1-s2.0-S0378512208003551-main.pdf

7/25/2019 1-s2.0-S0378512208003551-main.pdf

1/13

*This article is a reprint of a previously published article, for citation purposes please use the original publication details; Maturitas, 42(3), pp. 173185.

**DOI of original article: doi:10.1016/S0378-5122(02)00024-5

Review

The nature and utility of the phytoestrogens: a review ofthe evidence

Paola Albertazzi *, David W. Purdie

Centre for Metabolic Bone Disease, H. S. Brocklehurst Building, Hull Royal Infirmary, 220-236Anlaby Road, Hull HU3 2RW,

UK

Received 17 August 2001; received in revised form 27 November 2001; accepted 7 February 2002

Abstract

Non-prescription remedies are becoming increasingly popular particularly amongst postmenopausal who in this

market are the largest consumers. Phytoestrogens are a large family of plant derived molecules possessing various

degrees oestrogen like activity. Food or food supplements containing phytoestrogen are often been advocated as an

alternative to hormonal replacement therapy (HRT) in women with contraindications to the use of conventional

oestrogen replacement, or simply wanting a more natural alternatives. There have been several studies performed

with phytoestrogen in various aspects of the postmenopausal women health. Results have been sometimes conflicting

and difficult to interpret. The lack of knowledge of what precisely is the active ingredient, its minimally effective

doses, the lack of standardisation of the preparations used as well as the large individual variability of metabolismof precursors introduced with the diet may all have played a role in confusing the issue about effectiveness of these

compounds. Phytoestrogen fall in the gray area between food and drugs hence in spite of the vast public interest,

there are no interests in company producing these supplements in investing in research from which they will not

exclusively benefit from. It is difficult for the physician to know how to advise patients on this matter. In this paper

we critically review the clinical data available to date in an attempt to answer some of the most commonly asked

questions about dose and type of phytoestrogens supplementation most likely to be effective in different aspects of

climacteric woman health. 2002 Elsevier Science Ireland Ltd. All rights reserved.

Keywords:Phytoestrogen; Oestrogen; Menopause; Review

1. Introduction

Phytoestrogens are so named, because, they are

plant-derived molecules possessing oestrogen-like

activity. Their chemical structure is a steran

frame, as with all steroid hormones, althoughtheir effects are estimated to be some thousand-

fold weaker compared with those of 17 oestra-

diol [1]. Phytoestrogen containing foods such as

soy, rye and burgen bread, and other products,

now widely available as food supplements, are

increasingly becoming part of the vocabulary of

patients in gynaecology and menopause clinics.

* Corresponding author. Tel.: +44-1482-675300; fax: +44-

1482-675301

E-mail address: [email protected] (P. Al-

bertazzi).

0378-5122/02/$ - see front matter 2002 Elsevier Science Ireland Ltd. All rights reserved.

PII: S 0 3 7 8 - 5 1 2 2 ( 0 2 ) 0 0 0 2 4 - 5

Maturitas 61 (12) (2008) 214229

Reprint of

7/25/2019 1-s2.0-S0378512208003551-main.pdf

2/13

P. Albertazzi, D.W. Purdie /Maturitas 61 (12) (2008) 214229 215

Women with personal objections, or clinical con-

tra-indications to the use of conventional oestro-

gen replacement, or who are simply seeking a

more natural treatment for menopausal symp-

toms, are increasingly requesting information

about the efficacy of these forms of diet

supplementation.There are no good data for the prevalence of

complementary or alternative medicine by climac-

teric women in the UK. However, it is estimated

[2] that over one third of North Americans over

18 years of age use herbal remedies-at an annual

cost of $US 13.7 billion-and about 4% of women

treat their menopausal symptoms by such means

[3]. A recent study from Sweden of over 6000

women showed that, while 21% took estrogen

replacement therapy, 45% took a non-hormonal

variety [4].

Phytoestrogens bind to the oestrogen receptors.But the morphology of the ligand binding domain

(LBD) of the receptor, particularly the position of

helix 12, differs depending on the type of ligand

that binds the receptor (Fig. 1). When genistein-

one (GEN) of the phytoestrogens -binds to the

receptor the position of helix 12 is similar to that

of raloxifene (RAL) when bound to the same

receptor [5]. This has been used to explain some

of the biological effects of GEN. Furthermore,

GEN shows a greater affinity for the recently

discovered oestrogen receptor (ER) than for

the classical oestrogen receptor (ER). This

differential affinity might be of functional signifi-

cance as the two receptor sub-types differ in their

tissue distribution and possibly in biological activ-

ity [6].

Differential affinity for oestrogen receptors may

not, however, fully account for phytoestrogen ac-

tion. A recent study has shown that the isoflavonephytoestrogen, GEN, has higher efficacy in induc-

ing production, in-vitro, of a reporter protein

through ER than through ER, in spite of its

higher affinity for ER[7]. Finally, although phy-

toestrogens compete effectively with oestradiol for

receptor binding at nanomolar (109 M) concen-

trations, in higher micromolar (106 M) concen-

trations, they inhibit several enzymes including

protein kinase and thyrosin kinase. This may

contribute substantially to certain of the clinical

effects, particularly their antiproliferative actions

[8].The overall research effort which is currently

centred on phytoestrogens seeks to determine if

they may be a viable alternative to conventional

oestrogens through delivering a bone sparing, and

an atheroprotective effect without the adverse ef-

fects on the reproductive tissues of breast and

uterus encountered with HRT regimens [9].

Japanese women consuming a traditional diet

have been found to have a low incidence of breast

cancer, cardiovascular disease, osteoporosis, and

climacteric symptoms. The high concentration of

soy-derived isoflavones present in their diet is one

factor adduced to explain these findings. Whetherincreasing phytoestrogens in the diet of Western

men and women would have a favourable influ-

ence on health is unresolved and is the subject of

considerable research.

