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Oestrogeen werkende stoffen / Fyto-oestrogenen

Fyto-oestrogenen zijn een specifieke groep van secundaire plantenstoffen die de menselijke gezondheid beïnvloeden. Soja wordt gezien als een van de belangrijkste bronnen van deze fyto-oestrogenen. De volgende eigenschappen van fyto-oestrogenen (biochanin A, formononetin, daidzein, genistein en coumestrol) zijn inmiddels aangetoond: zowel oestrogene als anti-oestrogene werking, anti-oxidatieve, anti-carcinogene en cardioprotectieve werking, evenals cholesterolverlagende, botbehoudende, antivirale, antibacteriële en fungistatische eigenschappen. Tenslotte zijn ook anti-proliferatieve eigenschappen gemeten met betrekking tot verschillende typen tumoren zowel in celcultures als in dierlijke studies.



Sommige stoffen in etherische olie kunnen een oestrogene werking hebben, sommige zelfs een hormon-like werking. Een hormone-like werking heeft een breder spectrum dan alleen een oestrogene werking!
  • In etherische olie die fenol-methyl-ethers bevatten kan zich de specifieke stof Anethol bevinden deze komt voor in de EOʼs van Anijs, Steranijs en Venkel. Deze drie EOʼs bezitten fytooestrogene eigenschappen.
  • In EOʼs die sesquiterpeenalcoholen kan de specifieke stof viridifloral een fyto-oetrogene werking hebben deze stof komt bijvoorbeeld voor in de EO van Niaoli
  • Etherische olie met esters, kunnen een een hormon-like werking hebben. Volgens Franchomme (blz 207) is dit exceptioneel. Het zou dan gaan om lachnophyllum methyl-ester en matricaria methyl-ester (beide methylsalicilaat stoffen). Bij die specifieke inhoudstoffen moet je denken aan de EOʼs van bijvoorbeeld Berk, Wintergroen.
  • EOʼs waarin zich ketonen bevinden, kunnen ook een hormon-like werking hebben. EOʼs met ketonen moet je hoe dan ook voorzichtig zijn. De meeste ketonen zijn toxisch ze zijn vaak abortief en kunnen bij (inwendige) overdosering stuipen en epileptische aanvallen uitlokken. Sommige Ketonen kunnen zelfs coma en de dood veroorzaken. Ketonen mogen niet gebruikt worden bij kinderen (onder de 30 maanden), zwangere vrouwen en moeders die borstvoeding geven. Denk aan de EOʼs van Karwij, Helicryse, Salie. In bad met Rozemarijn als zwanger is niet verstandig!
  • EOʼs waarin zich Terpenen bevinden, kunnen een een hormon-like werking hebben. Er zijn klinische onderzoeken gedaan naar het hormonale werkingseffect op mannen. De EO van de Pinus sylvestris de Grove Den, deze olie wordt ingezet voor seksuele asthenie. Bij vrouwen komt de hormon-like werking van terpenen tot uiting in de EO van Tanacetum annuum. Gebruik van deze EO heeft een emmenagoge werking


Sources of phyto-oestrogens
There are more than 20 compounds that can be found in more than 300 plants, such as herbs, grains, and fruits. The three main classes of dietary phyto-oestrogens are isoflavones, lignans, and coumestans:
  • Isoflavones (genistein, daidzein, glycitein, and equol) are primarily found in soy beans and soy products, chickpeas and other legumes.
  • Lignans (enterolactone and enterodiol) are found in oilseeds (primarily flaxseed), cereal bran, legumes, and alcohol (beer and bourbon).
  • Coumestans (coumestrol) can be found in alfalfa and clover.
Most food sources containing these compounds include more than one class of phyto-oestrogens.

Effects of phyto-oestrogens
Much of the evidence about phyto-oestrogens in bone metabolism is based on animal studies. Soybean protein, soy isoflavones, genistein, daidzein and coumestrol have all been shown to have a protective effect on bone in animals after oophorectomy.

