Soy, Phytoestrogens and Metabolism a Review [Volume] Molecular and Cellular Endocrinology [Issue]

8/9/2019 Soy, Phytoestrogens and Metabolism a Review [Volume] Molecular and Cellular Endocrinology [Issue]

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Please cite this article in press as: Cederroth, C.R., Nef, S., Soy, phytoestrogens and metabolism: A review. Mol. Cell. Endocrinol. (2009),doi:10.1016/j.mce.2009.02.027

ARTICLE IN PRESSG Model

MCE7153113

Molecular and Cellular Endocrinology xxx (2009) xxxxxx

Contents lists available at ScienceDirect

Molecular and Cellular Endocrinology

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m c e

Review

Soy, phytoestrogens and metabolism: A review2

Christopher R. Cederroth, Serge Nef3

Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva 4, Switzerland4

5

a r t i c l e i n f o6

7

Article history:8

Received 14 January 20099

Accepted 24 February 20090

Keywords:2

Dietary soy3

Phytoestrogens4

Isoflavones5

Genistein6

Endocrine disruptor7

Obesity8

Glycemia9

a b s t r a c t

Of any plant, soy contains the largest concentration of isoflavones, a class of phytoestrogens. Phytoestro-

gens are structurally similar to estradiol and mimic its effects. Soy and phytoestrogens receive increasing

attention due to the health benefits associated withtheir consumption. Herewe review the datacollected

on theeffects of soy andphytoestrogens on glucose andlipid metabolism andtheir possible mechanismsof action. Overall, there is a suggestive body of evidence that soy and dietary phytoestrogens favorably

alter glycemic control, improve weight and fat loss, lower triglycerides, low density lipoprotein (LDL)

cholesterol and total cholesterol. However, these results must be interpreted with care, and additional

evidence is needed before a firm conclusion can be drawn. In particular, since not all activities related

to soy can be assigned to the estrogenic-like activity, further studies are needed to identify firstly which

soy constituent(s) improve metabolic parameters when ingested and secondly, which are the mecha-

nisms whereby dietary soy improves metabolic-related conditions like obesity and diabetes. Finally, the

potential detrimental effects of soy and phytoestrogens are briefly discussed.

2009 Published by Elsevier Ireland Ltd.

Contents0

1. Metabolic diseases and therapeutic alternatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

2. Soybean composition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002

3. Absorption and metabolism of isoflavones . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003

4. Soy consumption and phytoestrogen levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004

5. Phytoestrogens: complex hormetic compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005

6. Role of estrogens in metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006

7. Effects of soy protein and phytoestrogens on human metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007

8. Actions of soy on metabolism in rodents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 008

9. Central actions of phytoestrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 009

10. Potentially adverse effects in consuming soy and soy-derive d phytoestrogens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 00

11. Summary and conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003

4

1. Metabolic diseases and therapeutic alternatives5

Obesity and its related disorders, such as type 2 diabetes, car-6

diovascular diseases (CVD),high bloodpressure, dyslipidemia[high7

levels of circulating triacylglycerols and low density lipoprotein8

(LDL) cholesterol, and low levels of high density lipoprotein (HDL)9

cholesterol],have recentlybecome a major health problemreaching0

pandemic proportions (Engelgau et al., 2004). These diseases, com-

monly referred to as the Metabolic Syndrome (MS), are beginning2

Corresponding author.

E-mail address: [email protected] (S. Nef).

to surpass malnutrition and infectious diseases as the most sig-

nificant contributor to worldwide morbidity. In western societies,

for the first time in modern history, life expectancy of newborns is

declining as a result of these metabolic disorders (Olshansky et al.,

2005). The rapid increase in obesity suggests that life-style factors

such as high-calorie diets, physical inactivity and potentially envi-

ronmental endocrine disruption, rather than genetics, are the most

plausible causes.

Although the source of metabolic disorders is often the diet

itself, nutrition can also form part of the solution, in fact provid-

ing health benefits. Usually dietary intervention to control excess

body weight, hyperglycemia and dyslipidemia has included low

energy and low fat diets, but these are of limited efficacy due to

0303-7207/$ see front matter 2009 Published by Elsevier Ireland Ltd.

doi:10.1016/j.mce.2009.02.027
http://dx.doi.org/10.1016/j.mce.2009.02.027http://www.sciencedirect.com/science/journal/03037207http://www.elsevier.com/locate/mcemailto:[email protected]://dx.doi.org/10.1016/j.mce.2009.02.027http://dx.doi.org/10.1016/j.mce.2009.02.027mailto:[email protected]://www.elsevier.com/locate/mcehttp://www.sciencedirect.com/science/journal/03037207http://dx.doi.org/10.1016/j.mce.2009.02.027


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2 C.R. Cederroth, S. Nef / Molecular and Cellular Endocrinology xxx (2009) xxxxxx

the strict and long-termcommitment required.However, long term

health benefits can be gained from dietary proteins and bioac-

tive non-nutrients, called phytochemicals, which could be either

incorporated into the diet or be part of the food itself. These phyto-

chemicals are biologically active plant-derived compounds, which

structurally and functionally mimic estrogens (Dixon, 2004). Phy-

toestrogens are found in numerous fruits and vegetables and are

categorized into three classes, namely the isoflavones, lignans and

coumestans. While phytoestrogens are ubiquitous within the plant

kingdom, isoflavones are mainly found in the soybeanthe most

important dietary source of phytoestrogens for humans, cattle and

rodents. Isoflavones have a non-steroidal structure but possess a

phenolic ring that enables them to bind the estrogen receptor (ER)

and act either as estrogen agonists or antagonists (Makela et al.,

1994, 1995).