Wholegrain cereal, fruits, legumes and berries

are rich in phytoestrogens. However, diet modifi-

cation is often not easily to implement and there-

fore, the market had been flurried with

preparations containing varying concentrations of

isolated phytoestrogens of different origins. Some

of the products currently available over-the-coun-

ter in health food outlets in the UK are presentedin Fig. 2. The safety of these products as well as

their effectiveness needs to be individually as-

sessed. These products are all sold as food supple-

ments and, not being subjected to any regulatory

Fig. 1. Schematic representation of the conformation of the

estrogen receptor -LBD in the presence of (GEN), estradiol

(E2) and RAL. When RAL is bound, the overall position of

helix 12 (green cylinder) resembles that seen with the selective

estrogen receptor modulator (SERM) RAL. [5] Illustration

kindly provided by Ashley C.W Pike, University of York.

7/25/2019 1-s2.0-S0378512208003551-main.pdf

3/13

216 P. Albertazzi, D.W. Purdie /Maturitas 61 (12) (2008) 214229

Fig. 2. Schematic presentation of phytoestrogens subtypes.

close to the outer fibre-containing layer, a part

that modern European and North American

milling techniques usually eliminate. As a result,

phytoestrogens are seldom present in cereal-

derived food in Western societies.

Single plants often contain more than one type

of phytoestrogen, and different plants containdifferent concentrations of the several phytoestro-

gen types (Table 1).

3. Phytoestrogens: metabolism

The majority of phytoestrogens are introduced

into the diet as inactive compounds. After the

consumption of plant lignans and isoflavones, a

complex enzymatic conversion occurs in the gas-

trointestinal tract resulting in the formation of

compounds with a steroidal structure similar tooestrogens.

Isoflavones are the most common form of the

phytoestrogens. Two of the major isoflavones are

GEN and daidzein. Typically, soybeans-a princi-

pal source contain both. In plants, isoflavones are

mainly present as inactive glycosides: genistin and

daidzin. However, when the sugar residue is re-

moved, these compounds become activated as

GEN and daidzein. The similarity in spelling and

pronunciation between inactive and active forms

is unfortunate and can be confusing. The active

forms are produced through deconjugation by

bacteria in the gut.Following the ingestion of a controlled quantity

of soy, there is a variable individual metabolic

response, with up to a 1000-fold variation in

subsequent isoflavone excretion [14]. Setchel et al.

have hypothesised that the composition of the

intestinal flora, intestinal transit time, and vari-

ability in redox potential of the colon, might all

contribute to this variability in humans [15]. This

large variability in phytoestrogen metabolism is

potentially clinically significant as it may influence

biological responses.

With regard to lignans, ingestion leads to theproduction of Enterolactone and enterodiol in the

gut, and their excretion in the urine. Vegetables

such as carrots, spinach, broccoli and cauliflower

are the main sources of lignans.

controls, they vary in quality. Independent quality

control checks of commercially available prepara-

tions have shown that the phytoestrogens content

in these tablets varies greatly, and in some casesare totally absent [10]. Furthermore, the miscon-

ception-engendered by heavy marketing-that what

is natural is therefore automatically safe, may

lead to their use in high dosage. The effects of this

are quite unknown since dose-ranging studies

have never been performed. A general indication

about dose might derive from the average daily

consumption among the Japanese. Unfortunately,

such a calculation is far from simple. Dietary

assessment is always imprecise and phytoestrogen

exposure, extrapolated from phytoestrogen intake

in Oriental populations, have yielded very dis-crepant results. Estimates vary between an intake

50 mg [11] and 200 mg [12] of phytoestrogen per

day in a traditional Japanese diet.

2. Phytoestrogens: biology

The phytoestrogens are a large family of com-

pounds, of which the three main branches are

isoflavones, lignans and cumestans. In plants,

phytoestrogens functions primarily as antioxi-

dants while in animals and humans they are be-lieved to function both as oestrogen agonists and

antagonists [13]. They can be found in many

foods, particularly leguminous plants, seeds, nuts

and berries. Lignans precursors occur in grains

7/25/2019 1-s2.0-S0378512208003551-main.pdf

4/13


The brewing of green, but not black tea in hot

water liberates lignans in high quantities [16] and

it is perhaps noteworthy that the drinking of high

quantities of green tea has been reported as

beneficial in the prevention of ischaemic heart

disease [17].

4. Soy

The phytoestrogen intake of the Asian popula-

tion derives mainly from soybeans (Glycine max).

Soy flour, toasted soy flour, and isolated soy

protein (ISP) contain inactive conjugated

isoflavones, whereas fermented soy foods such as

miso and tempeth, both staples of the Oriental

diet, contain the active deconjugated forms.

Although the conjugation profile of isoflavones

present in soy can be influenced by heat, the total

content remains constant indicating that

isoflavones are stable at the usual temperatures

encountered in the preparation of food. The con-

centration of isoflavones in soybeans range from

0.5 to 2 mg/g. They bind to protein in soy, and

most soy protein fractions prepared for human

use have similar isoflavons concentrations. An

exception is soy protein concentrate prepared by

extracting soy flour with an alcohol solution. This

procedure removes almost all the small organic

molecules in soy including the phytoestrogens

[18]. The presence of active compound thus de-

pends on the type of industrial processing to

which the soy is subjected and may explain some

of the variations in effect obtained with different

soy preparations in clinical trials.

Soy flour has a high phytoestrogen concentra-

tion while soy milk and soy sauce contain rela-

tively low amounts. Tofu (soy cheese) contains

Table 1

Quantities of phytoestrogens in food, mean (g/100 g)

FormomonetineBiochanin AMetairesinolSECO CoumestrolDaidzeinGenistein

Soy

70Soy-flower 13067 400 3093 900

7600 Kikkoman firm 21 300

tofu

Hatcho Miso 730014 500

700 Soy drink 2100

Soymilk 30310

1027 369 900Lin-seeds

Cloer seeds 323 178 13 3.8 381 1270 5.3

Wheat

Whole grain 32.9 2.6

8.1Traces Traces White wheat

meal

6.9 3.5 110Wheat bran

Oat

3.5 110 0Bran 6.9

0 13.4 0.3 Meal

Rye

47Meal 65

Bran 167132

Mung

365 9.7Bean 172 0.25 14 7.5 1.80.87468 10327451902Sprouts

1.53 0.56 21 370Pumpkin seeds

11.4 8.4 838 215 5Chick peas 76.3

Modified from Adlercreutz H & Mazur W. Phytoestrogens and western disease. Ann Med 1997; 29: 95120.

