Theoretical Concerns Versus Clinical Knowledge and Applications

Phytoestrogens:
Theoretical Concerns Versus Clinical
Knowledge and Applications
Britta Engert & Yiota Panayiotis
Introduc4on As interest in the prac.se of Chinese Herbal Medicine (CHM) grows in the United Kingdom and Europe, it has naturally come under the scru.ny of the western biomedical model and the poli.cal, legisla.ve and cultural context within which it finds itself. It has therefore become necessary for the profession as a whole to adapt the tradi.onal approach and applica.on of Chinese herbs in order to beber suit the western mind; with scien.fic research being at the forefront of this movement. One such explora.on first began quite independently to Chinese medicine as epimediological studies in the eigh.es found lower incidences of breast cancer in the East compara.ve to the West.1 It was suggested at the .me that a higher consump.on of phytoestrogens in the Eastern diet were the reason for this, and so differences were abributed to lifestyle factors rather than gene.cs. Thirty years on, there has been con.nued and growing interest in phytoestrogens and whether they can help or exacerbate oestrogen sens.ve disorders, par.cularly 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 theore.cal concerns have remained largely inconclusive scien.fically, it raises the ques.on of safety to the clinical applica.on 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 con.nue to develop its own knowledge base and understanding. On this basis, safe and responsible prac.ce can con.nue and dialogue with our biomedical colleagues encouraged, as it is only here that the integrity of our own tradi.on can con.nue 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 menstrua.ng women. Because of this similarity, phytoestrogens have been found to have both oestrogenic and an.-­‐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 ac.on, for example, ERs can be found in breast .ssue, ovarian cells, endometrial .ssue and the hypothalamus. There are two types of ERs, namely, ER-­‐α and ER-­‐β and phytoestrogens appear to have a higher affinity for ER-­‐β, 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 ac.vate 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 reac.on they deac.vate 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, modula.ng homeosta.c 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 circula.on, these are then metabolised by the liver through a process called glucoronida.on where they are prepared for excre.on from the body through the bowel or the urinary system. It is important to note at this stage that effec.ve excre.on of oestrogens through the bowel is largely dependent on the presence of healthy intes.nal bacterial flora and liver metabolism, otherwise there is a high risk of oestrogen reabsorp.on.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 prolifera.on (PI3-­‐K/Akt pathways).19 RESEARCH POSTER PRESENTATION DESIGN © 2011
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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 Sensi4ve 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 Coumestans Isoflavones Coumestans Lignans Isoflavones Coumestans Saponins Gan Jiang Sheng Ma Ge Gen Zingiberis rhizoma Cimicifuga racemosa Beta-­‐Sitosterol Isoflavones Coumestans Lignans Puerariae radix Isoflavones Coumestans Study name Hirata et al, 1997 2 Quella et al, 2000 3 Davis et al, 2001 4 Ren Shen Shao Yao Astragalus membranacus Ginseng radix Paeonia lac>flora Beta-­‐SitoSterol Saponins Beta-­‐Sitosterol Saponins Beta-­‐Sitosterol Double-­‐ blind, randomized, placebo-­‐controlled Interven4ons Double-­‐ blind, randomized, placebo-­‐
