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Phytoestrogens: Theoretical Concerns Versus Clinical Knowledge and Applications Britta Engert & Yiota Panayiotis. Introduction. What Are Phytoestrogens and What D o T hey D o?. Mechanism of Phytoestrogen Action on Estrogen Receptors and Gene Activation 20. - PowerPoint PPT PresentationTRANSCRIPT
RESEARCH POSTER PRESENTATION DESIGN © 2011
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Phytoestrogens: Theoretical Concerns Versus Clinical Knowledge and Applications
Britta Engert & Yiota Panayiotis
Introduction
What Are Phytoestrogens and What Do They Do?
Mechanism of Phytoestrogen Action on Estrogen Receptors and Gene Activation 20
Excretion
Gene Activation
Phytoestrogen
Phytoestrogen Categories
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
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.
Estrogen Molecule
Estrogen Receptor
DNA Molecule
Deactivated ER
Oestrogen Sensitive Disease
Breast Cancer Uterine Cancer
Prostrate Cancer Ovarian Cysts
Endometriosis Menopausal Symptoms
RESEARCH POSTER PRESENTATION DESIGN © 2011
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Phytoestrogens: Theoretical Concerns Versus Clinical Knowledge and Applications
Britta Engert & Yiota Panayiotis
Phytoestrogenic Components of Chinese Herbs 21-23
In Vivo Studies
Dan Dou Chi
Semen sojae preparatum
IsoflavonesCoumestans
Dang GuiAngelica sinensis
radixIsoflavonesCoumestans
Lignans
Gan CaoGycyrhizzae
radixIsoflavonesCoumestans
Saponins
Gan JiangZingiberis rhizomaBeta-
Sitosterol
Sheng MaCimicifuga racemosa
IsoflavonesCoumestans
Lignans
Ge GenPuerariae radixIsoflavonesCoumestans
Huang QiAstragalus
membranacusBeta-
SitoSterolSaponins
Ren ShenGinseng radix
Beta-SitosterolSaponins
Shao YaoPaeonia lactifloraBeta-
Sitosterol
Ku ShenSophorae
flavenscentis radix
Isoflavones
Mo YaoCommiphora
myrrhaBeta-
Sitosterol
Pu Gong Ying
Taraxacum officinaleBeta-
Sitosterol
Huai HuaSophorae flosIsoflavones
Xi Yang ShenPanax
quinquefoliumBeta-
SitosterolSaponins
Sheng Di Huang
Rehmannia radixBeta-
Sitosterol
Study name Study Design Interventions Participant Study Length
Outcome Measures Results
Hirataet al,
1997 2
Double- blind, randomized,
placebo-controlled
Dang gui vs
placebo
71 Post- menopausal
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, placebo-
controlled
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
CHMvs
placebo
55 postmenopausal
Australian women
12 weeks Vasomotor symptoms CHM was no more effective than placebo
Ziegler, 2004 24
Epidemiological Study
Intake of phytoestrogens
(lignans and isoflavones )
15000Dutch women
8Years
1) Phyto-estrogen intake2) Breast cancer rate
No association between phyto-estrogen intake
and breast cancer
Newton et al, 2006 5
Double- blind, randomized,
placebo-controlled
Black cohosh vsblack cohosh +multi botanical
vsmulti-
Botanical + soyvs
estrogensvs
placebo
351peri- or post- menopausal
women
12 month Vasomotor symptoms 1) Herbal intervention not different from placebo
2)Hormone therapy
superior to placebo
Kwee et al.2007 6
Double- blind, randomised placebo-
controlled
CHM vs HRT vs placebo
31 Dutch women
16 weeks Vasomotor symptoms 1)HRT most effective
2)CHM more effective
than placebo
Rotem andKaplan,2007 7
Double- blind, randomized,
placebo-controlled
Phyto-Complex(black cohosh, dang gui, milk
thistle, red clover, American ginseng, chaste-tree berry)
vsplacebo
50 pre and
postmenopausal women, aged 44–65 years
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 24months
Hot flushesEndometrial thickness
1)Genistein reduces hot
flushes2)
No difference in endometrial thickness
Lipovac, 2011 8
Double- blind, randomized,
placebo-controlledcross over
Red cloverVs
placebo
Post-menopausal
women
187 days Mucosal status Libido
TirednessMoods
Subjective improvement of all symptoms with
Red clover extract
Deng et al,2012 9
Multicenter follow-up study
Fufang vsplacebo
194 postmenopausal
women (47–70 years old)
5 years Potential adverse eventsand
fracture incidence
Fracture incidence 2.4 fold lower in the
treatment group than placebo
Summary of ResultsClinical 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
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).
RESEARCH POSTER PRESENTATION DESIGN © 2011
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Phytoestrogens: Theoretical Concerns Versus Clinical Knowledge and Applications
Britta Engert & Yiota Panayiotis
Conclusion
References and Bibliography
In Vitro Studies
Study Name Study Design Intervention Outcome Measure Results
DiPaola et al, 1998 10
1) Yeast assay2) Menopause mouse model3) Male patients with prostate cancer
PC-SPES (chrysanthemum, isatis, licorice, Ganoderma lucidum, Panax pseudo-ginseng, Rabdosia rubescens, saw palmetto, scutellaria)
1) Yeast proliferation rate2) Mouse uterus size3) 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 vitro2) Genistein plasma concentration in relation to diet3) Tumor growth with Genistein diet
1) Genistein concentration required to inhibit tumor growth can not be achieved with Soy diet2) 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 MCF-7 cell (cancer cell) proliferation2)CR-extract inhibited estrogen-induced proliferation of MCF-7 cells3)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 cells2)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 andproliferation
1)Black cohosh, Soy: no cytotoxic effectRed clover: cytotoxic at high concentration2)Soy and Red clover enhance MCF 7 proliferation, Black cohosh doesn’t
Xu et al, 2011 14
Menopause mouse model
Tiáo-Gēng-Tāng(TG)VsEstrogen
Estradiol, LH, FSH levels, Estrogen Receptor (ER) expression
TG less effective than estrogen in balancing female hormones, but stronger upregulation of ER
Martínez-Montemayor et al,
2011 15
In vitro: inflammatory breast cancer cells SUM-149
Ganoderma lucidum (Reishi)
1) apoptosis rate2) cell invasion assay3) Gene expression profile
1) Increased apoptosis,2) Reduced invasivenes, 3) Downregualation of cell cycle progression
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 non-physiological 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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