7/25/2019 1-s2.0-S0378512208003551-main.pdf

5/13


significant amounts of isoflavones (0.20.5 mg/g)

but the concentration is highly variable between

brands [19]. Isolated soy protein (ISP) is a powder

obtained from processed soy flour, this prepara-

tion contains 90% proteins and a controlled

amount of isoflavones. This preparation has been

used in several clinical studies as it is an easy way

of delivering consistent amounts of both protein

and phytoestrogen, in a form palatable for the

Western population. Furthermore, this form of

soy has a long shelf life and easily allows for the

double-blinding procedure necessary for trials.

5. Methods

This review has drawn on the search strategy

for identifying randomised controlled trials

(RCTs) with phytoestrogen in menopause along

with comparative studies of other designs as well.

This included searches of electronic databases as

well as hand-searching specialist menopause jour-

nals. Systematic reviews and an on-line Medline

search with the key-words phytoestrogens,

isoflaones, and menopause, were used (1966

2001). The Cochrane library-2001 second quarter

was searched and found to contain a protocol for

a systematic review of Phytoestrogen and

menopausal symptoms. The full review is not yet

available.

6. Hot flushes

Twelve randomised studies were found which

had examined the effect of phytoestrogens on the

incidence and severity of hot flushes in peri and

postmenopausal women (Table 2). Six studies

used wholegrain or soy preparation containing

proteins, [20 26] while five studies used concen-

trated isoflavones in tablets form either derived

from soy [2729] or red clover [30,31]. The US

Food and Drug Administration (FDA) recom-

mends a standard design for trials with drugs such

as hormonal replacement therapy to be used forthe treatment of hot flushes. This requires a trial

duration at least 3 months, a placebo arm, and

enrolment of patients with more than 60 moderate

to severe hot flushes per week [32].

All the studies performed with phytoestrogen

were randomised, nine were double-blind and all

but two had a placebo arm.

Albertazzi et al. showed that sixty grams of ISP

powder containing 40 g of proteins and 76 mg

phytoestrogens, in their active form, halve the

number of hot flushes in postmenopausal women

in a double blind, placebo-controlled trial. During

this study a coincidental brief decrease in the daily

amount powder intake was mirrored by a marked

reduction in efficacy. Sixty grams of ISP powder

containing 76 mg of phytoestrogens appear thus

to be the minimal effective dose required for

reduction of vasomotor symptoms in post-

menopausal women. In this study, soy had no

effects on the important oestrogen-sensitive symp-

tom of vaginal dryness [24].

Brzezinski et al. compared a diet high in phy-

toestrogen with one containing low phytoestrogenon hot flushes in postmenopausal women. The

phytoestrogen rich diet consisted of a daily con-

sumption of 80 g/day tofu (75 mg/g daidzeine, 200

mg/g GEN), 400 ml of soy drink (7 mg/g

daidzeine, 20 mg/g GEN), one teaspoon of miso

(40 mg/g daidzein, 35 mg/g GEN), two teaspoon

of ground linseeds (4 mg/g lignans). This would

amount to a consumption of approximately 33

mg of phytoestrogens per day. This was found to

be effective in reducing hot flushes and improving

vaginal dryness [21]. This study, however, was not

double-blind, admittedly difficult to achieve when

using conventional food, but important when in-

terpreting results since hot flushes are subject to a

high placebo response.

Mukies et al. in a double blind, non-placebo

controlled study, found a 40% reduction in the

number of hot flushes using 45 g of soy flour per

day (approximately 2390 mg of phytoestrogens)

but a similar amount of wheat flour, used as

control, also reduced hot flushes by about 20%

[20]. Delays et al. carried out a crossover study

using high phytoestrogen containing foods namely

45 g of soy grit, 45 g of linseeds versus a low

phytoestrogen containing food 45 g of wheatkibble turned into bread. The study involved a

total of 52 women of whom 44 completed the

study. In this study, the soy bread did not affect

hot flushes but significantly improved the matura-

7/25/2019 1-s2.0-S0378512208003551-main.pdf

6/13


Table 2

Phytoestrogen and hot flushed (continuation)

Phytoestrogen N Study design Hot Flushes (%)

Whole soy or grains

Murkies et al. 199 5 [20] 45 g soy flour, 4 5 g wheat 58 Ra ndomised double blind, 40 P0.001, 25

P0.01without placebo, 12 weeksflour80 g tofu, miso, 10 g 50 p0.00478, 36 Randomised, not blinded,Brezezinski et al 1996;

[21] linseeds normal diet without placebo 12 weeks

45 g soy grit enrichedDalais et al. [22] 1998; 52 20 NS, 40Randomised double blind

cross-over, without placebo, p0.009, 50bread, 45 g linseeds, 45 g

p0.00112 weekswheat kibble

20g soy protein containing NS ( severity)Washbum et al. 1998; 51 Randomised double blind

34 mg of phytoestrogen[23] placebo controlled,

cross-over trial, 6 weeks

104 Randomised double blind,60 g soy protein, 76 mgAlbertazzi et al. 1998 [24] 45 P0.001

isoflavones, aglycone placebo controlled 12 weeks

Soy protein containing 118Kostsopoulos et al. 2000 95 Randomised double blind NS

placebo controlled, 3mg of phytoestrogen[25]

months

Germain et al. 2001 [26] Randomised double blind NSSoy protein containing 4.4, 69

