Maturitas 61 (12) (2008) 214229

Review

Reprint of The nature and utility of the phytoestrogens: a review of

the evidence
Paola Albertazzi *, David W. Purdie
Centre for Metabolic Bone Disease, H. S. Brocklehurst Building, Hull Royal Inrmary, 220 -236 Anlaby 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 conicting
and difcult 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 metabolism
of 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 benet from. It is difcult 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
* Corresponding author. Tel.: + 44-1482-675300; fax: +441482-675301
E-mail address: p.albertazzi@medschool.hull.ac.uk (P. Albertazzi).

activity. Their chemical structure is a steran

frame, as with all steroid hormones, although
their effects are estimated to be some thousandfold weaker compared with those of 17b oestradiol [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.

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

*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

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

Women with personal objections, or clinical contra-indications to the use of conventional oestrogen replacement, or who are simply seeking a
more natural treatment for menopausal symptoms, are increasingly requesting information
about the efcacy of these forms of diet
supplementation.
There are no good data for the prevalence of
complementary or alternative medicine by climacteric 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 genisteinone (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 afnity for the recently
discovered oestrogen receptor b (ERb) than for
the classical oestrogen receptor a (ERa). This

Fig. 1. Schematic representation of the conformation of the

estrogen receptor b-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.

215

differential afnity might be of functional signicance as the two receptor sub-types differ in their
tissue distribution and possibly in biological activity [6].
Differential afnity for oestrogen receptors may
not, however, fully account for phytoestrogen action. A recent study has shown that the isoavone
phytoestrogen, GEN, has higher efcacy in inducing production, in-vitro, of a reporter protein
through ERa than through ERb, in spite of its
higher afnity for ERb [7]. Finally, although phytoestrogens compete effectively with oestradiol for
receptor binding at nanomolar (10 9 M) concentrations, in higher micromolar (10 6 M) concentrations, 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 effects 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 isoavones present in their diet is one
factor adduced to explain these ndings. Whether
increasing phytoestrogens in the diet of Western
men and women would have a favourable inuence on health is unresolved and is the subject of
considerable research.
Wholegrain cereal, fruits, legumes and berries
are rich in phytoestrogens. However, diet modication is often not easily to implement and therefore, the market had been urried with
preparations containing varying concentrations of
isolated phytoestrogens of different origins. Some
of the products currently available over-the-counter in health food outlets in the UK are presented
in Fig. 2. The safety of these products as well as
their effectiveness needs to be individually assessed. These products are all sold as food supplements and, not being subjected to any regulatory

216

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

close to the outer bre-containing layer, a part

that modern European and North American
milling techniques usually eliminate. As a result,
phytoestrogens are seldom present in cerealderived food in Western societies.
Single plants often contain more than one type
of phytoestrogen, and different plants contain
different concentrations of the several phytoestrogen types (Table 1).

3. Phytoestrogens: metabolism
Fig. 2. Schematic presentation of phytoestrogens subtypes.

controls, they vary in quality. Independent quality

control checks of commercially available preparations have shown that the phytoestrogens content
in these tablets varies greatly, and in some cases
are totally absent [10]. Furthermore, the misconception-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 discrepant 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 compounds, of which the three main branches are
isoavones, lignans and cumestans. In plants,
phytoestrogens functions primarily as antioxidants while in animals and humans they are believed 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

The majority of phytoestrogens are introduced

into the diet as inactive compounds. After the
consumption of plant lignans and isoavones, a
complex enzymatic conversion occurs in the gastrointestinal tract resulting in the formation of
compounds with a steroidal structure similar to
oestrogens.
Isoavones are the most common form of the
phytoestrogens. Two of the major isoavones are
GEN and daidzein. Typically, soybeans-a principal source contain both. In plants, isoavones are
mainly present as inactive glycosides: genistin and
daidzin. However, when the sugar residue is removed, 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 isoavone excretion [14]. Setchel et al.
have hypothesised that the composition of the
intestinal ora, intestinal transit time, and variability in redox potential of the colon, might all
contribute to this variability in humans [15]. This
large variability in phytoestrogen metabolism is
potentially clinically signicant as it may inuence
biological responses.
With regard to lignans, ingestion leads to the
production of Enterolactone and enterodiol in the
gut, and their excretion in the urine. Vegetables
such as carrots, spinach, broccoli and cauliower
are the main sources of lignans.

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

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
benecial in the prevention of ischaemic heart
disease [17].

