Endocr Relat Cancer 2001 (Jun); 8 (2): 129–134 ~ FULL TEXT
This P, De La Rochefordiere A, Clough K, Fourquet A, Magdelenat H;
The Breast Cancer Group of the Institut Curie
Service de Chirurgie a orientation Senologique,
The current extension of the indications for adjuvant chemotherapy, which predisposes to early menopause, and the media coverage of the benefits of hormone replacement therapy (HRT) have led patients with a history of breast cancer to seek treatments for estrogen deprivation. In breast cancer survivors, most physicians avoid HRT because of concern regarding the potential promotion of growth of occult malignant cells by estrogens, due to the estrogen dependence of breast cancer. Soy phytoestrogens are being promoted as the 'natural alternative' to HRT and have been available without restrictions for several years as nutritional supplements. In this paper, data on the complex mammary effects of phytoestrogens in epidemiological studies, in in vitro studies, as well as in in vivo studies on animal carcinogenesis are reviewed. The potential benefits and risks of phytoestrogens are analyzed, and the prescription of phytoestrogens to postmenopausal women after breast cancer and the coprescription with the anti-estrogen tamoxifen are discussed. The absence of controlled trials and technical checking of extraction and titration in these preparations on 'free sale' raise a new problem in terms of public health and justify close reasoning and a cautious attitude of physicians, as well as straight information given to women, especially after breast cancer.
From the FULL TEXT Article:
The current extension of the indications for adjuvant
chemotherapy predisposing to early menopause, the media
coverage of the benefits of menopausal hormone replacement
therapy (HRT), and the well-founded desire of an optimal
quality of life have led more and more patients with a history
of breast cancer to seek treatments for estrogen deprivation.
The prescription of HRT after breast cancer raises a
number of problems due to the estrogen dependence of breast
cancer, while the possible increased risk of breast cancer in
healthy women taking HRT has to be considered (Schairer
et al. 2000). Some authors have proposed the prescription of
HRT after breast cancer (Vassilopoulo-Sellin et al. 1999),
but these prescriptions remain limited to a few experimental
studies; most physicians continue to avoid HRT in breast
cancer survivors because of concern regarding the promotion
of growth and dissemination of occult malignant cells while
on HRT. Besides these treatments, which are prescribed
under medical control, soy phytoestrogens derived from
plants are being promoted as the ‘natural alternative’ to HRT,
and have been available without restriction as nutritional
supplements for several years. After breast cancer, some
women decide, sometimes ‘by themselves’, to take these
phytoestrogens to alleviate menopausal symptoms. Recently,
Ginsburg (2000) underlined the marked contrast between the
rigid testing procedures required for synthetic estrogens and
the absence of controlled trials or standardization of dose in
those preparations on ‘free sale’ to the public. But patients
who present contra-indications to traditional HRT are the
potential users of these products. Can they be used safely
after breast cancer? What will be the real benefits of these
preparations? And what about the association of
phytoestrogens and tamoxifen (Tam), the anti-estrogen
widely prescribed as a long term adjuvant treatment of breast
Interests of phytoestrogens for the treatment of estrogen deprivation
Estrogen deprivation induces three orders of symptoms: in
the short term, women will present climacteric symptoms,
hot flushes, vaginal dryness, and sometimes, psychological
and sexual disorders. Some years later, they will present
osteoporosis and cardiovascular events.
What are phytoestrogens?
Phytoestrogens have a similar chemical structure to estrogens
(for reviews see Murkies et al. 1998, Setchell 1998, Tham
et al. 1998). They are classified into two main categories:
isoflavones and lignanes. The two main isoflavones are
genistein and daidzein which are essentially found in
leguminous vegetables and soy beans. Lignanes are found in
high concentrations in linseed. The two main lignanes are
enterolactone and enterodiol.
Many factors influence the availability of isoflavones and
lignanes after ingestion, especially the presence of fibers, the
individual characteristics of metabolism, the ingestion of
Phytoestrogens and menopausal disorders
The rarity of hot flushes in Japanese women has led some
authors to test the efficacy of a soy-rich diet on this symptom.
Albertazzi et al. (1998) carried out a double-blind parallel
multi-center randomized placebo-controlled trial of 104
post-menopausal women: patients were taking 60 g of
isolated soy protein daily (containing 76 mg isoflavones)
versus 60 g of placebo. Soy was significantly superior to
placebo (P>0.01) in reducing the mean number of hot flushes
per 24 h after 4, 8, and 12 weeks of treatment. This study
did not find an effect of phytoestrogen on the other symptoms
of menopause (Kupperman index).