80 mg of isoflavones, placebo controlled, 6monthsaglicone

Isolated isoflaones Red

cloer deried

51Barber et al. 1999 [30] Randomised double blind40 mg NS

cross over 12 weeks

37Knight et al. 1999 [31] Randomised double blindPlacebo 40, 160 mg NS

controlled 12 weeks

Isolated isoflaones Soy

deried

50 mg isoflavones glyconeScambia et al. 2000 [27] 39 Randomised double blind 45 P0.001

placebo controlled 6 weeksu31 mg aglycone

177 Randomised double blind50 mg isoflavones 28 P0.078Upmalis et al. 2000 [29]

placebo controlled 12 weeks

177, 77% on Randomised double blind150 mgQuella et al. 2000 [28] NS

tamoxifene cross over 4 weeks

NS, non-significant.

tion of the vaginal epitelium [22]. Hot flushes

were, however, significantly reduced by the wheat

and the linseed bread. The sample size in this

study was small, and the study had only a 60%

power to detect a decrease of 40% in hot flushes.

Washburn et al. observed a reduction in the sever-

ity of hot flushes but not in their number, by

supplementing the diet of 51 perimenopausal

women with 20 g of ISP containing 34 mg ofphytoestrogen [23]. These negative results might

have been partially due to the study design itself,

since the eligibility criteria allowed the participa-

tion of women who had as little as 3 months

amenorrhoea in the preceding 12 months. It is

standard practice to restrict such trials to women

with at least 6 months of amenorrhoea in order to

minimise chances of improvement in symptoms

due to sporadic production of endogenous oestro-

gen. Given the levity of the starting symptoms, a

much larger sample size might have been neces-

sary to observe a small effect with treatment.

Kotsopoulus et al. [25] found no climactericsymptom relief in 94 postmenopausal women en-

rolled in a 3 months double-blind placebo trial

using ISP containing 118 mg of isoflavones per

day. Again, the study design had several limita-

7/25/2019 1-s2.0-S0378512208003551-main.pdf

7/13


tions. Women were not required to keep a daily

account of the number of hot flushes, and

symptoms were scored only in term of climac-

teric questionnaires. Furthermore, women en-

rolled in this study had only mild climacteric

symptoms. This may have also contributed to

the under estimation of all but a major effect of

the treatment under trial. The combination of a

relatively low number of hot flushes per day

coupled with a small sample size might have

also contributed to the apparent lack of effect

of the soy preparation used in the study by

Germain et al. [25] In this study 69 women were

assigned to either a soy protein preparation con-

taining 80 mg of isoflavones aglycone, a soy

protein preparation virtually devoid of

isoflavones and a whey protein control for 24

weeks.

Two studies have been performed with con-centrated phytoestrogens tablets derived from

red clover. In these studies doses of 40 and 160

mg failed to reduce hot flushes over a 3-month

period [30,31]. These studies both involved only

a small number of women, and once again the

small sample size might have unfavourably influ-

enced outcome.

Two randomised placebo-controlled studies

have been performed with isoflavones derived

from soy. Patients received 50 mg of phytoestro-

gens daily and a decrease of between 28 and

45% in the number of hot flushes was observed[27,29]. On the other hand, Quella et al. failed

to show a reduction in hot flushes in breast can-

cer survivors taking 150 mg of phytoestrogen

orally [28]. This study had, again, several flaws.

The cross-over design had two phases lasting

only 4 weeks, not separated by a wash out pe-

riod and thus a carry-over effect cannot be ex-

cluded. The number of patients studied was

substantial:177, but over half of them had a mi-

nor symptomatology (17% with two to three hot

flushes per day and 50% with four to nine hot

flushes per day). Furthermore, 70% of women

on the trial were taking tamoxifen and hence alarger dose of phytoestrogen might have been

required to overcome the known antiestrogenic

action of tamoxifen on the central nervous sys-

tem. Lastly, the authors did not specify the

quantity of isoflavones present in the active

form in the preparation used. Low levels of

isoflavones in the active form would have af-

fected the overall efficacy of treatment.

7. Effect of phytoestrogens on the uterus and

vaginal epithelium

There have been three studies looking at the

effect of phytoestrogen supplementation on the

endometrium of postmenopausal women. No ef-

fects have been observed, either in endometrial

thickness as measured with transvaginal ultra-

sound [27,29,30], or in uterine artery pulsatility

index when compared with placebo [30]. Foth

and Cline have studied the effects of supple-

menting the diet of postmenopausal macaques

with soy protein isolated containing 148 mg ofphytoestrogen per day for 6 months. Even such

a comparatively high dose of isoflavone for such

a long duration failed to induce any prolifera-

tive effects on endometrial histology. Moreover,

phytoestrogens appeared to antagonise the pro-

liferative effects of oestrogen when the two

preparation where given in association [33].

Vaginal dryness is a frequent complaint in

postmenopausal women. It is usually assessed ei-

ther in terms of intensity of symptoms or, more

objectively, by cytological assessment of matura-

tion of vaginal epithelium. Nine studies havelooked at maturation of vaginal

epitelium[20,22,24,27,29 31,34,35] with phy-

toestrogen supplementation. Two studies [22,35]

found it to be improved, but one of these was

of only 2 weeks duration [35]. No changes were

observed in vaginal maturation in the remaining

seven studies. Brzezinski et al. [21] and Kotso-

poulus et al. [25] collected data on the subjective

perception of vaginal dryness and found it to be

improved. Many psychological variables, how-

ever, might have influenced this outcome, not

least that patients, in the study of Brzezinski et

al. were not blinded. Presently, there is no obvi-ous reason for concern about detrimental effect

of phytoestrogen on the endometrium and hence

no argument for the concomitant use of a

progestogen, as is required for HRT.

7/25/2019 1-s2.0-S0378512208003551-main.pdf

8/13


8. Breast cancer protection

Asians consume high amounts of phytoestro-

gens and have a low incidence of breast cancer.