The fact that isoflavones have been shown to exert estrogenic

effects raises the possibility that this class of phytochemicals

may affect glucose and lipid metabolism. In fact, estradiol itself

is a well known modulator of glucose homeostasis, which also

affects obesity development. For instance, postmenopausal women

develop visceral obesity and insulin resistance and are at an

increased risk of diabetes but estrogen replacement therapy nor-

malizes these abnormalities (Ahmed-Sorour and Bailey, 1980;

Bailey and Ahmed-Sorour, 1980; Gambacciani et al., 1997). Fromgenetic studies in rodents, it has been shown that these effects

are mediated by estrogen receptors (see below). This has caused

researchers to focus on the identification of Selective Estro-

gen Receptor Modulators (SERMs) that could be of potential

therapeutic interest for the treatment of metabolic disorders,

without having negative effects. Studies in humans and rodents

support the hypothesis that soy proteins or soy-derived phytoe-

strogens may be beneficial for the prevention of obesity and

diabetes (Bhathena and Velasquez, 2002; Velasquez and Bhathena,

2007).

The complex interactions between soy proteins and isoflavones

are fairly well understood. To understand these intricate relation-

ships, one must assess the biological activity of soy components,

both in isolation and in combination. So far, few studies haveshown that pure soy-proteins or soy proteins isolate (SPI) alone

(in absence of isoflavones) can provide beneficial metabolic effects

(Velasquez and Bhathena, 2007). The majority of the studies using

SPI remain difficult to interpret because of the lack of clarity con-

cerning the presence or absence of isoflavones in the diet. On

the other hand, soy-derived phytoestrogens have received more

attention mainly due to their benefits in decreasing age related

diseases (e.g. osteoporosis, cardiovascular disease), or hormono-

dependent cancers (e.g. prostate) (Setchell, 1998; Tham et al.,

1998; Sacks et al., 2006). Concerning metabolism, the American

Food and Drug Administration (FDA) authorized in 1999 the label-

ing of health claims on food containing soy proteins, referring to

the beneficial role of soy protein in reducing the risk of coro-

nary heart disease (CHD). The beneficial effects on metabolismin humans have been hotly debated, but studies in rodents may

help in identifying the biologically relevant soy components and

the intimate mechanisms involved. The purpose of this review is

to examine the evidence regarding the use of soy and phytoestro-

gens in the prevention of obesity and diabetes mellitus in animals

and humans. We also discuss the mechanisms by which soy and

dietary phytoestrogens may affect glucose and lipid metabolism

and improve the control of body weight and glucose homeosta-

sis. To provide context and the requisite background information,

we begin with a brief overview about soybeans, the nutritional

composition of soy. We also present scientific evidence both in

humans and rodents supporting or refuting the potential ben-

eficial effects of soy and phytoestrogens on glucose and lipid

metabolism.

2. Soybean composition

Soybean (Glycine max) is composed of macronutriments such

as lipids, carbohydrates and proteins. Soybean lipids, which are

deprived of cholesterol, contain about 15% of saturated fat, 61% of

polyunsaturated fat, and 24% of monounsaturated fat (USDA, 1979).

Carbohydrates make up about 30% of theseed, with 15% being solu-

ble carbohydrates (sucrose, raffinose, stachyose) and 15% insoluble

carbohydrates (dietary fiber). The protein content of soybean varies

from 36% to 46% depending on the variety (Garcia et al., 1997;

Grieshop and Fahey, 2001; Grieshop et al., 2003 ). Storage proteins

are predominant, such as the 7S globulin (-conglycinin) and 11Sglobulin (glycinin), which represent about 80% of total protein con-

tent, as well as less abundant storage proteins such as 2S, 9S, and

15S globulins (Garcia et al., 1997). Interestingly, -conglycinin butnotglycinin is capable of improving serum lipid profiles in mice and

humans, in the absence of phytoestrogens (Moriyama et al., 2004;

Kohno et al., 2006).

Soybean also contains micronutriments, which include

isoflavones, phytate, soyaponins, phytosterol, vitamins and

minerals. Although beneficial effects of micronutriments such as

saponins and phytosterols on cholesterol levels and absorption

have been reported (Oakenfull, 2001; Lukaczer et al., 2006), there

is an increasing body of literature suggesting that isoflavones mayadditionally have a beneficial role in lipid and glucose metabolism.

Soybeans are the most abundant source of isoflavones in food.

Studies have shown that there is a large variability in isoflavone

content and composition in soybeans. This is function of the

variety of soy grown, as well as environmental conditions ( Wang

andMurphy, 1994; Caldwell et al., 2005). Abiotic and biotic stresses

such as variation in temperature, drought or nutritional status,

pest attack or light conditions may modify isoflavone content

and composition. As a consequence, total isoflavone content may

vary up to 3-fold with growth of the same soy cultivar in different

geographical areas and years (Wang and Murphy, 1994).

3. Absorption and metabolism of isoflavones

The metabolism of isoflavones is rather complex. The two major

isoflavones, genistein and daidzein, are present in soy as -D-glycosides, namely genistin and daizin (Fig. 1). These glycoside

forms are biologically inactive (Setchell, 1998). Once ingested,

isoflavone glycosides are hydrolyzed by bacterial -glucosidasesin the intestinal wall, resulting in the conversion to their corre-

sponding bioactive aglycones (genistein and daidzein). Only the

aglycone forms are absorbed by the intestinal tract and are there-

fore biologically active. Daidzein can be further metabolized to

equol and O-demethyangolensin, and genistein to p-ethyl phenol.

In fact, genistein, daidzein,equoland O-demethyangolensin are the

major isoflavones detected in the blood and urine of humans and

animals (Setchell, 1998). In rodents, equol is the major circulat-

ing metabolite among isoflavones representing up to 7090% of

all circulating isoflavones. While all rodents are equol producers,

only 30% of humans are able to metabolize daidzein into equol

(Atkinsonet al., 2005). It remains unclear whether the effectiveness

of dietary phytoestrogens in reducing the risks of obesity, diabetes,

and cardiovascular disease in humans correlates with the ability of

individuals to metabolize daidzein into equol. However, it is a likely

source of variability and therefore should be taken into account

when performing clinical trials with soy or dietary phytoestrogens.

4. Soy consumption and phytoestrogen levels

In soybean, isoflavones are tightly associated with proteins.