controlled Double-­‐ blind, randomized, placebo-­‐controlled Dang gui vs placebo Soy tablets vs placebo CHM vs placebo Par4cipant Study Length Outcome Measures Rotem and Kaplan, 2007 7 Lipovac, 2011 8 Deng et al, 2012 9 Results 1)Endometrial No difference between thickness treatment and placebo 2) Vaginal cell group matura.on 3) Vasomotor flushes 177 4 weeks Hot flashes Soy not more effec.ve Breast cancer than placebo survivors 71 Post-­‐ 24 weeks menopausal women 55 12 weeks Vasomotor symptoms postmenopausal Australian women 1) Phyto-­‐estrogen intake Epidemiological Intake o
f 15000 8 Ziegler, Study phytoestrogens Dutch women Years 2) Breast cancer rate 2004 24 (lignans and isoflavones ) Double-­‐ blind, Black cohosh vs 351 12 month Vasomotor symptoms Newton et al, randomized, black c
ohosh +
peri-­‐ o
r p
ost-­‐ 2006 5 placebo-­‐controlled mul4 botanical menopausal vs women mul4-­‐ Botanical + soy vs estrogens vs placebo Double-­‐ b
lind, CHM v
s H
RT v
s 31 16 w
eeks Vasomotor symptoms Kwee et al. randomised placebo-­‐
placebo Dutch women 2007 6 controlled D’Anna, 2009 25 Huang Qi Study Design CHM was no more effec.ve than placebo No associa.on between phyto-­‐estrogen intake and breast cancer 1) Herbal interven.on not different from placebo 2) Hormone therapy superior to placebo 1) HRT most effec.ve 2) CHM more effec.ve than placebo Double-­‐ blind, Phyto-­‐Complex 50 3 month Menopausal symptoms Phyto-­‐Complex randomized, (black cohosh, pre and significantly higher placebo-­‐controlled dang gui, milk postmenopausal reduc.on in thistle, red clover, women, aged menopausal American ginseng, 44–65 years symptoms to placebo chaste-­‐tree berry) vs placebo 1) Double-­‐ blind, Genistein vs n=389 24 Hot flushes Genistein reduces hot randomized, placebo months Endometrial thickness flushes placebo-­‐controlled 2) No difference in endometrial thickness Double-­‐ blind, Red clover Post-­‐ 187 days Mucosal status Subjec.ve improvement randomized, Vs menopausal Libido of all symptoms with placebo-­‐controlled placebo women Tiredness Red clover extract cross over Moods Mul.center Fufang vs 194 5 years Poten.al adverse events Fracture incidence 2.4 follow-­‐up study placebo postmenopausal and fold lower in the women (47–
fracture incidence treatment group than 70 years old) placebo Summary of Results Ku Shen Mo Yao Pu Gong Ying Sophorae flavenscen>s radix Commiphora myrrha Taraxacum officinale Isoflavones Beta-­‐Sitosterol Beta-­‐Sitosterol Clinical research into the use of herbs with phytoestrogen components in pa.ents at risk of, or with, oestrogen sensi.ve cancers is limited. Current evidence, which is mostly epidemiological, would not support any effect of phytoestrogens, neither posi.ve nor nega.ve. 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 effec.ve.5,6,7,8,9,25 Huai Hua Xi Yang Shen Sheng Di Huang Sophorae flos Panax quinquefolium Rehmannia radix Beta-­‐Sitosterol Saponins Beta-­‐Sitosterol Isoflavones RESEARCH POSTER PRESENTATION DESIGN © 2011
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The design of almost all clinical studies does not take into account the theory and prac.ce of classical CHM, but applies them in isola.on from their usual formulas, some.mes even only using components of single herbs, for short .me frames, and outside the classical CHM diagnos.c framework (pabern discrimina.on). Phytoestrogens:
Theoretical Concerns Versus Clinical
Knowledge and Applications
Britta Engert & Yiota Panayiotis
In Vitro Studies Study Name DiPaola et al, 1998 10 Santell et al, 2000 26 Study Design Interven4on 1) Yeast assay PC-­‐SPES (chrysanthemum, 2) Menopause mouse isa4s, licorice, Ganoderma model lucidum, Panax pseudo-­‐
3) Male pa.ents with ginseng, Rabdosia prostate cancer rubescens, saw palmedo, scutellaria) Mice inoculated with Genistein diet MDA-­‐MB-­‐231 cells (breast cancer cells) Bodinet and Freudenstein, 2002 11 Cell Prepara.on Black cohosh (Cimicifuga racemosa [CR]), on estrogen-­‐dependent mammary cancers Wang et al, 2003 12 Bodinet and Freudenstein, 2004 13 Osteoporo.c mouse model Puerariae radix diet In vitro: MCF 7 and HeLa cell line Prolifera4on and toxicity assay using Black cohosh, Soy, Red clover Xu et al, 2011 14 Menopause mouse model Marqnez-­‐