High excretion of phytoestrogens in plasma and

urine, indicating high intake, has been connected

with a low incidence of breast cancer in two

Australian case-control studies [36,37]. Only two

short-term prospective studies have been per-

formed to-date on the effect of soy on the breast.

One reported the effects of 2 weeks of soy supple-

mentation on the breast of premenopausal women

due to have surgery for either benign or malig-

nant breast disease [38]. Soy had no adverse ef-

fects on any histological index of proliferation.

However, a rise of pS2 protein and lowering of

apolipoprotein D was observed in the nipple aspi-

rate of women taking soy compared with controls

[38]. A similar effect has been observed in-vitrowhen breast cells are challenged with oestrogen

[39,40]. This latter result has been interpreted as

possible evidence of an oestrogenic effect of soy

on the breast epithelium, although it is not known

if it corresponds with in-vivo effects on breast

histology. A second study has shown an increased

secretion from the nipple in pre- but not post-

menopausal women taking soy for 6 months [41].

This might confirm a slight stimulatory effect of

soy in premenopausal women, although continued

stimulation of the breast alone might have also

explained this finding. Foth and Cline, in the

longest prospective study so far performed, failed

to show any proliferative effects on breast histol-

ogy of postmenopausal macaques after 6 months

of ISP supplementation containing 145 mg of

isoflavones per day [33].

9. Risk factors for cardiovascular disease

Recent reports have linked the dietary intake of

soy-based foods with a reduction of coronary

heart disease (CHD) [42,43]. Intact soy protein

appears to be effective in both animal and hu-mans in lowering plasma total cholesterol, LDH

cholesterol and tryglicerides. The magnitude of

LDL cholesterol improvement in humans is di-

rectly related to the initial cholesterol concentra-

tion. The benefit is also proportional to amount

of soy intake [44]. Improvement of HDL choles-

terol is also directly proportional to the initial

plasma HDL cholesterol concentration, [45] and

to gender [46]. A greater effect is apparent in

postmenopausal women compared with men. The

protein component seems to play a crucial role in

the cardio-protective effect of soy. When soy-ex-

tracted phytoestrogens are added to animal

derived protein (casein) no effects on lipids are

observed [47]. But when both the proteins and

phytoestrogens contents of soy are present, then

the lipid-lowering effect is directly proportional to

the phytoestrogen concentration [48].

An average daily consumption of 47 g of soy

protein per day has been shown to decrease

plasma triglycerides concentration by 11%,

plasma low-density lipoprotein (LDL) cholesterol

concentration by 13% and increase in high-densitylipoprotein (HDL) cholesterol by 2%. The effects

of dietary soy supplementation in lowering the

lipid profile was found to be dose-related and

more robust the highest the plasma cholesterol

was at baseline [44]. Preparations containing 25 g

of soy protein have been awarded a healthclaim

for cholesterol lowering by the FDA in October

1999. Furthermore, isolated soy protein, rich in

phytoestrogen, enhances vascular reactivity in fe-

male monkeys with atherosclerosis, an effect simi-

lar to that observed with oestrogen replacement

therapy. The effect appears dependent on the

phytoestrogen content of soy and is not observed

when animals are fed soy protein devoid of its

phytoestrogen content [49]. One in-vitro study

performed on rabbit coronary arteries has demon-

strated that the effect is likely due to a calcium

channel blocking mechanism, [50] although an

ER mediated action cannot be excluded [51].

Supplementation with purified GEN, one of the

isoflavones present in soy, has been shown to

reduce the extension of ischaemic lesions in

murine models of stroke [52] and mycardial in-

farction [53]. This protective effect of GEN on

ischaemia appears to be mediated by its antioxi-dant effect. In humans, a similar mechanism has

been used to describe the reduced susceptibility of

LDL to oxidation observed in both normal [54]

and hypercholesterolemic [55] individuals fed a

7/25/2019 1-s2.0-S0378512208003551-main.pdf

9/13


soy or phytoestrogen diet. Both the antioxidant

effect and the enhancement of vascular reactivity

may further contribute to the cardiovascular dis-

ease protection offered by the lipid-lowering effect

of soy.

Red clover contains high concentrations of

isoflavones but in a rather different composition

compared with soy. Clover has an high concentra-

tion of formonetine and biochanine-A compared

with soy. For reasons still unknown, concentrated

phytoestrogens derived form red clover do not

appear to be effective in improving lipid profile in

either normal or hypercholestolemic subjects

[56,57]. The only potentially useful finding ob-

tained so far with these compounds has been the

improvement of ultrasound measured arterial

compliance in postmenopausal women. This was

defined as the increase in volumetric blood flow in

both thoracic aorta and right carotid artery.

10. Effects on the central nervous system

A lower incidence of dementia is found in

Asian populations particularly amongst Japanese

[58]. The correlation found recently between

midlife tofu consumption and risk of dementia

and brain atrophy later life in Japanese immi-

grants in Hawaii was thus rather puzzling [59].

The study in question, however, was specifically

designed to investigated the effect of diet ofmidlife with the incidence of cardiovascular dis-

ease and not to investigate specifically the influ-

ence of phytoestrogen intake with disease later in

life. It is thus possible that the statistical signifi-

cant correlation found might have occurred by

chance and that tofu consumption might be a

marker for some other rather unfavourable expo-

sures rather than a cause of disease. Reassuring

data on the effect of a soy diet on memory has

recently been produced in the rat where the radial

arm maze has been used to show the beneficial

effects of oestrogen in working memory. Ovariec-

tomised rats fed with a ISP containing up to 144mg of phytoestrogens had an improvement in

radial arm maze performance comparable to that

of oestrogen. The beneficial effect obtained with

soy was dose-related and did not antagonise the

effects of oestrogen when the two compounds

were given together [60]. Human data are now

required.

11. Osteoporosis prevention

There have been several in-vitro and animal

studies that have shown that phytoestrogen

present prevents postmenopausal bone loss, [61]

and an anabolic effect of GEN on bone of

ovariectomised mice has been observed [62] (Fig.