In humans the evidence is conflicting:
  • Epidemiological studies show that compared with Caucasian populations, women in Hong Kong, China and Japan, where dietary phyto-oestrogen intake is high, have lower rates of hip fracture. Vertebral fractures are almost as common in Asian women as they are in white women.
  • In addition, reports suggest that Japanese women have a greater risk of sustaining a vertebral fracture than Caucasian women.
  • Several studies have explored the effects of soy isoflavones on bone, but results have been mixed, ranging from a modest impact to no effect. Most of these studies have serious limitations, including their short duration and small sample size, making it difficult to evaluate fully the impact of these compounds on metabolism of bone.
  • A 3-year study of more than 400 postmenopausal women concluded that ipriflavone did not prevent bone loss. The substance was also linked to lymphocytopenia in a significant number of subjects.[2]
  • A Cochrane review also concluded they had no effect on postmenopausal vasomotor symptoms.[3]
  • There is some evidence of soya protein and/or isoflavones having beneficial effect on both blood lipid profile and bone density in postmenopausal women.[4][5] Soy isoflavones have no effect on bone density in younger, menstruating women.[6]
  • A systematic review of randomised controlled trials (RCTs) was unable to give unequivocal support for the benefit of phyto-oestrogens for the prevention of osteoporosis.[7] There is some evidence of adverse effects on laboratory animals, but studies to assess the problem in humans are not yet forthcoming.[8] There is also suggestion that phyto-oestrogens may enhance osteogenesis at low concentration and inhibit it at higher concentrations.[9]
Phyto-oestrogens and breast cancer
Some studies suggest that, unlike oestrogens, phyto-oestrogens do not appear to increase the risk of breast cancer or uterine cancer. They seem more like selective oestrogen receptor modulators (SERMs) such as raloxifene and tamoxifen. However, in other studies, high isoflavone levels have been linked to an increased risk of breast cancer. Clearly, additional research is needed and is currently being undertaken.
The effect of consumption of soy as a risk for breast cancer is controversial:

A review concluded that the evidence was not strong in any direction and that even women who have had breast cancer may safely consume soy.[10] Foods, herbs and spices may contain phyto-oestrogens and phyto-progestins that may function as agonists or antagonists.[11]
Studies have indicated that countries with the highest phyto-oestrogen consumption have the lowest rates of breast cancer, but other epidemiological studies suggest the lack of a causative relationship.[12] Some foodstuffs are beneficial.[13] No studies have found an increased risk of breast cancer with increased soy consumption. It may be dangerous to read too much into epidemiological studies on diet for a multifactorial condition.
There is also evidence that isoflavones and lignans may exert protection against cancer through mechanisms not associated with oestrogenic activity.[14] Isoflavones exhibit some antioxidant activity, which may contribute to cancer prevention.[15][16]
Several studies have reported that phyto-oestrogens have anti-angiogenesis effects, discouraging the growth of new blood vessels in tumours.[17]
Prostatic disease
Phyto-oestrogens are also recommended as anti-androgens and hence are of possible protective benefit with regard to carcinoma of prostate and benign prostatic hyperplasia.[18][19] Whether they also reduce sperm count has not been examined.

Isoflavones in infants
Children with lactose intolerance or atopic eczema are often given a soya-based feed instead of milk:These children may have plasma phyto-oestrogen concentrations of up to 7,000 nm/L, which compares with an average of 744 nm/L in adult Japanese women.[20]
The daily exposure to phyto-oestrogens from baby formula is 6 to 11 times higher than a hormonally active dose in adults and plasma concentrations of isoflavones are some 13,000 to 22,000 times higher than endogenous oestrogen concentrations in infants.[21] This seems disastrous, but the only readily identified problem in these children is allergy in 2% or 3% and possibly inadequate intake of calcium.
Studies following children through adolescence have not reported any obvious adverse reproductive effects.[20] Nevertheless, the Chief Medical Officer (CMO) advises that soya-based infant formulas should not be used as the first choice for the management of infants with proven cow's milk sensitivity, lactose intolerance, galactokinase deficiency and galactosaemia.[22] As an alternative to soya-based products, more appropriate hydrolysed protein formulas are available and can be prescribed. Soya-based formulas should only be used in exceptional circumstances to ensure adequate nutrition. For example, they may be given to infants of vegan parents who are not breast-feeding or infants who find alternatives unacceptable.
A retrospective cohort study examined 811 subjects in their 20s and 30s, and found no statistically significant differences between those who had soy formula and those who had cow's milk as infants.[21]
Whether or not early exposure to high doses of isoflavones has any positive or negative effects on cancer rates or cognitive and neurological parameters in later life is not yet known.