Montemayor et al, 2011 15 In vitro: inflammatory breast cancer cells SUM-­‐149 Outcome Measure Conclusion Results 1) Yeast prolifera.on rate Marked oestrogenic effect in vitro and in vivo 2) Mouse uterus size 3) Human PSA and Testosterone level 1) Genistein concentra.on required to inhibit tumor growth in vitro 2) Genistein plasma concentra.on in rela.on to diet 3) Tumor growth with Genistein diet 1) CR-­‐extract inhibited MCF-­‐7 cell (cancer cell) prolifera.on 2) CR-­‐extract inhibited estrogen-­‐induced prolifera.on of MCF-­‐7 cells 3) Prolifera.on-­‐inhibi.ng effect of tamoxifen was further enhanced by the CR-­‐extract femoral bone mineral density 1) Genistein concentra.on required to inhibit tumor growth can not be achieved with Soy diet 2) In vivo tumor growth not inhibited by Genistein 1) Non-­‐estrogenic, or estrogen-­‐antagonis.c effect of CR on human breast cancer cells 2) Breast cancer treatment with CR – extract is safe Puerariae radix prevented osteoporosis Cell toxicity and prolifera.on 1) Black cohosh, Soy: no cytotoxic effect Red clover: cytotoxic at high concentra.on 2) Soy and Red clover enhance MCF 7 prolifera.on, Black cohosh doesn’t Tiáo-­‐Gēng-­‐Tāng(TG) Estradiol, LH, FSH levels, TG less effec.ve than estrogen in balancing Vs Estrogen Receptor (ER) female hormones, but stronger upregula.on of Estrogen expression ER Ganoderma lucidum (Reishi) 1) apoptosis rate 1) Increased apoptosis, 2) cell invasion assay 2) Reduced invasivenes, 3) Gene expression profile 3) Downreguala.on of cell cycle progression Cell culture studies suggest that some phytoestrogens may increase oestrogen sensi.ve 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. Oren results from pre-­‐clinical studies (cell culture, animal) can not be translated into posi.ve results in (human) clinical studies.16 Current research into Chinese medicinal herbs with phytoestrogenic components is driven by theore.cal concerns around safety and poten.al commercial exploita.on, such as, breast cancer risks and HRT replacements that promise treatment without the oestrogen side effects. However, it is difficult to jus.fy such concerns given the evidence. Firstly, concerns around cancer and cell prolifera.on 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 an.-­‐estrogenic ac.vity of structurally diverse natural phytoestrogens is complex, which is consistent with published data that oren give contradictory results for these compounds.’ Also, one can see from both the in vivo and in vitro studies, that the scien.fic methods applied do not account for CHM theory and the diagnosis of an individual pa.ents syndromes. Typically research aims to find new biomedical components for exploita.on in orthodox medicine, rather than aiming to show clinical efficacy of a CHM formula. Herbs are only considered in isola.on and based on their ac.ve 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 prac.ce, 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 scien.fic 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 diagnos.c framework and prescribing methods. CHM prac..oners should lead the way and promote clinical setngs that facilitate modern research and move away from a mostly historical approach. Ideally, CHM hospitals need to be established and, in collabora.on with individual prac..oners, become centres of clinical research. References and Bibliography 14. Xu LW, Kluwe L, Zhang TT, Li SN, Mou YY, Ma J, Sun ZJ. Chinese Herb Mix Tiao-­‐Geng-­‐Tang Possesses An.aging and An.oxida.ve effects and Upregulates Expression of Estrogen Receptors 1. Peeters PHM, Keinan-­‐Boker L, van der Schouw YT, Grobbee DE. Phytoestrogens and Breast Cancer Risk. Breast Cancer Research and Treatment 2003;77: 171-­‐183. hbp://igitur-­‐archive.library.uu.nl/med/
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www.ncbi.nlm.nih.gov/pubmed/15167307 (accessed 26 October 2012). RESEARCH POSTER PRESENTATION DESIGN © 2011
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