As mentioned, the abundance of isoflavones varies according
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Fig. 1. The molecular structure of isoflavones resembles thatof 17-estradiol. Isoflavonesare found in vegetables and fruits in a biologically inactiveglycoside form(genistin,

daidzin andglycitin).Afteringestion,-glucosidasesfromthe intestine cleavethe glucosylresidue andgeneratebiologically activeaglycones(genistein,daidzeinand glycitein).

Daidzein can be further metabolized into equol.

to soy variety and culture conditions, but is also dependent

on the way soybeans have been processed. Indeed, isoflavones2

can be dissociated from soy-proteins using alcohol extraction3

which significantly diminishes the amount of bound-isoflavones4

(Bhathena and Velasquez, 2002). This explains the substantial vari-5

ability of phytoestrogen content found in soy products [0.15 mg6

isoflavones/g of soy protein in mature and roasted soybeans,7

0.3 mg/g soy protein in green soybeans and tempeh, 0.12 mg/g8

soy protein in tofu and some soy milk preparations (Bhathena and9

Velasquez, 2002)].0

Numerous studies have included the investigation of the plasma

concentration of phytoestrogens and their metabolites in humans2

and animals consuming a diet with or without soy (Adlercreutz3

et al., 1993a; Morton et al., 1994; Coward et al., 1996 ). In humans4

consuming soy-free diets, plasma concentration of isoflavones is5

usually in the nanomolar range 40nM (Morton et al., 1994; van6

Erp-Baart et al., 2003). In contrast, acute ingestion of dietary soy7leads to a rapid increase in the plasma concentration of isoflavones8

up to the micromolar range (Adlercreutz et al., 1993b; Xu et al.,9

1994; King and Bursill, 1998; Watanabe et al., 1998). Pharmacoki-0

netic studies confirm that healthy adults absorb isoflavones rapidly

and efficiently (Setchell et al., 2001). The fates of daidzein, genis-2

tein and their respective-glycosides are similar. The average time3takenafter ingestingthe aglyconesto reach peakplasma concentra-4

tions is 47 h, which is delayed to 811 hours for the corresponding5

-glycosides. This suggests that the rate-limiting step for absorp-6tion is the initial hydrolysis of the glycosidic moiety. The half-life7

for daidzein and genistein was reported to be 9.3 and 7.1 h respec-8

tively, indicating that isoflavones or their metabolites are rapidly9

excreted. Finally, factors that might influence isoflavone bioavail-0

ability include intestinal microflora, food matrix, the administered

dose, intestinal transit time and the chemical composition of the

dietary isoflavones.

5. Phytoestrogens: complex hormetic compounds

In plants, the synthesis of phytoestrogens, such as soy

isoflavones, generally coincides with environmental stresses such

as pest infection, drought or lack of nutrients (Howitz and Sinclair,

2008). Recently it has been suggested that stress-induced plant

compounds upregulate stress resistance pathways in animals. This

phenomenon, called xenohormesis, proposes that chemical clues

from autotrophs (e.g. plants) provide an advance warning about

the deterioration of the environment, allowing heterotrophs (e.g.

mammals) to mount a preemptive defense response while condi-

tions are still favorable (Howitz and Sinclair, 2008). This theory has

been recently adopted to explain the health benefits provided bystress-induced phytochemicals such as polyphenols, a groupwhich

includes stilbenes (e.g. resveratrol found in red wine and peanuts),

catechins (e.g. epigallocatechin-3-gallate or EGCG found in green

tea), anthocyanidins, and most relevant to this review, isoflavones.

Similarly, we believe that the isoflavones genistein and daidzein

mediate most of their biological effects through the modulation of

key mammalian enzymes and receptors of stress-response path-

ways or estrogen-dependent pathways, rather than through their

well known antioxidant (Vedavanam et al., 1999) or tyrosine kinase

inhibitory properties (Akiyama et al., 1987). The affinity of phy-

toestrogens for estrogen receptors results in effects on a large

number of estrogen-regulated systems, including the cardiovascu-

lar, metabolic, reproductive, skeletal and central nervous systems.

A significant characteristic of isoflavones is their capacity to bind


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Table 1

Relative binding affinity (RBA) and relative transactivation activity (RTA) of various estrogenic compounds, isoflavones and endocrine disruptors in comparison with 17 -Q3estradiol.

Compound Relative binding affinity Relative transactivation

ER ER ER ER

17-estradiol 100 100 100 100

Diethylstilbestrol (DES) 236 221 117 69

Tamoxifen 4 3 6 2

Coumestrol 20 140 102 98

Isoflavones Genistein 4 87 198 182

Daidzein 0.1 0.5 97 80

Formononetin


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an ER-dependent mechanism (Ogawa et al., 2003). Both estro-3gen receptors are found in the hypothalamic nuclei and modulate4

food intake (Liang et al., 2002) and locomotor activity (Ogawa et5

al., 2003). Specific silencing of ER in the hypothalamus of female6rodents leads to similar phenotypes to those observed in consti-7

tutive mutant mice, including obesity, hyperphagia and reduced8

energy expenditure (Musatov et al., 2007). Although it remains9

unknown whether or not these phenotypes are associated with0

changes in the expression of hypothalamic neuropeptides, these

results show that hypothalamic ER is essential in theregulation of2energybalance. Supportinga direct effectof E2 on the hypothalamic3

control of adiposity, it was shown that E2 modulates hypothalamic4

synapticity by bypassing the leptin receptor to act directly on the5

downstream Stat3 signaling in the hypothalamus, thus decreasing6

body weight (Gao et al., 2007).7

Overall, estrogens appear to be crucial regulators of metabolic8

functionsby directlyand indirectly(via theCNS) modulating energy9

homeostasis. Whether or not dietary soy and phytoestrogens have0

effects on energy homeostasis through estrogen-mimics is still a

matter of controversial debate, but is clearly a plausible hypothesis.2

7. Effects of soy protein and phytoestrogens on human3

metabolism4

The low frequency of obesity and related metabolic disorders5

in Asian populations has drawn attention towards soy, which is a6

characteristic component in asiatic diets. We searched the PubMed7

literature database for epidemiological and clinical studies evaluat-8

ing the effects of soyor isolated isoflavones on human metabolism,9

and the main results are summarized in Tables 25.0

Epidemiological studies have shown that type-2 diabetes is four

times less prevalent in Japanese people in Tokyo than in Japanese-2

Americans in Seattle (Fujimoto et al., 1987, 1991). Consumption of3

more than 12.6 grams of soy protein per day is associated with a4

lower risk of glycosuria, a strong predictor of diabetes (Yang et al.,5

2004). Similarly, several studies have reported that isoflavone con-6

sumption by postmenopausal women correlated with lower body7mass index (BMI), and higher HDL levels (Guthrie et al., 2000;8