Effects on the brain
The American National Institute for Health funded a cohort study which followed 3,734 Japanese men in Hawaii who had been tracked since 1965 for a cardiovascular longitudinal study:[23]

Cognitive function was assessed according to standard parameters in the living participants and their wives (aged 71-93 years).
MRI and later autopsies looked for changes in brain tissue.
Those who had consumed the greatest quantity of tofu in midlife had lower cognitive test performance and lower brain weight than those who had consumed the least tofu.
The authors noted that the degree of impairment in the highest consumption versus the lowest consumption group was "roughly of the magnitude as would be caused by a four-year difference in age or a three-year difference in education."
They postulated that the observed effect might be due to isoflavones inhibiting key enzymes in oestrogen synthesis pathways. Oestrogen is known to be involved in repair of neural structures that degenerate over time, and it has been observed that higher levels of oestrogen are associated with lower incidence of Alzheimer's disease in women. Around the menopause some women become forgetful. Another study found a beneficial effect of phyto-oestrogens on mood and cognitive function in postmenopausal women.[24]

Thyroid function
Isoflavones in soy and flavonoids from other sources inhibit the enzyme thyroid peroxidase, which is involved in the synthesis of thyroxine. The inhibitory effects of genistein and daidzein can be completely reversed by the addition of sufficient iodine.[25] It would appear only to be a problem where there is borderline iodine deficiency.

Black cohosh
This is a substance that is recommended by herbalists for a variety of conditions and it is highly recommended for menopausal symptoms, although some authorities say that it has anti-oestrogenic effects. There are many side-effects associated with it and the European Medicines Agency has given warning about the possibility of hepatitis resulting from its use.[26]

Chronic kidney disease
There is some evidence of a protective effect against the progression of chronic kidney disease by phyto-oestrogens.[27]

Conclusion
There is a great deal of evidence about phyto-oestrogens, but there is also much confusion:
Much of the evidence relates to animals and in vitro studies and there are questions as to how readily it should be extrapolated to humans
Oestrogens and similar substances are highly complex and variable. Some may have an agonistic effect on bone, an antagonistic effect on breast tissue and a neutral effect on the endometrium as we have seen with selective oestrogen receptor modulators (SERMs). There may be considerable variation with regard to the effect of plant chemicals too.
When a substance is not given as a drug in a predetermined dose but is part of the diet the amount ingested may be highly variable and there may also be problems such as an agonist effect at low dose and an antagonist effect at higher doses.
Some of the results, such as those related to cognition, are contradictory. This may be due to agonists and antagonists working in different directions.
Epidemiological studies about multifactorial diseases must be interpreted with care. When comparing different populations we cannot be sure that only one parameter is changed.
There is very little good, long-term evidence about the effects of phyto-oestrogens in human populations. Many questions remain to be answered. If a diet high in phyto-oestrogens does protect women against breast cancer, osteoporosis and heart disease, does it also impair fertility? If it protects men against prostatic cancer, does it also impair spermatogenesis?
The evidence to suggest that phyto-oestrogens are protective against osteoporosis is at best poor. Long-term safety is not established.
There have been many studies on the efficacy and safety of mammalian HRT, including the enormous 'Million Women Study'.[28][29] The Million Women Study was basically very reassuring but it did outline some causes for concern. The assumption that plant oestrogens are as effective but safer is a very unsafe premise.
For patients who still insist that anything produced by the pharmaceutical industry is hazardous whilst anything that is 'natural#' is safe, there is one piece of mischief to drop in their direction. Most soya comes from America, both the USA and further south such as Argentina and much of the soya that we import is genetically modified (GM).[30] There is no evidence that GM food is dangerous to those who eat it, but the response will be interesting.