On the other hand, Quella et al. (2000) recently
conducted a double-blind placebo-controlled trial of the
effect of 150 mg isoflavones/day on hot flushes in patients
treated for breast cancer: no significant difference was
observed compared with placebo, but the duration of
treatment was brief (4 weeks) and 68% of patients in each
group also took tamoxifen, which competes with genistein
for binding to estrogen receptors (ER).
We can conclude from these studies that phytoestrogens
have a moderate effect on hot flushes, but do not appear
markedly to improve other parameters of the Kupperman
index that reflect the other symptoms of menopause.
Phytoestrogens and osteoporosis
Osteoporotic fracture rates are lower in Asian women. Once
again, it has been hypothesized that a soy-rich diet has a
protective effect on bone (Tham et al. 1998), but there are
many confounding factors (lifestyle, socio-cultural and
morphological factors) distinguishing Asian women from
Animal studies have demonstrated a favorable effect of
isoflavones on bone: a diet rich in isoflavones partially
prevents bone loss induced by ovariectomy in female rats
(Arjmandi et al. 1996).
Studies on ipriflavone, a synthetic isoflavone, have also
shown that this derivative slightly prevents bone loss in
women treated with a gonadotropin-releasing hormone
agonist (Gambacciani et al. 1994). However, this is a
synthetic derivative used at pharmacological doses and its
effects therefore cannot be extrapolated to those of natural
Only a few clinical trials have been reported. Potter et
al. (1998) showed in postmenopausal women that a diet rich
in isoflavones taken for 6 months resulted in slightly
increased lumbar bone mineral density (2%), but this was a
short-term study conducted on a small number of women.
Although isoflavones appear to prevent bone loss under
certain experimental conditions, their effect must be
confirmed by longer term studies on sufficient sample sizes,
and by focusing, in the intermediate term, on intermediate
factors such as bone mineral density, and in the long-term,
on the fracture risk.
Phytoestrogens and cardiovascular protection
The protective role of a soy-rich diet on cardiovascular
diseases has been suggested by several authors, based on the
decreased incidence of cardiovascular disease in Asian
countries. Once again, this is only an hypothesis, as Asian
populations have a completely different lifestyle and their
diet also differs from Western diets by its much higher fiber
content and lower saturated fat content (Tham et al. 1998).
However, studies concerning the effects of soy on lipid
parameters appear to show a reduction of cholesterol in
response to soy-rich diets. These studies are delicate
(difficulties of retrospective evaluation of soy content in the
diet) and are often based on small sample sizes. The
meta-analysis of 38 studies by Anderson et al. (1995), taking
into account the fat content of these diets, showed that a
diet containing an average of 47 g soy protein decreased total
cholesterol by about 9.3%, low density lipoprotein
(LDL)-cholesterol by 12.9%, and triglycerides by 10.5%.
The change in serum cholesterol and LDL-cholesterol
concentrations were directly related to the initial serum
cholesterol concentrations. In contrast, high density
lipoprotein (HDL)-cholesterol was not significantly modified.
Although these results are encouraging, it should be noted
that they were obtained with soy-rich diets, and not
isoflavone supplements. Once again, further studies are
required to prove that dietary phytoestrogen supplementation
has a real long-term cardiovascular protective effect.
Phytoestrogens and the breast
Soy intake and breast cancer: epidemiological data
There is a geographical variation of breast cancer risk. It is
higher in the United States and in Western Europe, and lower
in Chinese, Japanese, and Asian women in general, when
they live in their country of origin (where the risk is sixfold
lower). In contrast, the risk of breast cancer in Asian woman
increases after several generations when they emigrate to the
United States. Therefore this variation of incidence is
probably not related to a genetic factor, but to an
environmental factor. The diet of Asian women differs
considerably from that of Western women, and contains less
fat and more fiber. Several investigators have proposed the
hypothesis that the lower incidence of breast cancer in Asia
is related to the consumption of soy rich in phytoestrogens.