Goodman-Gruen and Kritz-Silverstein, 20 01, 20 03).9

Clinical studies also suggest that soy protein or isoflavones may0

improve metabolic parameters. For instance, a metaanalysis of 38

trials (Anderson et al., 1995) as well as more recent reports (Crouse2

et al., 1999; Takatsuka et al., 2000; Teixeira et al., 2000; Gardner et3

al., 2001; Jayagopal et al., 2002; Greany et al., 2004 ) demonstrated4

a significant reduction in plasma concentrations of total and LDL5

cholesterol in humans exposed to soy proteins. In addition, post-6

menopausal Japanese women treated for 24 weekswith isoflavones7

exhibited a lower fat mass (Wuet al., 2006). Obese patients treated8

with soy protein isolates for 12 weeks had lower body weight and

BMI, with decreasedcholesterol andLDL levelsin theblood(Allison

et al., 2003). Additionally, a 6-month clinical trial was conducted

to compare the effects of isoflavones with that of conjugated estro-

gens on blood glucose, insulin, andlipidprofilesin postmenopausal

Taiwanese women. The study revealed that during fasting both glu-

cose andinsulin levels weresignificantlyreduced bysoy isoflavones

(100 mg/day) and conjugated estrogens (0.625 mg/day) (Cheng et

al., 2004).

In contrast to the above mentioned trials, a significant number

of studies reported an absence of beneficial effects of soy on classi-

cal metabolic parameters such as body weight, serum lipid profiles,

fat mass, blood glucose and insulin profiles (Yamashita et al., 1998;

Anderson and Hoie, 2005; Li et al., 2005; Hall et al., 2006; Ikeda

et al., 2006; Anderson et al., 2007). These discrepancies make it

difficult to draw firm conclusions regarding the beneficial effect

of soy on glucose and lipid metabolism. When comparing these

different clinical trials, the underlying causes of conflicting results

are probably related to the variability of experimental designs and

exposition protocols (route of administration, composition, dose,

and duration), the capacity of individuals to produce equol and

the genetic susceptibility. Clearly more standardized studies are

needed to further evaluate these putative beneficial effects.

8. Actions of soy on metabolism in rodents

The current scientific evidence concerning the role of soy and

isoflavones in rodents is based on studies where animals have been

exposed either to purified isoflavones (injected or supplemented

in the diet itself) or soy protein isolates (SPIs) (for a complete

list of studies, see Tables 610). The difficulty in analyzing SPI

studies arises from the fact that information on isoflavone levels

and composition are quite often incomplete, making interpreta-

tions problematic and comparisons hazardous. On the other hand,

supplementation of the diet with soy proteins is more relevant

than injection-based studies. This does, however, raise questions

as to which compound is responsible for the observed effects andwhether the relative benefits of soy are not in fact due to the poor

performance of casein itself, which is usually used as control pro-

tein.

In comparison to human studies which mainly focus on serum

lipid analysis because of the clinical importance of atherosclero-

sis and the risk in cardiovascular diseases, reports in rodents are

rather oriented towards the assessment of soy-derived compounds

on weight and fat loss, and in fewer cases, insulin sensitivity. Still

concerning the effects of soy or isoflavones on serum lipid profiles,

most rodent studies that have assessed these parameters under

healthy or diabetic states point towards an improvement in total

Table 2

Epidemiological studies evaluating the effects of soy or isoflavones on human metabolism.

Epidemiological studies evaluating the effects of soy or isoflavones on human metabolism

Model Number of

individuals (total)

Dose Metabolic Effects References

Pre and postmenopausal women 323 Soy protein intake >12.61g/day For >12.61g/day: Lower risk in glycosuria in

postmenopausal women with BMI

1 mg/day No effects on G, I, TC, LDL, TG Goodman-Gruen and

Kritz-Silverstein (2001)

Lower F/BMI, increased HDL

Postmenopausal women 939 Isoflavone intake >0.236mg/day No effects on F/BMI, TC, LDL, HDL, Lower TG de Kleijn et al. (2002)

In these studies, serum isoflavone levels were not evaluated.Abbreviations: W,weight;F/BMI, fat or body mass index;G, serumglucose;I, serum insulin; TC, totalcholesterol;

LDL, low density lipoprotein; HDL, high density lipoprotein; TG, triglycerides; FFA, free fatty acids; ND, not determined. Parameters listed here that do not appear in the table

were not analyzed in the article in question.


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Table 3

Clinical studies performed using dietary supplementation with soy protein isolates (SPI).