3). To date, however, only three human studies

have been reported (Table 3). One study, by Pot-

ter et al. was double blind and placebo-controlled

involving 66 postmenopausal women, but only

lasted 6 months. Forty mg of ISP containing 90

mg of isoflavones resulted in a 2.2% increase inthe lumbar spine bone mineral density compared

with baseline. This difference was statistically sig-

nificant [63]. A second similar study was per-

formed in 69 perimenopausal women. Eighty

milligram of phytoestrogen in the daily diet pre-

vented lumbar spine bone loss while a 1.28% loss

was observed in the placebo group [64]. Clifton

Bligh [65] performed a single blind 6 months

study in postmenopausal women. Two doses of

isolated isoflavones57 and 85 mg derived

from red clover determined a non-dose dependent

increase of mineral density of 34% at proximalradius and ulna. Unfortunately, given the preci-

sion of densitometry, 24 weeks is probably too

short a time to observe conclusive changes in

Fig. 3. Effects of GEN on bone loss of ovariectomised mice

(OVX+GEN) compared with ovariectomised mice on no

treatment (OVX) and sham operated controls (Sham).

Modified from [62]. Reproduced with permission.

7/25/2019 1-s2.0-S0378512208003551-main.pdf

10/13


Table3

Phytoestrogenandbonerandomisedcontrolledtrails

Numberof

Design

Age(range)

D

urationof

Doseof

Supplement

Average

BMD

BMD

spine

(%)differen

ce

proximal

isoflavon

es

used

patients

th

estudy

monthsof

amenorrhea

radiusand

withbaselin

e

ulna(%)

differencewith

baseline

Doubleblind

Potteretal.,

22,

22,

22

59(49-73),61

Isolatedsoy

6

months

12

0.2,

2.2*,

56mg,9

0mg,

1998[63]

0.6

(39-83),61

caseinplacebo

protein

controlled

(51-74)

trial

Alekeretal.,

4.4mg,80

Isolatedsoy

24,

24,

21

50(41-61),50

Doubleblind

6

months

9

0.6

6,

0.20,

mg,whey

(44-59),49

protein

2000[64]

controlled

1.2

8*

(44-55)

trial

placebo

Isoflavones

28mg,5

7mg,

CliffonBligh

15,

16,

15

56

6

months

6

2.6,

4.2

*,

Singleblind

etal.2001

2.9

*

noplacebo

85mg

derivedfrom

[65]

redclover

BMD,

bonemineraldensity;*,resultstatisticallysignificant.S,notstatisticallysignificant;Spi,soyproteinisolate.

7/25/2019 1-s2.0-S0378512208003551-main.pdf

11/13


bone mineral but provide strong support for

longer studies.

12. Conclusions

Pytoestrogens are a complex group of plant-derived molecules whose concentrations vary in

different food-stuffs. Variability in metabolism

might also influence clinical effects. Soy or other

phytoestrogens containing food providing ap-

proximately 5080 mg of isoflavones are expected

to produce a 4050% reduction in the number of

hot flushes. Similarly, the consumption of soy

containing at least 25 g of protein might be ex-

pected to reduce LDL cholesterol by about 10

15%. The effects of soy on protecting against

breast cancer is still mainly supported by epidemi-

ological data, well-designed prospective studies in

human are needed. The effect of soy on the

central nervous system is controversial The only

prospective study so far performed on this topic

was done on rodent and is reassuring. Further

human data is awaited. Preliminary data had also

shown a positive effect on bone density. The use

of isolated isoflavones such a GEN or daidzein

might in the future prove helpful to achieve better

clinical effects. Presently, however, the use of

isolated phytoestrogens in tablet form should be

discouraged until efficacy and safety are satisfac-

torily attested.

References

[1] Lindner HR. Occurrence of anabolic agents in plants and

their importance. Environ Qual Safety Suppl 1976;5:151

8.

[2] Eisenberg DM, Kessler RC, Foster C, Norlock FE,

Calkins DR, Delbanco TL. Unconventional medicine in

the United States. Prevalence, cost and pattern of use.

New Engl J Med 1993;328:24652.

[3] Johnston BA. One third of nations adults use herbal

remedies. Herbal Gram 1997;40:49.

[4] Stadberg E, Mattsson L, Milsom I. The prevalence and

severity of climacteric symptoms and the use of differenttreatment regimens in a Swedish population. Acta Obstet

Gynecol Scand 1997;76:4428.

[5] Pike ACW, Brzowski AM, Hubbard RE. A structural

biologists view of the oestrogen receptor. J Steroid

Biochem Mol Biol 2000;74:2618.

[6] Kuiper GGJM, Carlsson B, Grandien K, et al. Compari-

son of the ligand binding specificity and transcript tissue

distribution of estrogen receptor and . Endocrinology

1997;138:86370.

[7] Barkhem T, Carlsson B, Nilsson Y, et al. Differential

response of estrogen receptor and estrogen receptor to

partial estrogen agonist and antagonist. Mol Pharmachol

1998;54:10512.[8] Whitten PL, Naftolin F. Reproductive effects of phy-

toestrogens. Baillieres Clin Endocrinol Metab

1998;12:66790.

[9] Finkel E. Phytoestrogen: the way to postmenopausal

health. Lancet 1998;352:1762.

[10] Setchell KDR, Brown NM, Desai P, et al. Bioavailability

of pure isoflavones in healthy human and analysis of

commercial soy isoflavone supplements. J of Nutrition

2001;131:13625755.

[11] Barnes S. Phytoestrogen and breast cancer. Baillieres

Clin Endocrinol Metab 1998;12:55979.

[12] Cassidy A, Bingham S, Setchell K. Biological effects of a

diet of soy protein rich isoflavones on the menstrual cycle

of premenopausal women. Am J Clin Nutr 1994;60:333

40.[13] Anderson JB, Garner SC. Phytoestrogen in bone. Baillier-

res Clin Endocrinol Metab 1998;12:54357.