Further reading & references
  1. Branham WS, Dial SL, Moland CL, et al; Phytoestrogens and mycoestrogens bind to the rat uterine estrogen receptor. J Nutr. 2002 Apr;132(4):658-64. [abstract]
  2. Alexandersen P, Toussaint A, Christiansen C, et al; Ipriflavone in the treatment of postmenopausal osteoporosis: a randomized controlled trial. JAMA. 2001 Mar 21;285(11):1482-8. [abstract]
  3. Lethaby AE, Brown J et al; Phytoestrogens for vasomotor menopausal symptoms. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD001395. DOI: 10.1002/14651858.
  4. Potter, S. M. et al.; Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr 1998;68(suppl):1375S–9S.
  5. Cassidy A, Hooper L; Phytoestrogens and cardiovascular disease. J Br Menopause Soc. 2006 Jun;12(2):49-56. [abstract]
  6. Anderson JJ, Chen X, Boass A, et al; Soy isoflavones: no effects on bone mineral content and bone mineral density in healthy, menstruating young adult women after one year. J Am Coll Nutr. 2002 Oct;21(5):388-93. [abstract]
  7. Whelan AM, Jurgens TM, Bowles SK; Natural health products in the prevention and treatment of osteoporosis: systematic review of randomized controlled trials. Ann Pharmacother. 2006 May;40(5):836-49. Epub 2006 May 2. [abstract]
  8. Reinwald S, Weaver CM; Soy isoflavones and bone health: a double-edged sword? J Nat Prod. 2006 Mar;69(3):450-9. [abstract]
  9. Dang ZC, Lowik C; Dose-dependent effects of phytoestrogens on bone. Trends Endocrinol Metab. 2005 Jul;16(5):207-13. [abstract]
  10. Messina MJ, Wood CE; Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and Nutr J. 2008 Jun 3;7:17. [abstract]
  11. Zava DT, Dollbaum CM, Blen M; Estrogen and progestin bioactivity of foods, herbs, and spices. Proc Soc Exp Biol Med. 1998 Mar;217(3):369-78. [abstract]
  12. Lof M, Weiderpass E; Impact of diet on breast cancer risk. Curr Opin Obstet Gynecol. 2009 Feb;21(1):80-5. [abstract]
  13. Hanf V, Gonder U; Nutrition and primary prevention of breast cancer: foods, nutrients and breast Eur J Obstet Gynecol Reprod Biol. 2005 Dec 1;123(2):139-49. [abstract]
  14. Kim H, Peterson TG, Barnes S; Mechanisms of action of the soy isoflavone genistein: emerging role for its effects via transforming growth factor beta signaling pathways. Am J Clin Nutr. 1998 Dec;68(6 Suppl):1418S-1425S. [abstract]
  15. Ruiz-Larrea MB, Mohan AR, Paganga G, et al; Antioxidant activity of phytoestrogenic isoflavones. Free Radic Res. 1997 Jan;26(1):63-70. [abstract]
  16. Mitchell JH, Gardner PT, McPhail DB, et al; Antioxidant efficacy of phytoestrogens in chemical and biological model systems. Arch Biochem Biophys. 1998 Dec 1;360(1):142-8. [abstract]
  17. Messina MJ, Loprinzi CL; Soy for breast cancer survivors: a critical review of the literature. J Nutr. 2001 Nov;131(11 Suppl):3095S-108S. [abstract]
  18. Adlercreutz H, Mazur W, Bartels P, et al; Phytoestrogens and prostate disease. J Nutr. 2000 Mar;130(3):658S-9S.
  19. Holzbeierlein JM, McIntosh J, Thrasher JB; The role of soy phytoestrogens in prostate cancer. Curr Opin Urol. 2005 Jan;15(1):17-22. [abstract]
  20. Badger TM, Ronis MJ, Hakkak R, et al; The health consequences of early soy consumption. J Nutr. 2002 Mar;132(3):559S-565S. [abstract]
  21. Setchell KD, Zimmer-Nechemias L, Cai J, et al; Exposure of infants to phyto-oestrogens from soy-based infant formula. Lancet. 1997 Jul 5;350(9070):23-7. [abstract]
  22. CMO's update, Dept of Health, 2004
  23. White LR, Petrovitch H, Ross GW, et al; Brain aging and midlife tofu consumption. J Am Coll Nutr. 2000 Apr;19(2):242-55. [abstract]
  24. Casini ML, Marelli G, Papaleo E, et al; Psychological assessment of the effects of treatment with phytoestrogens on postmenopausal women: a randomized, double-blind, crossover, placebo-controlled study. Fertil Steril. 2006 Apr;85(4):972-8. [abstract]
  25. Divi RL, Chang HC, Doerge DR; Anti-thyroid isoflavones from soybean: isolation, characterization, and mechanisms of action. Biochem Pharmacol. 1997 Nov 15;54(10):1087-96. [abstract]
  26. Black Cohosh. Risk of liver problems, Medicines and Healthcare products Regulatory Agency (MHRA), July 2006
  27. Ranich T, Bhathena SJ, Velasquez MT; Protective effects of dietary phytoestrogens in chronic renal disease. J Ren Nutr. 2001 Oct;11(4):183-93. [abstract]
  28. Beral V; Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2003 Aug 9;362(9382):419-27. [abstract]
  29. Beral V, Bull D, Reeves G; Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet. 2005 Apr 30-May 6;365(9470):1543-51. [abstract]
  30. IGD information sheets
  31.  of Reading, 1998http://www.patient.co.uk/doctor/Phyto-oestrogens.htm