Clinical Studies performed using dietary supplementation with soy protein isolates (SPI)

Model Number of

individuals

Duration SPI and isoflavones intake Serum isoflavone Metabolic effects References

Young healthy normolipidemic

men and women

Total = 2 2 13 days High isoflavone SPI

(56 mg/day) vs low

isoflavone SPI (2 mg/day)

Genistein: 0.75 No effects on TC, LDL,

TG

Sanders et al. (2002)

Daidzein: 0.3 Increased HDL

Equol: 0.1

Obese women 22 (21) 16 weeks SPI (15 g/day)

(150mg/day isoflavones)

vs casein (15g/day)

(10mg/day isoflavones)

ND No effects on W,

F/BMI, G, I, TC, LDL,

HDL, TG

Anderson et al. (2007)

Po stme nopaus al women 10 0 (10 2) 12 mo nths S PI ( 25. 6 g/ day)

(99 mg/day isoflavones)

vs milk

ND No effects on F/BMI Kok et al. (2005)

Moderate

hypercholesterolemic

postmenopausal women

31 (33) 12 week s SPI with isoflavone

(80 mg) or without vs

milk (42g/day)

ND No effects on W,

F/BMI, HDL, TG

Gardner et al. (2001)

Lower TC, LDL

Moderate

hypercholesterolinemic men

and women

Total= 146 9 wee ks S PI ( 25 g /day) (62 mg/ day

isoflavones) vs Casein

(25 g/day)

ND No effects on HDL, TG Crouse et al. (1999)

Lower TC, LDL

Normocholesterolinemic 71 (72) 6 week s SPI with isoflavones

(44.3 mg/day) vs milk

ND No effects on W,

F/BMI, TC, LDL, HDL,

TG

Greany et al. (2004)

Mildly hypercholesterolinemic 71 (72) 6 weeks SPI with isoflavones

(44.3 mg/day) vs milk

ND No effects on W, F/BMI Greany et al. (2004)

Lower TC, LDL, TG

Increased HDL

Obese men and women 50 (50) 12 weeks SPI vs control ND No effects on HDL Allison et al. (2003)

Lower W, BMI, TC, LDL

Overweight and obese men

and women

Total =90 12 weeks SPI vs milk ND No effects on W, G, TC,

LDL, HDL, TG

Anderson and Hoie (2005)

Obese male and women 17 (19) 16 weeks SPI vs meat ND No effects on W,

F/BMI, G, TC, LDL, HDL,

TG

Yamashita et al. (1998)

Obese men and women 46 (36) 3 or 6 months SPI vs individual dietary

intervention

ND No effects on I, TC,

LDL, HDL, TG

Li et al. (2005)

Lower W, F/BMI, G

12 months SPI vs individual dietary

intervention

ND No effects on W,

F/BMI, G, I, TC, LDL,

HDL, TG

Li et al. (2005)

Abbreviations: SPI, soy protein isolate; W, weight; F/BMI, fat or body mass index; G, serum glucose; I, serum insulin; TC, total cholesterol; LDL, low density lipoprotein; HDL,

high density lipoprotein; TG, triglycerides; FFA, free fatty acids; ND, not determined. Parameters that do not appear in the table were not analyzed in the article in question.

Serum isoflavone values are expressed in M. For control groups, the number of individuals (n) is shown in parentheses.

cholesterol (TC) and/or triglyceride (TG)levels after consumption of

dietary soy, SPI, isoflavones or genistein (Kirket al., 1998; Nasagawa1

et al., 2003; Ae Park et al., 2006; Penza et al., 2006; Cederroth et al.,

2008; Nordentoft et al., 2008; Torre-Villalvazo et al., 2008). Only

one study shows an absence of effects on total cholesterol and TG

after consumption of SPI (Aoyama et al., 2000a,b).

As mentioned above, most studies have evaluated the effectsof soy-derived compounds on adiposity. For instance, Long-Evans

rats or ovariectomized (OVX) ddY mice fed with a soy-rich diet

have reduced weight and less adipose deposition than those fed

on a soy-free diet (Wu et al., 2004; Bu and Lephart, 2005). Simi-

larly, Long-Evans rats or CD-1 male mice fed with dietary soy (with

serum levels of genistein and daidzein reaching 0.5M and equolabout 10M) have 50% decreased adipose weight (Lephart et al.,2004a; Cederroth et al., 2007). In addition, dietary supplementa-

tion with 5001500 ppm of genistein, with a serum equivalent of

about2M,decreasesfatpadweightsby50%inC57/BL6mice(Naazet al., 2003). The effects on adiposity are dose-dependent, since the

magnitude of adipose weight reduction correlates with increasing

doses of soy-derived phytoestrogens (Lephart et al., 2004b). Simi-

larly,subcutaneousinjections of genistein(8200 mg/kg/day) for21

days in C57/BL6 ovariectomized mice decrease adipose gain (Naaz 4

et al., 2003). In contrast, in a study where male mice were exposed 4

to daily oral doses of genistein of up to 50 mg/kg/day, fat mass was 4

increased. However fat mass decreased at doses of 200 mg/kg/day 4

(Penza et al., 2006). Overall, these results suggest that high phar- 4

macological doses of phytoestrogens yielding serum levels in the 4

micromolar range inhibit adipose tissue deposition. 4The mechanisms by which dietary soy and phytoestrogens 4

reduce adiposity are unclear. Recently it was found that increased 4

energy expenditure and locomotor activity coupled with a marked 4

shift towards the use of lipids as fuel source were two important 4

contributing factors for the leanness observed in mice exposed to 4

dietary phytoestrogens (Cederroth et al., 2007). This decrease in 4

fat abundance correlates with an increased activation, in periph- 4

eral tissues, of the AMP-activated protein kinase (AMPK) and its 4

downstream target Acetyl-CoA carboxylase (ACC) (Cederroth et al., 4

2008), two enzymes which are key regulators of fatty acid oxida- 4

tion (Winder and Hardie, 1996; Ruderman and Prentki, 2004). In 4

these mice, two targets of AMPK, peroxisome proliferator activated 4

receptor (PPAR) co-activator (PGC)-1 and (PPAR), which regu- 4

late mitochondrialand peroxisomal metabolism respectively (Zong4


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Table 4

Clinical Studies performed using dietary supplementation with phytoestrogens or isoflavones.

