**Soybean Phytoestrogens – Friends or Foes?**

Branka Šošić-Jurjević, Branko Filipović and Milka Sekulić *University of Belgrade, Institute for Biological Research "Siniša Stanković", Serbia* 

#### **1. Introduction**

130 Recent Trends for Enhancing the Diversity and Quality of Soybean Products

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Proper and balanced nutrition is very important in prevention and treatment of chronic diseases. Many individuals modify their diet and/or take different nutraceuticals expecting to attain optimum health, extend their lifespan and prevent diseases such as cardiovascular, cancer, osteoporosis, obesity, or diabetes type II.

Based on "Japanese phenomenon" (Adlercreutz, 1998), numerous advertisements suggest that soy-based diet, and its phytoestrogens (PE) in particular, provide protection against many chronic diseases and contribute to the long lifespan often observed in Asia. That is why soy and other phytoestrogen - rich plants became increasingly popular in the U.S. and western countries in the past 30 years. Furthermore, in these countries, PEs are often consumed in its purified form, as nutritional supplements, "designed" for special medical purposes. These supplements are freely available in pharmacies, health food shops, grocery shops and are usually consumed without medical control. There is a lack of awareness that uncontrolled consumption of natural PEs may be potentially harmful to human health. Even more concerning is that some people consume supplements in excess of suggested daily dosage (Wuttke et al., 2007).

The soybean (*Glycine max*), compared to other legumes, is richer in protein levels and quality, based on its digestibility and concentration of essential amino acids (Rand et al., 2003). It is also good source of fiber, certain vitamins and minerals, such as folate and potassium (Rochfort and Panozzo, 2007). It has very high antioxidant content, similar to fruits famous for their antioxidant activity (Galleano et al., 2010). Also, despite their high carbohydrate content, the glycemic load of soybeans is relatively low due to their low glycemic index. In addition, soy-food has high levels of iron in the form of ferritin (Lönnerdal et al., 2006). The concentration of calcium in soymilk is much lower than in cow milk, however, its absorption from soy milk is similar to that from cow milk (Reinwald and Weaver, 2010).

Besides the favorable nutritional attributes, soybean contains a number of biologically active components (saponins and lunasin, phytic acids, phytosterols, trypsin inhibitors, and peptides) including isoflavones genistein (G), daidzein (D) and glycitein (Gy). As soybean phytoestrogens, isoflavones are considered the most important in prevention and treatment of hormone-dependent cancers, cardiovascular diseases, osteoporosis, menopausal symptoms and other age-related diseases. In addition, some studies suggest that soy and its isoflavones affect body weight homeostasis.

Modern world is a controversy with ever-increasing obesity on one side, and a high percent of starving people around the globe, on the other side. Having that in mind, combined with

Soybean Phytoestrogens – Friends or Foes? 133

As a prerequisite for absorption, the sugar must be removed from the compound at some point during ingestion (Setchell et al., 2002). Soy isoflavone glycosides are hydrolyzed to their aglycones by lactase phloridizin hydrolase in the apical membrane of the lumen of the small intestine, as well as by bacterial intestinal glucosidases (Wilkinson et el., 2003). Aglycones undergo passive diffusion across the small and large intestinal brush border (Larkin et al., 2008). However, some authors claim that glycosides may be absorbed also through the active sodium–dependent glucose transporter (Gee et al., 2000). Results obtained when we examined effects of soy extract on fluidity of erythrocyte membrane, showed that genistein and isoflavone glucosides intercalate and increase the order and rigidity of the outer layer of cellular membrane. Therefore, isoflavone glucosides may be also transported across the cell membrane directly, via entropy-driven flip-flop (Ajdžanović

The absorption and bioavailability of isoflavones depends to some extent on interaction with other food components (Birt et al., 2001). The assumption that isoflavones are absorbed more efficiently from fermented than from non-fermented soy foods was re-examined and then rejected (Maskarinec et al*.*, 2008). Since intestinal microflora is capable of hydrolyzing the isoflavone glycosides from nonfermented soyfood, recommendations favoring

Genistein is stronger than daidzein in its agonistic activity for the ERs, as well as in its antioxidative potential. On the other hand, daidzein can be further metabolized into its bacterial metabolite equol, which has stronger estrogenic and antioxidative properties than both genistein and daidzein, or some other isoflavone metabolites (Mitchell et al., 1998). Although it appears that all animals produce equol following soy ingestion, in humans this is the case in approximately 30% of population (Lampe et al., 1998; Setchell et al., 2002). This is thought to be dependent on inter-individual variability in the presence of specific intestinal bacteria (Rowland et al., 2000). Besides the microflora composition, individual differences in gut transit time and redox potential of colon and genetic polymorphisms are likely to contribute to this great variability (Duffy et al., 2007). When evaluating the effects of age on equol production, it was demonstrated that during the first months of life, equol levels in plasma and urine were significantly lower than in adults, which may be due to the immature intestinal flora (Setchell et al. 2002). Lampe et al. (1998) detected no significant

The estrogenic effect of the isoflavones was first recognized when examining impaired fertility in grazing animals (Bennetts et al., 1946). Three decades later, Setchell et al. (1987) established that isoflavone-rich soy was a factor in reduced fertility of cheetahs in North American zoos. Isoflavones were classified as phytoestrogens following in vivo and in vitro demonstration of their binding potency of isoflavones for estrogen receptors (ER), as well as

Testosterone actions in numerous male tissues are mediated through its conversion to estrogen catalyzed by aromatase enzymes. Specific and β ER are detected in different male and female tissues (Korach, 1994), but the ratio between ERα and ERβ is different (Rosen, 2005). This finding has finally changed the classical view of the estrogens as exclusively female hormones. ERβ is known to modulate ERα transcriptional activity acting as an activator at low concentrations of mammalian estrogen - estradiol 17β (E2) and as an

et al., 2010, 2011). Biological significance of this mechanism is unclear.

differences in the prevalence of equol production between genders.

**3. Biological basis of soybean phytoestrogen actions** 

for sex-hormone binding globuline (Kuiper et al., 1998).

fermented soyfood cannot be justified.

observed beneficial health and weight-lowering effects, high nutritional value makes soy probably one of the most strategically important plants.

However, aside from potential beneficial effects (still under intensive investigation and not fully proven), soybean phytoestrogens may also act as endocrine disruptors, by interfering with the function of reproductive system, as well as with other endocrine systems, namely thyroid and adrenal, and may, under some circumstances, increase cancer risk. This is why scientists are intensively trying to precisely evaluate potential benefits versus adverse effects of soy. Due to the importance, the researches are done both in vitro and in vivo, using different experimental approaches, animal models and various human studies. Results obtained so far are highly inconsistent and depend on experimental conditions, applied doses, animals and humans' age and sex, type of diet, presence of other PE sources in the diet, or other factors. Moreover, it remains unclear whether soy extracts, soy concentrate and purified isoflavones have identical effects. This is why the role of soy food in diet became a somewhat confusing topic in recent years. With approximately 2000 soy-related papers published annually, and half of it related to isoflavones (Messina, 2010), it is becoming extremely difficult to compare all of the available data.

Due to the many differences in the chemical composition of soy products, and the fact that two thirds of human population cannot produce equol (Setchell et al., 2002), the authors decided to primarily focus their attention on effects of purified genistein and daidzein. We will evaluate the latest findings, using clear statements from the literature, as well as our own results, focusing on major potential healthful effects while also considering adverse effects of purified soybean phytoestrogens. More important, the authors will try to analyze the data in order to evaluate whether the net beneficial /adverse effect for each targeted organ system depends on sex and age.
