Phytoestrogens:
Theoretical Concerns Versus Clinical
Knowledge and Applications
Britta Engert & Yiota Panayiotis
Introduction
As interest in the practise of Chinese Herbal Medicine (CHM) grows in the United Kingdom and Europe, it has naturally come under the scrutiny
of the western biomedical model and the political, legislative and cultural context within which it finds itself. It has therefore become necessary
for the profession as a whole to adapt the traditional approach and application of Chinese herbs in order to better suit the western mind; with
scientific research being at the forefront of this movement. One such exploration first began quite independently to Chinese medicine as
epimediological studies in the eighties found lower incidences of breast cancer in the East comparative to the West.1 It was suggested at the time
that a higher consumption of phytoestrogens in the Eastern diet were the reason for this, and so differences were attributed to lifestyle factors
rather than genetics. Thirty years on, there has been continued and growing interest in phytoestrogens and whether they can help or exacerbate
oestrogen senstive disorders, particularly certain types of cancer, endometriosis and menopausal symptoms. More recently, studies have also
focused on the natural sources of these phytoestrogens, some of which are the herbs that are familiar to CHM.2-15
As the theoretical concerns have remained largely inconclusive scientifically, it raises the question of safety to the clinical application and use of
certain herbs that are known for their high phytoestrogen content. The aim here is to explore the issues that come up in recent research, so
that the profession can continue to develop its own knowledge base and understanding. On this basis, safe and responsible practice can continue
and dialogue with our biomedical colleagues encouraged, as it is only here that the integrity of our own tradition can continue to evolve.
What Are Phytoestrogens and What Do They Do?
Phytoestrogens are plant-derived compounds that share a similar
structure to estradiol, the predominant oestrogen that is found in
menstruating women. Because of this similarity, phytoestrogens have
been found to have both oestrogenic and anti-oestrogenic effects inside
the human body, through their ability to bind to estrogen receptors
(ER). ERs are protein molecules found in cells that are targets for
oestrogen action, for example, ERs can be found in breast tissue,
ovarian cells, endometrial tissue and the hypothalamus. There are two
types of ERs, namely, ER-a and ER-b and phytoestrogens appear to
have a higher affinity for ER-b, but can bind to both.16
By binding to ER sites, phytoestrogens have been shown to have an
effect on the levels of endogenous oestrogen in various ways. Firstly
they can act as ligands that are agonists, that is, once bound to ERs
they can activate an oestrogenic response that influences cell DNA, but
the effect on cell DNA of a phytoestrogen would be much weaker than
estradiol. Secondly, they can act as antagonists, in that they bind to an
ER but produce no oestrogenic response. In both instances
phytoestrogens compete with endogenous oestrogen but in an
antagonist reaction they deactivate ERs through there binding. How it is
determined whether a phytoestrogen acts as an agonist or antagonist is
unclear, but it is thought to be either dependant on the source of the
phytoestrogen, or, through their ability to act as adaptogens, modulating
homeostatic response according to the body’s needs.16
Regardless as to whether the phytoestrogen acts as agonist or
antagonist, the body will respond to endogenous oestrogen in various
ways as a result. The very binding of phytoestrogens to ERs will result
in an excess of endogenous oestrogens in circulation, these are then
metabolised by the liver through a process called glucoronidation where
they are prepared for excretion from the body through the bowel or
the urinary system. It is important to note at this stage that effective
excretion of oestrogens through the bowel is largely dependent on the
presence of healthy intestinal bacterial flora and liver metabolism,
otherwise there is a high risk of oestrogen reabsorption.16
Although the main way that phytoestrogens are synthesised are through
this mechanism of ER binding, more recent research has also shown
that they have the ability to inhibit enzymes (such as aromatase)17,18
that are involved in conversion of other steroids into oestradiol.