Clinical Studies performed using dietary supplementation with phytoestrogens or isoflavones

Model Number of

individuals

Duration Isoflavone intake Serum or urinary isoflavone Metabolic effects References

Po stmen opaus al wo men Total= 136 6 months Is oflavon es

(75 mg/day) vs

placebo

Serum genistein: 0.32 (0.28) No effects on TC, TG Wu et al. (2006)

Daidzein: 0 .89 (0 .27) Lowe r F/ BMI

Equol: 0.19 (0.07) Increased HDLGlycitein: 0.19 (0.06)

Postmenopausal women Total = 3 4 2 months Isoflavones

(50 mg/day) vs

placebo

Urinary genistein: 12.2 (0.65)

Daidzein: 8.1 (0.22)

Equol: No effects on W,

F/BMI, G, I

Weickert et al. (2006)

- Equol producers: 5.8 (0.237)

- Non-producers: 0.245 (0.160)

Healthy Postmenopausal women Total= 117 8 weeks Isoflavones vs

placebo

Urinary genistein: 7.27 (0.42) No effects on G, I, TC,

LDL, HDL, TG

Hall et al. (2006)

Daidzein: 5.76 (0.22)

Equol:

- Equol producers: 2.61 (0.13)

- Non-producers: 0.15 (0.094)

Postmenopausal women 38 (40) 3 months Isoflavones

(118 mg/day) vs

placebo

ND Dalais et al. (2003)

No effects in TC, HDL

Lower LDL, TG

Postmenopausal women with

type 2 diabetes

Total=32 12 weeks Phytoestrogens

vs placebo

ND No effects on W, G,

HDL, TG

Jayagopal et al. (2002)

Lower I, TC, LDL



Serum isoflavone values are expressed in M. Urinary isoflavone values are expressed in mM. For control groups the number of individuals (n) and the corresponding serumor urinary isoflavone values are shown in parentheses.

et al., 2002; Lin et al., 2005), were preferentially upregulated in7

adipose tissue (Cederroth et al., 2008). Additionally, in vitro expo-8

sure of cultured 3T3-L1 adipocytes to genistein has been reported9

to significantly activate AMPK and ACC (Hwang et al., 2005). Fur-0

thermore, in vitro studies using isolated rat adipocytes have shown

that genistein stimulates lipolysis through the inhibition of cAMP2

phosphodiesterases (Szkudelska et al., 2000). Similarly, it has been3

recently shown that an isoflavone-free peptide mixture from black4

soybean (BSP) significantly activates both AMPK and ACC in C2C125

myocytes, in a dose dependent manner (Jang et al., 2008). Interest-6

ingly, a high fat diet containing 10% of this same BSP fed to mice7

for 13 weeks, led to AMPK activation in WAT of mice compared to8

control animals.9

Fewer studies have evaluated the effects of soy and phytoe-0

strogens on glucose homeostasis. Rats fed with SPI exhibit lower

glucose and insulin levels in the plasma (Hurley et al., 1998) as well2

as increased peripheral insulin sensitivity (Lavigne et al., 2000).3

In rat models of obesity and type 2 diabetes (SHR/N-cp rats and

ZDFxSHHF rats), treatment with isoflavones decreases glycemia or

circulating insulin levels (Ali et al., 2005; Davis et al., 2005). Sim-

ilarly, in mice models of obesity and diabetes, treatment with soy

protein or genistein lowers glycemia (Aoyama et al., 2000a; Ae Park

et al., 2006).

Potential mechanisms by which dietary soy may improve

glucose metabolism have been recently proposed. Dietary soy

improves insulin sensitivity by increasing glucose uptake prefer-

entially in skeletal muscles (Cederroth et al., 2008). This improved

insulin responsiveness in mice exposed to dietary soy may take

place, at least in part, by an improvement of the PI(3)K-Akt sig-

naling by the dietary soy-activated AMPK (Cederroth et al., 2008).

Whether these effects are due to soy proteins or phytoestrogens

remains unknown.

The effects of soy and phytoestrogens on the pancreas are less

known. Recently, an in vivo study has evaluated -cell function

Table 5

Clinical Studies performed using dietary supplementation with -conglycitin.

Clinical Studies performed using dietary supplementation with -conglycitin

Model Number of individuals Duration Design Metabolic effects References

Hyperlipidemic male and women 69 (69) 12 weeks Beta-conglycinin vs

casein

No effects on W, F/BMI, G, I, TC,

LDL decreased TG, FFA

increased HDL

Kohno et al. (2006)

Obese male and women 24 (22) 12 weeks Beta-conglycitnn vs

casein

No effects on TC, LDL, HDL, TG

lower W, F/BMI, FFA

Kohno et al. (2006)



For control groups, the number of individuals (n) is shown in parentheses.


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Table8

Animalstudiesperformedusingdietarysupplementationwithgenistein.

AnimalStudiesperformedusingdietarysupplementationwithGenistein

Species

Duration(days)

Doseppm

Serumgenistein

levels

Numberof

animals

Weight

Foodintake

Fatmass

Glycemia

Circulatin

g

insulin

Reference

Malemice

C57BL/6

15

800

0.09

20

Noeffect

Noeffect

Increased

ND

NDa,b

Penzaetal.(2006)

Db/Db-C57BL/KSJ

42

2000

ND

10(10)

Noeffect

Noeffect

ND

Decreased

Noeffectc

AeParketal.(2006)

Avy/a

18,duringgestation

250

ND

ND

Decreased

ND

ND

ND

ND

Dolinoyetal.(2006)

FemaleMice

Avy/a

18,duringgestation

250

ND

ND

Decreased

ND

ND

ND

ND

Dolinoyetal.(2006)

FemaleOVXMice

C57BL/6

12days

300

1.02(0.08)

4(4)

ND

ND

Noeffect

ND

ND

Naazetal.(2003)

500

1.79(0.08)

4(4)

ND

ND

Decreased

ND

ND

Naazetal.(2003)

1000

2.55(0.08)

4(4)

ND

ND

Decreased

ND

ND

Naazetal.(2003)

1500

3.81(0.08)

4(4)

ND

ND

Decreased

ND

ND

Naazetal.(2003)

Forclarity,dataonserumlipidprofilesarenotpresented.A

bbreviations:OVX,ovariectomized;ND,notdetermined.Symbols:*Totalisoflavonecont

ent.