Case-control studies evaluating the breast cancer risk
according to the soy content of the woman’s diet have been
conducted to validate this hypothesis (for review see Wu et
al. 1998). Some of these studies demonstrated a reduction of
the relative risk (RR) of breast cancer (RR of about 0.4) in
women consuming large quantities of soy, but exclusively in
premenopausal women, while other studies indicated a
moderate and non-significant reduction of this risk.
These studies also present a number of methodological
problems: it is difficult precisely to define the exact quantities
of phytoestrogens ingested by means of sometimes
nonspecific nutritional questionnaires.
This problem was overcome by Ingram et al. (1997)
who, in a case-control study of 144 women with breast
cancer and their matched controls, showed that the risk of
breast cancer was significantly decreased in women with a
high urinary excretion of two phytoestrogens, equol and
Although these data are interesting, it must be
remembered that the protective role of soy phytoestrogens
for breast cancer is only an hypothesis: the protection
provided for Asian women could also be due to other
characteristics of their diet, other ingredients of soy beans,
or other socio-cultural or medical factors (for example
Phytoestrogens and breast tissue: experimental data
The chemical structure of phytoestrogens and their structural
relationship with estrogens allows them to bind to estrogen
receptors (ER). Phytoestrogens can be considered as weak
estrogens, presenting an activity 100 to 1000 times lower
than that of 17β-estradiol (E2), depending on the system
studied (Martin et al. 1978, Markiewicz et al. 1993, Zava &
Duwe 1997). However, in individuals with a moderate soy
intake, plasma concentrations of phytoestrogens are 1000
times higher than endogenous estrogen concentrations in
women of reproductive age. Plasma genistein concentrations
are of the order of 0.1 to 3 µM/l (Zava & Duwe 1997). The
affinities of genistein and daidzein for ER are also lower than
that of estradiol. The order of magnitude varies according to
the system studied; for example, the affinity of genistein for
ER is 20 to 100 times lower than that of E2 (Martin et al.
1978, Kuiper et al. 1997). Finally, a second type of ER has
recently been demonstrated and cloned, ERβ, which has a
specific anatomical distribution (bone, brain, vascular
endothelium), and for which phytoestrogens appear to have
a higher affinity than for ERα (Kuiper et al. 1997).
In vitro studies on breast cancer cells
Over recent years, many in vitro studies on mammary cells
have identified the effects of the main phytoestrogens,
especially genistein and daidzein (Martin et al. 1978,
Sathyamoorty & Wang 1997, Wang & Kurzer 1997, Zava &
Duwe 1997, Hsieh et al. 1998). Studies of the effects of
increasing doses of genistein on induction of an
estrogen-dependent protein (pS2) and on the quantity of
DNA, reflecting proliferation, in cultures of MCF7 cancer
cells (expressing the ERα estrogen receptor), demonstrated a
biphasic effect of genistein on mammary cells, depending on
the concentrations in the culture medium:
‘physiological’ doses (i.e. at doses corresponding to plasma
concentrations achieved with a high soy intake (100 nM/l to
1 µM/l), genistein stimulates cellular proliferation and this
effect is dependent on ER;
(ii) at physiological doses, in the
presence of physiological doses of estradiol, genistein
behaves like a competitive inhibitor for the binding site of
E2 to ER and slightly inhibits cellular proliferation, since it
has a lower activity than E2;
(iii) at pharmacological doses
(>10 µM/l), it markedly inhibits cellular proliferation. This
effect is not ER-dependent and is probably related to
inhibition of the tyrosine kinase activity of growth factor
On clearly defined systems, the key determinants of the
activity of genistein therefore appear to be the genistein and
estradiol concentrations in the culture medium.
How can these results be extrapolated to man?
Theoretical inhibitory concentrations of genistein are much
higher than the concentrations obtained as a result of
moderate soy intake, providing between 20 mg and 80 mg
genistein (soy intake in the USA is 1 to 3 mg/day). There is
also a marked individual variability of phytoestrogen
metabolism: for example, 30% of individuals metabolize
daidzein into equol, which has a higher affinity for ER
(Sathyamoorty & Wang 1997).
Therefore, this raises the problem of the steroid
concentrations actually available in breast tissue: without a
precise knowledge of intramammary estradiol and genistein
concentrations, it is impossible to predict whether the final
effect will be markedly inhibitory (due to inhibition of
tyrosine kinase), slightly inhibitory (due to competitive
inhibition of the binding of E2 to ER), or stimulatory (when
local E2 concentrations are very low).