Phytoestrogens are also found to inhibit cell signalling pathways that
influence cell proliferation (PI3-K/Akt pathways).19
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Phytoestrogen
Estrogen Molecule
Estrogen
Receptor
Excretion
Deactivated ER
DNA Molecule
Gene Activation
Mechanism of Phytoestrogen Action on Estrogen Receptors
and Gene Activation 20
Phytoestrogen Categories
Oestrogen Sensitive Disease
Breast Cancer
Uterine
Cancer
Prostrate
Cancer
Ovarian Cysts
Endometriosis
Menopausal
Symptoms
Phytoestrogens:
Theoretical Concerns Versus Clinical
Knowledge and Applications
Britta Engert & Yiota Panayiotis
Phytoestrogenic Components
of Chinese Herbs
In Vivo Studies
21-23
Dan Dou Chi
Dang Gui
Gan Cao
Semen sojae preparatum
Angelica sinensis radix
Gycyrhizzae radix
Isoflavones
Isoflavones
Isoflavones
Coumestans
Coumestans
Coumestans
Lignans
Saponins
Gan Jiang
Sheng Ma
Zingiberis rhizoma
Cimicifuga racemosa
Beta-Sitosterol
Isoflavones
Isoflavones
Coumestans
Coumestans
Study name
Study Design
Interventions
Participant
Study
Length
Outcome Measures
Results
Hirata
et al,
1997 2
Double- blind,
randomized,
placebo-controlled
Dang gui
vs
placebo
71 Postmenopausal
women
24 weeks
1)Endometrial
thickness
2) Vaginal cell
maturation
3) Vasomotor flushes
No difference between
treatment and placebo
group
Quella et al,
2000 3
Double- blind,
randomized, placebocontrolled
Soy tablets
vs
placebo
177
Breast cancer
survivors
4 weeks
Hot flashes
Soy not more effective
than placebo
Davis et al,
2001 4
Double- blind,
randomized,
placebo-controlled
CHM
vs
placebo
Vasomotor symptoms
CHM was no more
effective than placebo
Ziegler,
2004 24
Epidemiological
Study
Intake of
phytoestrogens
(lignans and
isoflavones )
15000
Dutch women
8
Years
Newton et al,
2006 5
Double- blind,
randomized,
placebo-controlled
Black cohosh vs
black cohosh +
multi botanical
vs
multiBotanical + soy
vs
estrogens
vs
placebo
351
peri- or postmenopausal
women
Kwee et al.
2007 6
Double- blind,
randomised placebocontrolled
CHM vs HRT vs
placebo
31
Dutch women
Ge Gen
Puerariae radix
Lignans
Huang Qi
Ren Shen
Shao Yao
Astragalus membranacus
Ginseng radix
Paeonia lactiflora
Beta-SitoSterol
Beta-Sitosterol
Beta-Sitosterol
Saponins
Saponins
55
12 weeks
postmenopausal
Australian
women
1) Phyto-estrogen intake
2) Breast cancer rate
No association between
phyto-estrogen intake
and breast cancer
12 month
Vasomotor symptoms
1)
Herbal intervention not
different from placebo
2)
Hormone therapy
superior to placebo
16 weeks
Vasomotor symptoms
1)
HRT most effective
2)
CHM more effective
than placebo
Rotem and
Kaplan,
2007 7
Double- blind,
randomized,
placebo-controlled
Phyto-Complex
50
(black cohosh,
pre and
dang gui, milk
postmenopausal
thistle, red clover, women, aged
American ginseng,
44–65 years
chaste-tree berry)
vs
placebo
3 month
Menopausal symptoms
Phyto-Complex
significantly higher
reduction in
menopausal
symptoms to placebo
D’Anna,
2009 25
Double- blind,
randomized,
placebo-controlled
Genistein vs
placebo
n=389
24
months
Hot flushes
Endometrial thickness
1)
Genistein reduces hot
flushes
2)
No difference in
endometrial thickness
Lipovac,
2011 8
Double- blind,
randomized,
placebo-controlled
cross over
Red clover
Vs
placebo
Postmenopausal
women
187 days
Mucosal status
Libido
Tiredness
Moods
Subjective improvement
of all symptoms with
Red clover extract
Deng et al,
2012 9
Multicenter
follow-up study
Fufang vs
placebo
194
postmenopausal
women (47–
70 years old)
5 years
Potential adverse events
and
fracture incidence
Fracture incidence 2.4
fold lower in the
treatment group than
placebo
Summary of Results
Ku Shen
Mo Yao
Pu Gong Ying
Sophorae flavenscentis radix
Commiphora myrrha
Taraxacum officinale
Isoflavones
Beta-Sitosterol
Beta-Sitosterol
Clinical research into the use of herbs with phytoestrogen components in
patients at risk of, or with, oestrogen sensitive cancers is limited. Current
evidence, which is mostly epidemiological, would not support any effect of
phytoestrogens, neither positive nor negative. However, only reports in the
English language have been reviewed. There may be a significant body of
research reported in Chinese or Japanese language, which could not be accessed.
Research into the use of CHM with phytoestrogens for menopause related
symptoms would suggest good safety and efficacy for herbs in the treatment of
mild symptoms, however for moderate or severe cases classic HRT is clearly
more effective.5,6,7,8,9,25
Huai Hua
Xi Yang Shen
Sheng Di Huang
Sophorae flos
Panax quinquefolium
Rehmannia radix
Isoflavones
Beta-Sitosterol
Beta-Sitosterol
Saponins
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The design of almost all clinical studies does not take into account the theory
and practice of classical CHM, but applies them in isolation from their usual
formulas, sometimes even only using components of single herbs, for short time
frames, and outside the classical CHM diagnostic framework (pattern
discrimination).