Q5

aNoeffectsonglucosetolerance.

bNoeffectsoninsulinsensitivity.SerumgenisteinvaluesareexpressedinM.Forcontrolgroup

s,thenumberofindividuals(n)forisshowninp

arentheses.

cIncreasedglucosetolerance.

after exposure of CD-1 male mice to dietary soy. Dietary soy lowers

pancreatic insulin content, while high glucose-stimulated insulin

secretion is unchanged, suggesting that insulin secretion is ame-

liorated (Cederroth et al., 2008). Although it is not clear whether

these beneficial effects are due to the isoflavones themselves or

other components of soy proteins, recent reports indicate that the

isoflavone genistein may itself have a direct beneficial effect on

pancreatic-cells. For example, genistein has been shown to stim-ulate insulin secretion in the insulin-secreting cell lines INS-1 and

MIN6 andin mouse pancreatic islets, at nano- andmicromolar con-

centrations (Liu et al., 2006). In addition, genistein has been also

reported to prevent cytokine-induced cell damage in rat insuli-

nomacells(RINcells)(Kimet al., 2007). Genisteinand daidzeinhave

been shown to prevent diabetes onset in non-obese diabetic (NOD)

mice by preserving pancreatic cell function (Choi et al., 2008).Similarly, Lee (2006) recently reported that in streptozotocin-

induced diabetic rats, supplementation with genistein (600 mg/kg

of diet) cause a 2 fold increase in plasma insulin levels. Collectively,

these data suggest that dietary soy and phytoestrogens may have

therapeutic significance in reducing the severity of diabetes, and

improving-cell survival and function. However, further researchis needed, first to confirm and then to analyze in detail, how phy-

toestrogens exert anti-hyperglycemic actions through pancreatic

-cells.

9. Central actions of phytoestrogens

Whether or not soy-derived compounds modulate energy

expenditure via the CNS is unclear, but recent data suggest that

some effects may be centrally mediated. In mice or rats fed

soy-rich diets, feeding behavior and locomotor activity were sig-

nificantly affected, suggesting that the central regulation of energy

balance in the hypothalamus may be modulated by soy or phy-

toestrogens (Lephart et al., 2003; Cederroth et al., 2007). For

example, in mice exposed to dietary soy, the increased loco-

motor activity and preferential use of lipids as fuel source is

associated with a 40% decrease in mRNA levels of AgRP in the

hypothalamus (Cederroth et al., 2007). AgRP is a key neuropep-

tide regulating energy expenditure in the arcuate nucleus of the

hypothalamus (Stutz et al., 2005). Mice lacking AgRP, or having

50% reduction of AgRP levels in the hypothalamus, display an

increased metabolic rate, lipid utilization and locomotor activity

(Makimura et al., 2002; Wortley et al., 2005). In a similar study,

rats exposed to the same soy-based diet exhibited higher expres-

sion of transcripts for NPY (an approximately 40% increase) in

the arcuate and paraventricular nuclei of the hypothalamus. NPY

is an orexigenic neuropeptide known to stimulate food intake

both in rodents and humans (Schwartz et al., 2000). Recently, it

has been reported that an isoflavone-free peptide mixture from

black soybean (BSP) significantly decreased food intake in rats and

leptin-deficient ob/ob mice ( Jang et al., 2008). The authors pre-

sented evidence that BSP has anorectic effects in association with

the induction of hypothalamic STAT3 phosphorylation, a major

pathway involved in suppression of food intake and energy expen-

diture (Bates and Myers, 2003). Further studies are needed to

ascertain whether or not soy peptides or dietary phytoestrogens

act directly on the hypothalamus to improve lipid and glucose

metabolism.

10. Potentially adverse effects in consuming soy and

soy-derived phytoestrogens

The extent to which soy food and its bioactive component

genistein pose potential health risks is still a matter of debate

(Setchell, 2006). In fact, the initial recognition and identification


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Table 9

Animal studies performed using subcutaneous injections or gavage of genistein.

Animal studies performed using subcutaneous injections or gavage of genistein

Species Duration

(days)

Dose Serum

genistein levels

Number of

animals

Weight Food intake Fat mass Reference

Subcutaneous injections

Female OVX mice

C57BL/6 21 20 mg/kg/day ND 10 (10) No effect No effect No effect Naaz et al. (2003)

80 mg/kg/day ND 10 (10) No effect No effect Decreased Naaz et al. (2003)

200 mg/kg/day ND 10 (10) No effect No effect Decreased Naaz et al. (2003)

Oral gavage

Male mice

C57BL/6 mice 15 50g/kg 35 (28) 20 (20) No effect No effect No effecta,b Penza et al. (2006)

500g/kg 66 (28) 20 (20) No effect No effect Increaseda,b Penza et al. (2006)

5,000g/kg 74 (28) 20 (20) No effect No effect Increaseda,b Penza et al. (2006)

50,000g/kg 98 (28) 20 (20) No effect No effect Increaseda,b Penza et al. (2006)200,000g/kg 223 (28) 20 (20) Decreased Decreased Decreased a,c Penza et al. (2006)

Female mice

C57BL/6 15 50g/kg 35 (28) 20 (20) No effect No effect No effecta,b Penza et al. (2006)

500g/kg 66 (28) 20 (20) No effect No effect No effecta,b Penza et al. (2006)

5,000g/kg 74 (28) 20 (20) No effect No effect No effecta,b Penza et al. (2006)

50,000g/kg 98 (28) 20 (20) No effect No effect No effect a,b Penza et al. (2006)

200,000g/kg 223 (28) 20 (20) Decreased Decreased Decreaseda,c Penza et al. (2006)

Forclarity, data on serum lipid profilesare not presented. In thefollowing studies, serum glucose andinsulinwerenot analyzed.Abbreviations: OVX, ovariectomized; ND, not

determined.a No effects on glucose tolerance.b No effects on insulin sensitivity. Serum genistein values are expressed in nM. For control groups, the number of individuals (n) and the corresponding serum genistein

values are shown in parentheses.c Increased insulin sensitivity.

of phytoestrogens as bioactive compounds was made in the 1940s

when it was found that formononetin, an isoflavone present in red

clover (Trifolium pratense L.), caused a devastating infertility syn-

drome in sheep grazing in clover pasture ( Bennetts et al., 1946).