217

content remains constant indicating that

isoavones are stable at the usual temperatures
encountered in the preparation of food. The concentration of isoavones 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 isoavons concentrations. An
exception is soy protein concentrate prepared by
extracting soy our 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 depends 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 our has a high phytoestrogen concentration while soy milk and soy sauce contain relatively low amounts. Tofu (soy cheese) contains

4. Soy
The phytoestrogen intake of the Asian population derives mainly from soybeans (Glycine max).
Soy our, toasted soy our, and isolated soy
protein (ISP) contain inactive conjugated
isoavones, whereas fermented soy foods such as
miso and tempeth, both staples of the Oriental
diet, contain the active deconjugated forms.
Although the conjugation prole of isoavones
present in soy can be inuenced by heat, the total
Table 1
Quantities of phytoestrogens in food, mean (mg/100 g)

Soy
Soy-ower
Kikkoman rm
tofu
Hatcho Miso
Soy drink
Soymilk
Lin-seeds
Clo6er seeds
Wheat
Whole grain
White wheat
meal
Wheat bran
Oat
Bran
Meal
Rye
Meal
Bran
Mung
Bean
Sprouts
Pumpkin seeds
Chick peas

Genistein

Daidzein

SECO

93 900
21 300

67 400
7600

130

14 500
2100
310

323

7300
700
30

178

369 900
13

Traces

Traces

32.9
8.1

Metairesinol

Biochanin A

Formomonetine Coumestrol

70

30

1027
3.8

381

1270

2.6

5.3

6.9

3.5

110

6.9

3.5
0

110
13.4

0
0.3

47
132

365
1902
1.53
76.3

9.7
745
0.56
11.4

172
468
21 370
8.4

65
167
0.25
0.87

14

838

7.5

215

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

1.8
1032

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

signicant amounts of isoavones (0.2 0.5 mg/g)

but the concentration is highly variable between
brands [19]. Isolated soy protein (ISP) is a powder
obtained from processed soy our, this preparation contains 90% proteins and a controlled
amount of isoavones. 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 journals. Systematic reviews and an on-line Medline
search with the key-words phytoestrogens,
isoa6ones, 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 ushes
Twelve randomised studies were found which
had examined the effect of phytoestrogens on the
incidence and severity of hot ushes in peri and
postmenopausal women (Table 2). Six studies
used wholegrain or soy preparation containing
proteins, [20 26] while ve studies used concentrated isoavones in tablets form either derived
from soy [27 29] or red clover [30,31]. The US
Food and Drug Administration (FDA) recommends a standard design for trials with drugs such
as hormonal replacement therapy to be used for
the treatment of hot ushes. This requires a trial
duration at least 3 months, a placebo arm, and
enrolment of patients with more than 60 moderate
to severe hot ushes 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 ushes 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 efcacy. 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 postmenopausal women. In this study, soy had no
effects on the important oestrogen-sensitive symptom of vaginal dryness [24].
Brzezinski et al. compared a diet high in phytoestrogen with one containing low phytoestrogen
on hot ushes in postmenopausal women. The
phytoestrogen rich diet consisted of a daily consumption 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 ushes and improving
vaginal dryness [21]. This study, however, was not
double-blind, admittedly difcult to achieve when
using conventional food, but important when interpreting results since hot ushes 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 ushes using 45 g of soy our per
day (approximately 2390 mg of phytoestrogens)
but a similar amount of wheat our, used as
control, also reduced hot ushes 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 food45 g of wheat
kibble 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 ushes but signicantly improved the matura-

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

219

Table 2
Phytoestrogen and hot ushed (continuation)

Whole soy or grains

Murkies et al. 1995 [20]
Brezezinski et al 1996;
[21]
Dalais et al. [22] 1998;

Washbum et al. 1998;

[23]

Phytoestrogen

Study design

Hot Flushes (%)

45 g soy our, 45 g wheat

our
80 g tofu, miso, 10 g
linseeds normal diet
45 g soy grit enriched
bread, 45 g linseeds, 45 g
wheat kibble
20g soy protein containing
34 mg of phytoestrogen

58

Randomised double blind,

without placebo, 12 weeks
Randomised, not blinded,
without placebo 12 weeks
Randomised double blind
cross-over, without placebo,
12 weeks
Randomised double blind
placebo controlled,
cross-over trial, 6 weeks
Randomised double blind,
placebo controlled 12 weeks
Randomised double blind
placebo controlled, 3
months
Randomised double blind
placebo controlled, 6
months

40 PB0.001, 25
PB0.01
50 pB0.004

Albertazzi et al. 1998 [24] 60 g soy protein, 76 mg

isoavones, aglycone
Kostsopoulos et al. 2000 Soy protein containing 118
[25]
mg of phytoestrogen
Germain et al. 2001 [26]

78, 36
52

51

104
95

Soy protein containing 4.4,

80 mg of isoavones,
aglicone

69

Isolated isoa6ones Red

clo6er deri6ed
Barber et al. 1999 [30]