Animal carcinogenesis studies
When newborn female rats are treated with genistein and
then exposed to a chemical carcinogen (DMBA), genistein
induces an increased latency and a decreased incidence and
number of induced mammary tumors compared with animals
treated with vehicle alone (Lamartinie`re et al. 1995). Barnes
(1997) demonstrated the fundamental role of the time of
exposure to isoflavones. This protective effect is much more
marked when animals are treated with genistein during the
neonatal or prepubertal period; the number of tumors is less
markedly decreased when genistein is administered later.
These in vivo studies suggest an antitumor activity of
Recently, Hsieh et al. (1998) found that dietary genistein
may act as an estrogen agonist in vivo. MCF7 cells were
implanted in ovariectomized athymic nude mice, and the
growth of the estrogen-dependent tumors was measured
weekly under various conditions: a control diet, a diet with
genistein, and a diet supplemented with estradiol. Tumors
were larger in the genistein diet group than in the control
group, and after 12 weeks they were similar in size to tumors
after two weeks of estradiol treatment, demonstrating that
dietary genistein was able to enhance the growth of the
MCF7 cells tumors in vivo. This study underlines the
potential for dietary genistein to stimulate the growth of
estrogen-dependent tumors in humans with low circulating
estrogen levels, such as those found in postmenopausal
Whether genistein acts as a chemopreventive agent or as
an agent to stimulate tumor growth will probably depend on
the age at which females receive genistein, on the timing of
genistein administration (i.e. before or after the induction of
the tumor), and on the dose of genistein.
Some authors believe that exposure at a young age to
high concentrations of isoflavones may induce the
differentiation of mammary cells and a subsequent decreased
sensitivity to estrogenic stimulation. The studies by Setchell
et al. (1997) showed that new-born infants fed with soy milk
have considerable plasma isoflavone concentrations (6 to 11
times higher than the concentrations per weight which
induced a hormonal effect in adults). Rather than daily
consumption during adulthood, the protective effect may be
due to exposure to high doses of isoflavones very early in
In vivo studies in women
In vivo studies in women are rare and methodologically
difficult, as they require either sampling of breast tissue
(selecting patients with pre-existing disease), or the study of
markers which are more difficult to interpret (nipple fluid
secretions). The time in the menstrual cycle at which the tests
are performed must also be taken into account.
McMichael-Philips et al. (1998) studied the effect of
supplementation with 45 mg isoflavones for a fortnight in
women requiring surgery for a benign or malignant breast
tumor, in whom breast tissue was taken from a healthy zone
for the study of proliferation markers (thymidine
incorporation index and Ki67). Cell proliferation rates were
increased in women treated with isoflavones, taking into
account the woman’s age and the phase of the menstrual
Hargreaves et al. (1999) studied the effect of 14-day
supplementation with 45 mg isoflavones in 84
non-postmenopausal women. The study of nipple aspiration
fluid showed increased levels of the estrogen-dependent
protein, pS2, in women treated with isoflavones.
In conclusion, the effect of phytoestrogens on breast
tissue is complex: intramammary genistein and estradiol
concentrations, and the timing of exposure appear to play a
major role in determining agonistic or antagonistic effects.
Indications for phytoestrogens
In postmenopausal women with no contraindications to HRT
Current descriptive epidemiology data in Asian women, and
the absence of any obvious harmful effects of soy-rich diets
constitute arguments which encourage Western women to
adopt a high-fiber diet, low in saturated fats and comprising
a soy supplement.
However, the supplementation of a diet with extracts
containing isoflavones needs to be considered more carefully.
Various preparations extracted from soy and containing
isoflavones are now freely available on the market. The
media coverage of treatments of the menopause, the fear of
the adverse effects of ‘classical’ treatments and the
‘ecological’ trend towards consumption of plant extracts,
often considered by patients to be ‘inoffensive’, all incite
women to use phytoestrogens. In view of the theoretical risk
of self-prescribed medication, physicians must define
precisely the place of phytoestrogens in the treatment of
disorders of the menopause and inform their patients
The general indications for phytoestrogens in
postmenopausal women are based on the current data in the
literature: there is no sufficient scientific evidence, at the
present time, to recommend phytoestrogen supplements
for either prevention of osteoporosis (either prevention
of ‘physiological’ postmenopausal bone loss or prevention of
the fracture risk in women with a low bone mass), or
prevention of cardiovascular disease.