Phytoestrogens:
Theoretical Concerns Versus Clinical
Knowledge and Applications
Britta Engert & Yiota Panayiotis
In Vitro Studies
Study Name
Study Design
Intervention
Outcome Measure
Conclusion
Results
DiPaola et al,
1998 10
1) Yeast assay
2) Menopause mouse
model
3) Male patients with
prostate cancer
PC-SPES (chrysanthemum,
isatis, licorice, Ganoderma
lucidum, Panax pseudoginseng, Rabdosia
rubescens, saw palmetto,
scutellaria)
1) Yeast proliferation rate
2) Mouse uterus size
3) Human PSA and
Testosterone level
Marked oestrogenic effect in vitro and in vivo
Santell et al,
2000 26
Mice inoculated with
MDA-MB-231 cells
(breast cancer cells)
Genistein diet
1) Genistein concentration
required to inhibit tumor
growth in vitro
2) Genistein plasma
concentration in relation
to diet
3) Tumor growth with
Genistein diet
1) Genistein concentration required to inhibit
tumor growth can not be achieved with Soy
diet
2) In vivo tumor growth not inhibited by
Genistein
Bodinet and
Freudenstein,
2002 11
Cell Preparation
Black cohosh (Cimicifuga
racemosa [CR]), on
estrogen-dependent
mammary cancers
1)
CR-extract inhibited MCF7 cell (cancer cell)
proliferation
2)
CR-extract inhibited
estrogen-induced
proliferation of MCF-7
cells
3)
Proliferation-inhibiting
effect of tamoxifen was
further enhanced by the
CR-extract
1)
Non-estrogenic, or estrogen-antagonistic effect
of CR on human breast cancer cells
2)
Breast cancer treatment with CR – extract is
safe
Wang et al,
2003 12
Osteoporotic mouse
model
Puerariae radix diet
femoral bone mineral
density
Puerariae radix prevented osteoporosis
Bodinet and
Freudenstein,
2004 13
In vitro: MCF 7 and
HeLa cell line
Proliferation and toxicity
assay using Black cohosh,
Soy, Red clover
Cell toxicity and
proliferation
1)
Black cohosh, Soy: no cytotoxic effect
Red clover: cytotoxic at high concentration
2)
Soy and Red clover enhance MCF 7
proliferation, Black cohosh doesn’t
Xu et al,
2011 14
Menopause mouse
model
Tiáo-Gēng-Tāng(TG)
Vs
Estrogen
Estradiol, LH, FSH levels,
Estrogen Receptor (ER)
expression
TG less effective than estrogen in balancing
female hormones, but stronger upregulation of
ER
In vitro: inflammatory
breast cancer cells
SUM-149
Ganoderma lucidum
(Reishi)
1) apoptosis rate
2) cell invasion assay
3) Gene expression profile
1) Increased apoptosis,
2) Reduced invasivenes,
3) Downregualation of cell cycle progression
MartínezMontemayor et al,
2011 15
Cell culture studies suggest that some phytoestrogens may increase oestrogen
sensitive cancers. This is in sharp contrast to early epidemiological studies
which suggest a reduced breast cancer rate in Asian women, possibly
phytoestrogen diet related.1
Most carcinogenic effects of phytoestrogens were only observed at nonphysiological serum levels, which can not be achieved through oral intake.
Often results from pre-clinical studies (cell culture, animal) can not be
translated into positive results in (human) clinical studies.16
Current research into Chinese medicinal herbs
with
phytoestrogenic components is driven by theoretical concerns
around safety and potential commercial exploitation, such as, breast
cancer risks and HRT replacements that promise treatment without
the oestrogen side effects. However, it is difficult to justify such
concerns given the evidence.
Firstly, concerns around cancer and cell proliferation from the use of
CHM with phytoestrogenic components have not been confirmed by
clinical data and it appears that phytoestrogenic components are
safe and efficient to treat mild menopausal symptoms. Overall,
research is largely inconclusive. As Carreau et al27(p183) state from
their own inconclusive findings:
‘This suggests that the estrogenic and/or anti-estrogenic
activity of structurally diverse natural phytoestrogens is complex,
which is consistent with published data that often give
contradictory results for these compounds.’
Also, one can see from both the in vivo and in vitro studies, that
the scientific methods applied do not account for CHM theory
and the diagnosis of an individual patients syndromes. Typically
research aims to find new biomedical components for exploitation in
orthodox medicine, rather than aiming to show clinical efficacy of a
CHM formula. Herbs are only considered in isolation and based on
their active phytoestrogenic ingredients. In contrast, classical CHM
uses herbs within polypharmacy formulas, leading to enhancement
and buffer effects, and an overall more balanced treatment.28
Most current research forces CHM into a western medical
framework, removing all the core CHM concepts, and consequently
developing conclusions of limited value to CHM practice, both from
an efficacy and safety point of view.
The long track record of CHM has shown good empirical efficacy for
menopausal symptoms with no obvious associated cancer risk. Clinical
research applying current scientific methods (randomised control
trials) is necessary to further consolidate this knowledge and secure
the survival of CHM in the modern world. However, this research
must take into account the classical CHM diagnostic framework and
prescribing methods.
CHM practitioners should lead the way and promote clinical settings
that facilitate modern research and move away from a mostly
historical approach. Ideally, CHM hospitals need to be established
and, in collaboration with individual practitioners, become centres of
clinical research.
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