40 mg

51

Knight et al. 1999 [31]

Placebo 40, 160 mg

37

39

Upmalis et al. 2000 [29]

50 mg isoavones glycone
u31 mg aglycone
50 mg isoavones

Quella et al. 2000 [28]

150 mg

177, 77% on
tamoxifene

Isolated isoa6ones Soy

deri6ed
Scambia et al. 2000 [27]

Randomised double blind

cross over 12 weeks
Randomised double blind
controlled 12 weeks

177

Randomised double blind

placebo controlled 6 weeks
Randomised double blind
placebo controlled 12 weeks
Randomised double blind
cross over 4 weeks

20 NS, 40
pB0.009, 50
pB0.001
NS ( severity)

45 PB0.001
NS

NS

NS
NS

45 PB0.001
28 PB0.078
NS

NS, non-signicant.

tion of the vaginal epitelium [22]. Hot ushes

were, however, signicantly 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 ushes.
Washburn et al. observed a reduction in the severity of hot ushes but not in their number, by
supplementing the diet of 51 perimenopausal
women with 20 g of ISP containing 34 mg of
phytoestrogen [23]. These negative results might
have been partially due to the study design itself,
since the eligibility criteria allowed the participation 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 oestrogen. Given the levity of the starting symptoms, a
much larger sample size might have been necessary to observe a small effect with treatment.
Kotsopoulus et al. [25] found no climacteric
symptom relief in 94 postmenopausal women enrolled in a 3 months double-blind placebo trial
using ISP containing 118 mg of isoavones per
day. Again, the study design had several limita-

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

tions. Women were not required to keep a daily

account of the number of hot ushes, and
symptoms were scored only in term of climacteric questionnaires. Furthermore, women enrolled 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 ushes 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 containing 80 mg of isoavones aglycone, a soy
protein
preparation
virtually
devoid
of
isoavones and a whey protein control for 24
weeks.
Two studies have been performed with concentrated phytoestrogens tablets derived from
red clover. In these studies doses of 40 and 160
mg failed to reduce hot ushes 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 inuenced outcome.
Two randomised placebo-controlled studies
have been performed with isoavones derived
from soy. Patients received 50 mg of phytoestrogens daily and a decrease of between 28 and
45% in the number of hot ushes was observed
[27,29]. On the other hand, Quella et al. failed
to show a reduction in hot ushes in breast cancer survivors taking 150 mg of phytoestrogen
orally [28]. This study had, again, several aws.
The cross-over design had two phases lasting
only 4 weeks, not separated by a wash out period and thus a carry-over effect cannot be excluded. The number of patients studied was
substantial:177, but over half of them had a minor symptomatology (17% with two to three hot
ushes per day and 50% with four to nine hot
ushes per day). Furthermore, 70% of women
on the trial were taking tamoxifen and hence a
larger dose of phytoestrogen might have been
required to overcome the known antiestrogenic
action of tamoxifen on the central nervous system. Lastly, the authors did not specify the

quantity of isoavones present in the active

form in the preparation used. Low levels of
isoavones in the active form would have affected the overall efcacy 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 effects have been observed, either in endometrial
thickness as measured with transvaginal ultrasound [27,29,30], or in uterine artery pulsatility
index when compared with placebo [30]. Foth
and Cline have studied the effects of supplementing the diet of postmenopausal macaques
with soy protein isolated containing 148 mg of
phytoestrogen per day for 6 months. Even such
a comparatively high dose of isoavone for such
a long duration failed to induce any proliferative effects on endometrial histology. Moreover,
phytoestrogens appeared to antagonise the proliferative 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 either in terms of intensity of symptoms or, more
objectively, by cytological assessment of maturation of vaginal epithelium. Nine studies have
looked
at
maturation
of
vaginal
epitelium[20,22,24,27,29 31,34,35] with phytoestrogen 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 Kotsopoulus et al. [25] collected data on the subjective
perception of vaginal dryness and found it to be
improved. Many psychological variables, however, might have inuenced this outcome, not
least that patients, in the study of Brzezinski et
al. were not blinded. Presently, there is no obvious 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.