[14] Murkies AL, Wilcox G, Davis SR. Phytoestrogens. J Clin

Endocrinol Metab 1998;83:297303.

[15] Setchel KDR, Borriello SP, Hulme P, Kirk DN, Axelson

M. Non-steroidal estrogens of dietary origin: a possible

role in gut hormone metabolism. Am J Clin Nutr

1984;40:56978.

[16] Mazur W. Phytoestrogen content in foods. Baillieres Clin

Endocrinol Metab 1998;12:72942.

[17] Geleijnse JM, Launer LJ, Hofman A, Pols AP, Witteman

JCM. Tea flavonoids may protect against atherosclerosis:

the Rotterdam study. Arch Inter Med 1999;159:170

2174.

[18] Coward L, Barnes NC, Setchell KDR, Barnes S. The

antitumoral isoflavones genistein and daidzein in soybean

food of American and Asian diets. J Agric Food Chem

1993;41:19617.

[19] Dwyer JT, Goldin BR, Saul N, Gualtieri L, Barakat S,

Adlercreutz H. Tofu and soy drinks contain phytoestro-

gens. J Am Diet Assoc 1994;94:73943.

[20] Mukies AL, Lombard C, Strauss BJG, Wilkox G, Burger

HG, Morton MS. Dietary flower suplementation de-

creases post-menopasual hot flushes:effect of soy and

wheat. Maturitas 1995;21:18995.

[21] Brzezinski A, Adlercreutz H, Shaoul R, Rosler A,

Shmueli A, Tanos V, Schenker GJ. Short-term effects of

phytoestrogen-rich diet on postmenopausal women.

Menopause 1997;4:8994.

[22] Dalais FS, Rice GE, Wahlqvist ML, et al. Effects of

dietary phytoestrogens in postmenopausal women. Cli-

macteric 1998;1:1249.

[23] Washburn S, Burke GL, Morgan T, Antony M. Effect of

soy protein supplementation on serum lipoproteins, blood

7/25/2019 1-s2.0-S0378512208003551-main.pdf

12/13


pressure, and menopausal symptoms in perimenopausal

women. Menopause 1999;6:713.

[24] Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini

E, De Aloysio D. The effects of soy supplementation on

hot flushes. Obstet Gynecol 1998;91:611.

[25] Kotsopoulus D, Dalais FS, Liang YL, McGrath PB,

Teede HJ. The effects of soy protein contain phytoestro-

gens on menopausal symptoms on postmenopausalwomen. Climacteric 2000;316:1617.

[26] Germain AS, Peterson CT, Robinson JG, Aleker L.

Isoflavone-rich or isoflavone -poor soy protein does not

reduce menopausal symptoms during 24 weeks of treat-

ment. Menopause 2001;8:1726.

[27] Scambia G, Mango D, Signorile PG, et al. Clinical effects

of a standardazided soy extract in postmenopausal

women: a pilot study. Menopause 2000;2:1501.

[28] Quella SK, Loprinzi CL, Barton DL, et al. Evaluation of

soy phytoestrogens for the treatment of hot flushes in

breast cancer survivors: a north central cancer treatment

group trial. J Clin Oncol 2000;18:106874.

[29] Upmalis DH, Lobo R, Bradley L, Warren M, Cone FC,

Lamia CA. Vasomotor symtomsrelief by soy isoflavone

extract tablets in postmenopausal women; a multicenter,

double-blind, randomized, placebo-controlled study.

Menopause 2000;7:23642.

[30] Baber RJ, Templeman C, Morton T, Kelly GE, West L.

Randomised placebo-controlled trial of an isoflavone sup-

plement and menopausal symptom in women. Climacteric

1999;2:8592.

[31] Knight DC, Howes JB, Eden JA. The effects of Promen-

sil an isoflavone extract on menopausal symptoms.

Climacteric 1999;2:7984.

[32] FDA HRT Working Group. Guidance for clinical evalua-

tion of combination estrogen/progestin-containing drug

products used for hormonal replacement therapy of post-

menopausal women. Menopause 1995;2:1316.

[33] Foth D, Cline MJ. Effects of mammalian and plantestrogen on mammary glands and uteri of macaques. Am

J Clin Nutr 1998;68(Suppl.):1413S7S.

[34] Baird DD, Umbach DM, Lansdell L, et al. Dietary

intervention study to assess estrogenincity of dietary soy

amongs postmenopausal women. J Clin Endocrinol

Metab 1995;80:168590.

[35] Wilcox G, Wahquist ML, Burger H, Medley G. Oestro-

genic effects of plant food in postemnopausal women. Br

Med J 1990;301:9056.

[36] Ingram D, Sanders K, Kolybaba M, Lopez D. Case

control study of pytoestroges and breast cancer. Lancet

1997;350:9904.

[37] Murkies A, Dalais FS, Briganti EM, Burger HG, Healy

DL, Wahlqvist ML, Davis SR. Phytoestrogen and breast

cancer in postmenopausal women: a case control study.Menopause 2000;7:28996.

[38] Hargreaves DF, Potten CS, Harding C, et al. Two-week

dietary soy supplemetation has an estrogenic effect on

normal premenopausal breast. J Clin Endocrinol Metab

1999;84:401724.

[39] Brown AMC, Jeltsch JM, Roberts M, Chambon P. Acti-

vation of the PS2 gene transcription is a primary response

to estrogen in human breast cancer cell line MCF-7. Proc

Natl Acad Sci USA 1984;81:63448.

[40] Harding C, Osudenko O, Tetlow L, Howell A, Bundred

NJ. Non invasive measurement of anti-oestrogen activity

in the breast. Eur J Cancer 1996;32A:13.

[41] Petrakis NL, Barnes S, King EB, et al. Stimulatoryinfluence of soy proteine isolate on breast secretion in pre-

and postmenopausal women. Cancer Epidemiol Biomark

Prev 1996;5:78594.

[42] Beaglehole R. International treands in coronary heart

disease mortality, morbidity and risk factors. Epidemiol

Rev 1990;12:115.