In another study, high levels of phytoestrogens were found in the

leaves of stunted desert annuals in a dry year, leading ultimately

to impaired reproduction when ingested by the California quail

(Lophortyx californicus). In wet yearsthesequails bred normally and

phytoestrogens were largely absent in these herbs (Leopold et al.,1976).

Numerous studies in rodents clearly show that purified genis-

tein (delivered by subcutaneous or intraperitoneal injections) has

detrimental effects. The incidence of uterine carcinoma increased

by 31% in neonatal mice treated subcutaneously with 50mg/kg/day

of genistein for a 5-day period (Newbold et al., 2001). Female mice

that received subcutaneous injections of 50 mg/kg/day postnatally,

while remaining fertile, could not deliver pups and had multi-

oocyte follicles (MOFs) (Jefferson et al., 2005, 2007). In adult male

rats, exposureto dietary soydecreasedandrogen levels andprostate

weight (Weber et al., 2001). Finally, it has been shown in female

mice that dietary phytoestrogens accelerated the time of vaginal

opening in immature CD-1 mice (Thigpen et al., 2003). However,

with the exception of dietary soy experiments, most of these find-

ings may have little relevance to humans consuming soy food, in

particular because the route of administration differs (oral versus 5

injection) resulting in the bypass of the intestines, which provide 5

a limiting barrier to the bioavailability of isoflavones. This is par- 5

ticularly relevant since the two main isoflavones, genistein and 5

daidzein, are present in soyas -D-glycosides, namely genistin and 5diadzin (Fig. 1). Both genistin and daidzin are biologically inactive 5

and require the hydrolyzation of the glycosidic bond by glucosi- 5

dases of the intestinal bacteria to produce the biologically active 5

aglycone forms.5

In humans, the use of soy or purified phytoestrogens in women 5

at high risk of, or diagnosedwith, breast cancer as well as in infants 5

fed with soy-based formula are legitimate areas of concern. Con- 5

cerning breast cancer, caution is warranted since the available data 5

are conflicting, and there is evidence for both inhibitory and stim- 5

ulatory effects of dietary soy on breast cancer cell growth (Duffy 5

et al., 2007). In vivo data from animals suggest that genistein may 5

interfere with the inhibitory effect of tamoxifen on breast cancer 5

cell growth (Ju et al., 2002; Liu et al., 2005), while epidemiolog- 5

ical studies in humans show that exposure in early childhood or 5

early adolescence protects against the development of breast can- 5

cer as an adult (Wu et al., 2002). Concerning soy-based formula, 5

caution should prevail, even though it has been consumed by mil- 5

lions of infants over thepast decades without apparentdetrimental 5

effects. Infancy is a very sensitive period for endocrine disruption, 5

Table 10

Animal studies performed using dietary supplementation with pure soy proteins.

Animal studies performed using Dietary supplementation with soy proteins (isoflavone-free)

Species Duration

(days)

Dose (%) Number of

animals

Weight Fat mass Glycemia Circulating

insulin

Reference

ICR 28 23.7 (-conglycinin) 10 (10) Decreased No effect Decreased Decreased Moriyama et al. (2004)

ICR 28 21.9 (glycinin) 10 (10) Decreased No effect No effect No effect Moriyama et al. (2004)

yellow KK-Ay 28 23.7 (-conglycinin) 10 (10) Decreased No effect No effect Decreased Moriyama et al. (2004)

yellow KK-Ay 28 21.9 (glycinin) 10 (10) Decreased No effect No effect No effect Moriyama et al. (2004)

Obese C57BL/6 91 Black soy protein 9 (9) Decreased No effect ND ND Jang et al. (2008)

For clarity, data on serum lipid profiles are not presented. Food intake was not measured in these studies. In the following studies, serum glucose and insulin were not

analyzed. For control groups, the number of individuals (n) is shown in parentheses.


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and exposure to significant levels of phytoestrogens mayultimately0

lead to adult onset diseases.

11. Summary and conclusion2

Current evidence from animal and human studies suggests that3

diets rich in soyand phytoestrogens have beneficialeffects on many4

aspects of diabetes and obesity. In animal studies, soy and phy-5

toestrogens are effective at reducing adipose tissue and improving6glucose uptake. However, available data fromhuman studies do not7

offer clear support, and further research is required before a firm8

conclusion can be made about the benefits of soy and phytoestro-9

gens in the context of adiposity control and glucose metabolism.0

The specific soy protein components that may lead to metabolic

improvements have yet to be determined. Phytoestrogens appear2

to have beneficial actions both on glucose and lipid metabolism3

but additional micronutriments such as saponins, phytosterols,4

trypsin inhibitors, as well as amino acid and protein composi-5

tion, may have additive or synergistic effects. Additional studies6

both in humans and animals will be required to identify precisely7

which components and constituents have beneficial roles. Unfortu-8

nately,comparisons between differentanimal or clinical studies are9

hampered by the lack of standardization of soy nomenclature, the0

differentformulations,doses, routes of exposure,time and duration

of exposure as well as bymajor differences in thesubsequentanaly-2

ses performedto evaluatethe effects and elucidatethe mechanisms3

by which phytoestrogens and soy potentially improve glucose and4

lipid metabolism. All of these variables make it difficult to compare5

and evaluate the putative beneficial effects of soy and phytoestro-6

gens on metabolism. Clearly more standardized studies, involving7

both basic research and clinical trials, are needed. Giventhe rapidly8

increasing prevalence and societal impact of metabolic disorders,9

such studies should have high priority.0

Acknowledgments

We thank Prof. J.-D. Vassalli for critical comments on the2manuscript. Authorswere fundedby grants fromthe SwissNational3

Science Foundation, Foundation Gertrude von Meissner, Fondation4

Ernst & Lucie Schmidheiny, the Sir Jules Thorn Charitable Overseas5

Trust Reg.,Schaan andthe Clotta foundation. Serge Nef is a founder6

of Amazentis S.A. and a member of its scientific advisory board.7

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Soy, Phytoestrogens and Metabolism a Review [Volume] Molecular and Cellular Endocrinology [Issue]