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

8. Breast cancer protection

Asians consume high amounts of phytoestrogens 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 performed to-date on the effect of soy on the breast.
One reported the effects of 2 weeks of soy supplementation on the breast of premenopausal women
due to have surgery for either benign or malignant breast disease [38]. Soy had no adverse effects on any histological index of proliferation.
However, a rise of pS2 protein and lowering of
apolipoprotein D was observed in the nipple aspirate of women taking soy compared with controls
[38]. A similar effect has been observed in-vitro
when 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 postmenopausal women taking soy for 6 months [41].
This might conrm a slight stimulatory effect of
soy in premenopausal women, although continued
stimulation of the breast alone might have also
explained this nding. Foth and Cline, in the
longest prospective study so far performed, failed
to show any proliferative effects on breast histology of postmenopausal macaques after 6 months
of ISP supplementation containing 145 mg of
isoavones 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 humans in lowering plasma total cholesterol, LDH
cholesterol and tryglicerides. The magnitude of
LDL cholesterol improvement in humans is directly related to the initial cholesterol concentra-

221

tion. The benet is also proportional to amount

of soy intake [44]. Improvement of HDL cholesterol 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-extracted 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-density
lipoprotein (HDL) cholesterol by 2%. The effects
of dietary soy supplementation in lowering the
lipid prole 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 female monkeys with atherosclerosis, an effect similar 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 demonstrated that the effect is likely due to a calcium
channel blocking mechanism, [50] although an
ERb mediated action cannot be excluded [51].
Supplementation with puried GEN, one of the
isoavones present in soy, has been shown to
reduce the extension of ischaemic lesions in
murine models of stroke [52] and mycardial infarction [53]. This protective effect of GEN on
ischaemia appears to be mediated by its antioxidant 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

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

soy or phytoestrogen diet. Both the antioxidant

effect and the enhancement of vascular reactivity
may further contribute to the cardiovascular disease protection offered by the lipid-lowering effect
of soy.
Red clover contains high concentrations of
isoavones but in a rather different composition
compared with soy. Clover has an high concentration 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 prole in
either normal or hypercholestolemic subjects
[56,57]. The only potentially useful nding obtained so far with these compounds has been the
improvement of ultrasound measured arterial
compliance in postmenopausal women. This was
dened as the increase in volumetric blood ow 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 immigrants in Hawaii was thus rather puzzling [59].
The study in question, however, was specically
designed to investigated the effect of diet of
midlife with the incidence of cardiovascular disease and not to investigate specically the inuence of phytoestrogen intake with disease later in
life. It is thus possible that the statistical signicant correlation found might have occurred by
chance and that tofu consumption might be a
marker for some other rather unfavourable exposures 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 benecial
effects of oestrogen in working memory. Ovariectomised rats fed with a ISP containing up to 144
mg of phytoestrogens had an improvement in
radial arm maze performance comparable to that
of oestrogen. The benecial 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 Potter 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 isoavones resulted in a 2.2% increase in
the lumbar spine bone mineral density compared
with baseline. This difference was statistically signicant [63]. A second similar study was performed in 69 perimenopausal women. Eighty
milligram of phytoestrogen in the daily diet prevented 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 isoavones 57 and 85 mgderived
from red clover determined a non-dose dependent
increase of mineral density of 34% at proximal
radius and ulna. Unfortunately, given the precision 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).
Modied from [62]. Reproduced with permission.

Double blind
controlled
trial
Double blind
controlled
trial
Single blind
no placebo
Isoavones
derived from
red clover

Isolated soy
protein

Isolated soy
protein

Supplement
used

Number of
patients

4.4 mg, 80
24, 24, 21
mg, whey
placebo
28 mg, 57 mg, 15, 16, 15
85 mg

56 mg, 90 mg, 22, 22, 22

casein placebo

Dose of
isoavones

59 (49-73), 61
(39-83), 61
(51-74)
50 (41-61), 50
(44-59), 49
(44-55)
56

Age (range)

6 months

6 months

6 months

Duration of
the study

12

Average
months of
amenorrhea

BMD, bone mineral density; *, result statistically signicant. S, not statistically signicant ; Spi, soy protein isolate.

CliffonBligh
et al. 2001
[65]

Aleker et al.,
2000 [64]

Potter et al.,
1998 [63]

Design

Table 3
Phytoestrogen and bone randomised controlled trails

0.66, 0.20,
1.28*

0.2, 2.2*,
0.6

BMD spine
(%) difference
with baseline

2.6, 4.2*,
2.9*

BMD
proximal
radius and
ulna (%)
difference with
baseline

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

223

224

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

bone mineral but provide strong support for

longer studies.
12. Conclusions
Pytoestrogens are a complex group of plantderived molecules whose concentrations vary in
different food-stuffs. Variability in metabolism
might also inuence clinical effects. Soy or other
phytoestrogens containing food providing approximately 50 80 mg of isoavones are expected
to produce a 40 50% reduction in the number of
hot ushes. Similarly, the consumption of soy
containing at least 25 g of protein might be expected to reduce LDL cholesterol by about 10
15%. The effects of soy on protecting against
breast cancer is still mainly supported by epidemiological 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 isoavones 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 efcacy and safety are satisfactorily attested.
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