Phytoestrogens

The term “estrogen” has come to refer to any substance that elicits a biological response similar to that of the principle human estrogen (17β-estradiol) in any hormone related assay; likewise, the term “phytoestrogen” does not indicate a particular chemical class, but has come to include all plant-derived compounds with some form of observed estrogenic activity. The biosynthesis of 17β-estradiol has been demonstrated in Phaseolus vulgaris L. (Young et al., 1977), and the principle human estrogen could therefore itself be regarded as a “phytoestrogen”. The term was first used to describe the observation that certain forage plants produced effects in farm animals similar to those known for estrogen (Bickoff, 1961). The estrogenic properties of isoflavonoids were first characterized by the Australian chemists Bradbury and White (1951), who were charged with elucidating the cause of an epidemic of infertility in sheep that was ravaging their nation’s wool industry. In 1951, the team reported the results of their decade-long effort. They had traced the cause of the epidemic to genistein present in “subterranean clover” (Trifolium subterraneum L.) growing in pastures where the sheep grazed. Genistein had previously been identified in soy (Baker and Robinson, 1928) but its hormonal properties were unknown until the work of Bradbury and White. It is noted that many animal feeds are soy-based and should not be used for estrogen-dependent assays (Brown and Setchell, 2001).

Numerous assays currently available are designed to characterize and/or identify estrogenic activity, from in vitro ligand-receptor binding and whole cell assays, to in vivo animal models. With the independent discovery by four different research groups of a novel subtype of the estrogen receptor in 1996 (the beta-estrogen receptor, or ERβ) in both rat (Inoue et al., 1996; Kuiper et al., 1996) and human tissues (Mosselman et al., 1996; Pink et al., 1996) a large body of research aimed at understanding the organ specific effects of each receptor subtype has been generated. ERα receptors are more common in the breast, liver, CNS and uterus, whereas ERβ receptors are expressed mainly in the intestine, prostate, ovaries, testes, and urogenital tract (Lecce et al., 2001; Pettersson and Gustafsson, 2001; Shughrue and Merchenthaler, 2001).

Many estrogenic substances have been identified from natural sources. Natural estrogen receptor ligands comprise a range of chemical classes, namely (in order of highest reported potency in ER binding assays), the steroids, polyketides (zearalenones), alkylated flavanones, isoflavones, phenylbenzofurans, anthraquinones, nor-neolignans (hinokiresinol), napyridiomycins, benzylchromanones, flavonols, isopropylbiphenyls, dihydrochalcones, alkaloids, flavones, chalcones, stilbenes, and 1,4-diphenylbutanones (Farnsworth, 2003).

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