[43] Thom TJ, Epstein FH, Feldman JJ, Leaveton PE, Wolz

M. Total Mortality from Heart Disease, Cancer and

Stroke from to 1987 in 27 Countries. Netional Institute of

Health publication number 02-3088. Bethesda, MD: Na-

tional Institute of Health, National Heart, Lung and

Blood Institute, 1950:1992.

[44] Anderson JW, Johnstone BM, Cook-Newell ME. Meta-

analysis of the effects of soy protein intake on serum

lipids. New Engl J Med 1995;333:27682.

[45] Sirtori CR, Galli G, Lovati MR, Cxarrara P, Bosisio E,

Kienle MG. Effects of dietary proteins on regulation of

liver lipoprotein receptors in rats. J Clin Nutr

1998;114:1493500.

[46] Baum JA, Teng H, Erdman JW, et al. Long-term intake

of soy protein improves blood lipids profiles and increases

mononuclear cell LDL receptor mRNA in hypocholes-

terolemic postmenopausal women. Am J Clin Nutr

1998;68:54551.

[47] Greaves KA, Parks JS, Williams JK, Wagner JD. Intact

dietary soy protein, but not adding an isoflavone-rich soy

extract to casein, improves plama lipids in ovariectomized

cunomologus monkeys. J Nutr 1999;129:158592.

[48] Crouse JR, Morgan T, Terry JG, Ellis J, Vitolins M,Burke GL. A randomized trial comparing the effect of

caseine with that of soy protein containing. Varying

amount of isoflavones on plasma concentration of lipids

and lipoproteins. Arch Intern Med 1999;159:20706.

[49] Honore EK, Williams JK, Antony MS, Clarkson TB.

Soy isoflavones enhance coronary vascular reactivity in

atherosclerotic female macaques. Fertil Steril

1997;67:14854.

[50] Figtree GA, Griffiths H, Lu YQ, Webb CM, MacLeod K,

Collins P. Plant-derived estrogen relax coronary artery in

vitro by a calcium antagonist mechanism. Am J Coll

Cardiol 2000;35:197785.

[51] Makela S, Savolainen H, Aavik E, et al. Differentiation

between vasculoprotective and uterotrophic effects of lig-

ands with different binding affinities to estrogen and .Proc Natl Acad Sci USA 1999;96:707782.

[52] Trieu VN, Utckun FM. Genistein in neuroprotective in

murine models of familiar amyotrophys lateral sclerosis

and stroke. Biochem Biophys Res Comun 1999;258:685

8.

7/25/2019 1-s2.0-S0378512208003551-main.pdf

13/13


[53] Deodato B, Altavilla D, Squadrito G, et al. Cardioprotec-

tion by the phytoestrogen genistein in experimental

ishaemia-reperfusion injury. Br J Pharmacol

1999;128:168390.

[54] Tikkanen MJ, Whahala K, Ojala S, Vihma V, Adler-

creutz HZ. Effects of phytoestrogen intake on low density

lipoprotein oxidation resistance. Proc Natl Acad Sci USA1998;95:310610.

[55] Jenkins DJA, Kendall CWC, Garsetti M, et al. Effects of

soy protein food on low density lipoprotein oxidation and

ex vivo sex hormone receptor activitya controlled cross

over trial. Metabolism 2000;49:53743.

[56] Nestel PJ, Pomeroy S, Kay S, Komesaroff P, Behrsing J,

Cameron JD, West L. Isoflavones from red clover im-

prove systemic arterial compliance but not plasma lipids

in menopausal women. J Clin Endocrinol Metab

1999;84:8958.

[57] Howes JB, Sullivan D, Lai N, Nestel P, Pomeroy S, West

L, Eden JA, Howes LG. The effects of dietary supplemen-

tation with isoflavones from red clover on the lipoprotein

profiles of post menopausal women with mild to moder-

aten hypercholesterolaemia. Atherosclerosis

2000;152:1437.

[58] Graves AB, Larson EB, Edland SD, et al. Prevalence of

dementia and its subtypes in the Japanese American

population of King country, Washinghton state. Am J

Epidemiol 1996;144:7601.

[59] White LR, Petrovitch H, Ross W, et al. Brain ageing and

midlife tofu consumption. J Am Coll Nutr 2000;19:242

55.

[60] Pan Y, Antony M, Watson S, Clarckson TB. Soy phy-

toestrogens improve radial arm maze performance in

ovariectomized retired breader rats and do not attenuate

benefit of 17-estradiol treatment. Menopause

2000;7:2305.

[61] Arjmandi BH, Alekel L, Hollis BW, Amin D, Stacewicz-

Sapuntzakis M, Guo P, Kukreja SC. Dietary soybean

prevents bone loss in an ovariectomised rat model of

osteoporosis. J Nutr 1996;126:1617.

[62] Ishimi Y, Miyaura C: Ohmura M, et al. Selective effects

of genistein, a soybean isoflavone, on B-lymphopoiesis

and bone loss caused by estrogen deficiency. Endocrinol-

ogy 1999;4:189339000.

[63] Potter SN, Baum JA, Teng H, Stillman RJ, Shay NF,

Erdman JW. Soy protein and isoflavones: their effects on

blood lipids and bone density in postmenopausal women.

Am J Clin Nutr 1998;68:1375S9S.

[64] Alekel DL, Germain AS, Peterson CT, Hanson KB,

Steward JW, Toda T. Isoflavone-rich soy protein isolate

attenuate bone loss in the lumbar spine of peri-

manopausal women. Am J Clin Nutr 2000;72:84452.

[65] Clifton-Bligh PB, Barber RJ, Fulcher GR, Nery ML,

Moreton T. The effect of isoflavones extracted from red

clover (rimostril) on lipid and bone metabolism.

Menopause 2001;8:25965.

1-s2.0-S0378512208003551-main.pdf

Documents

Transcript of 1-s2.0-S0378512208003551-main.pdf