Therefore, the current indications for phytoestrogens
appear to be limited to the treatment of hot flushes in
postmenopausal women who either refuse or do not tolerate
conventional estrogen-based HRT because of metrorrhagia or
In postmenopausal women presenting a contraindication to HRT
A distinction must be made for patients presenting a
contraindication to HRT, especially after a hormonedependent
cancer such as a breast cancer: it would be very
tempting to propose, in patients in whom the prescription of
estrogens is theoretically contraindicated, a ‘substitute’ for
HRT which, in addition, would also possess possible
We have seen that animal carcinogenesis data
demonstrate an antitumor effect of phytoestrogens, but only
at high doses, and only when they are administered during
the neonatal or peripubertal periods. We have also seen that
in vitro data have clearly established the biphasic and largely
dose-dependent effect of phytoestrogens especially genistein,
which must be considered to be true weak estrogens rather
than selective estrogen receptor modulators (SERM)
(molecules binding to ER and exerting either agonist or
antagonist effects, depending on the tissue). The final effect
on breast tissue depends on the intramammary genistein and
estradiol concentrations which, in turn, depend on the
individual tissue metabolism. Some groups have recently
underlined the importance of the intratissue biosynthesis of
steroids (intracrine concept) (Blankenstein et al. 1999,
Chetrite et al. 2000). Current scientific data are unable to
predict the final effect of phytoestrogens in the breast
(Zava & Duwe 1997). On the other hand, the efficacy of
anti-estrogen adjuvant therapy after breast cancer (Early
Breast Cancer Trialists’ Collaborative Group 1998) suggests
the possibility that the use of a weak estrogen could be
harmful in patients after a hormone-dependent cancer at the
stage of micrometastases, and justifies a cautious attitude
(Hargreaves et al. 1999, Ginsburg 2000).
A combination of phytoestrogens and Tam for the
control of hot flushes after breast cancer (Quella et al. 2000)
also raises the problem of their possible competition. In the
case of genistein, this corresponds to administering two
molecules, an antagonist and a weak agonist, at equivalent
plasma concentrations, with approximately the same affinity
for ERα (Kuiper et al. 1997)! According to the cell culture
studies by Zava and Duwe (1997), genistein probably
partially displaces Tam from ER, thus decreasing its
inhibitory effect. In contrast, Tam and genistein at very high
doses effectively exert a synergistic anti-proliferative action,
but at these doses, the effects are no longer dependent on
estrogen receptors (Zava & Duwe 1997, Shen et al. 1999).
As precise scientific data on the intramammary
concentrations of these two molecules are not yet available,
it does not seem logical to coprescribe a product with Tam
that is likely to decrease its efficacy.
In conclusion, prescription of phytoestrogens after breast
cancer can only be considered in patients
(i) fully informed about the real benefits and risks of these preparations,
(ii) in order to treat postmenopausal hot flushes,
(iii) after seeking the oncologist’s advice (good prognosis breast cancer, a long
time after the diagnosis),
(iv) in the absence of coprescription of Tam, and
(v) with careful breast surveillance.
treatment should only be continued when it has a marked
efficacy on the symptoms.
The unrestricted sale of plant products constitutes a new
situation for physicians with little training in phytotherapy.
The qualitative and quantitative diversity of the commercially
available preparations, their variable phytoestrogen
contents (essentially depending on extraction techniques), the
absence of precise prescribing guidelines, and the risk of
self-prescribed medication justify the introduction of
‘phyto-vigilance’ procedures and practical proposals.
A list of the available preparations should be established,
patients should be clearly informed about the properties and
uncertainties of phytoestrogens, and randomized
placebo-controlled clinical trials should be conducted, in
parallel with ongoing research, to determine the efficacy of
phytoestrogens on the improvement of quality of life, and
their safety (especially endometrial). A register of patients
taking phytoestrogens after breast cancer could be proposed
but, in order to be rigorous, it would ideally have to take into
account the precise qualitative and quantitative content of the
products consumed, including those in the diet, and the
individual metabolism of phytoestrogens.
Finally, combined administration of Tam and
phytoestrogens should only be considered in the context of
randomized trials designed to test the in vivo impact of this
combination, not only on menopausal symptoms, but also on
the efficacy of adjuvant treatments for breast cancer.
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