; unpublished image

Phytoestrogens may elicit a bone sparing effect by both genomic and nongenomic mechanisms. They are able to interact with enzymes and receptors and, their stable structure and low molecular weight enables them to pass through cell membranes (Adlercreutz et al., 1998). The structural similarity of phytoestrogens to mammalian estrogens and their ability to bind to estrogen receptors (Setchell et al., 1999) suggests that the actions of phytoestrogens are mediated via estrogen receptors. ERα and ERβ have been detected in bone (Arts et al., 1997; Onoe et al., 1997). The relative binding affinity of phytoestrogens for ERβ is greater than that for ERα, and the protective effect of phytoestrogens on bone is probably produced through binding to estrogen receptors, particularly ERβ (Kuiper et al., 1998). In addition, phytoestrogens such as coumestrol, genistein and daidzein increase alkaline phosphatase activity in osteoblast-like cells (Kanno et al., 2004). Daidzein stimulates

resorption (Rassi et al., 2002).

postmenopausal osteoporosis prevention.

of Filipovic et al.

NO production causes relaxation of artherial myocites (Mahn et al., 2005). Research on the effect of genistein on plasma nitric oxide concentrations, endothelin-1 levels and endothelium-dependent vasodilatation in postmenopausal women revealed that genistein therapy improved flow-mediated endothelium-dependent vasodilatation in healthy postmenopausal women. This improvement is probably mediated by a direct effect of genistein on vascular function and could be the result of an increased ratio of nitric oxide to endothelin (Squadrito et al., 2002).

In conclusion, despite the fact that dietary soy products and isoflavones are heavily advertised for their hypolipidemic effect, their therapeutic potential is lesser than was previously hoped and depend on many factors related to inter-individual differences.
