Phytoestrogens

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for main article see Ethnopharmacology

Phytoestrogens, sometimes called "dietary estrogens", are a diverse group of naturally occurring non steroidal plant compounds that, because of their structural similarity with estradiol (17-β-estradiol), have the ability to cause estrogenic or/and antiestrogenic effects.[1]

Chemical structures of the most common phytoestrogens found in plants (top and middle) compared with estrogen (bottom) found in animals.

Their name comes from phyto = plant and estrogen = estrus (period of fertility for female mammals) + gen = to generate.

The similarities, at molecular level, of estrogens and phytoestrogens allow them to mildly mimic and sometimes act as antagonists of estrogen[1]. Phytoestrogens were first observed in 1926 [1][2] but it was unknown if they could have any effect in human or animal metabolism. In the 1940s it was noticed for the first time that red clover (a phytoestrogens-rich plant) pastures had effects on the fertility of grazing sheep.[1][3] Researchers are exploring the nutritional role of these substances in the regulation of cholesterol, and the maintenance of proper bone density post-menopause. Evidence is accruing that phytoestrogens may have protective action against diverse health disorders such as prostate, breast, bowel, and other cancers, cardiovascular disease, brain function disorders and osteoporosis,[1][3][4] though there is no evidence to support their use in alleviating the symptoms of menopause.[5]

Phytoestrogens cannot be considered as nutrients given that the lack of these in diet doesn't produce any characteristic deficiency syndrome, nor do they participate in any essential biological function.[1]

A COT draft report from the UK Food Standards Agency presents an update of methods for a more accurate analysis of phytoestrogen content in plants and food, concluding that research in recent years is more reliable than previous studies.[6]

Contents

[edit] Structure

Phytoestrogens mainly belong to a large group of substituted phenolic compounds known as flavonoids: the coumestans, prenylated flavonoids and isoflavones are three of the most active in estrogenic effects in this class. The best-researched are isoflavones, which are commonly found in soy and red clover. Lignans have also been identified as phytoestrogens, although they are not flavonoids[1]. Mycoestrogens have similar structures and effects, but are not components of plants, these are mold metabolites of Fusarium, a fungus that is frequently found in pastures as well as in alfalfa and clover. Although mycoestrogens are rarely taken into account in discussions about phytoestrogens, these are the compounds that initially generated the interest on the topic.[7]

[edit] Mechanism of action

Phytoestrogens exert their effects primarily through binding to the estrogen receptor (ER).[8] There are two variants of the estrogen receptor, alpha (ER-α) and beta (ER-β) and many phytoestrogen display somewhat higher affinity for ER-β compared to ER-α.[8]

The key structural elements that enable phytoestrogens to bind with high affinity to estrogen receptors and display estradiol-like effects are:[1]

  • The phenolic ring that is indispensable for binding to estrogen receptor
  • The ring of isoflavones mimicking a ring of estrogens at the receptors binding site
  • Low molecular weight similar to estrogens (MW=272)
  • Distance between two hydroxyl groups at the isoflavones nucleus similar to that occurring in estradiol
  • Optimal hydroxylation pattern

In addition to interaction with ERs, phytoestrogens may also modulate the concentration of endogenous estrogens by binding or inactivating some enzymes and may affect the bioavailability of sex hormones by binding or stimulating the synthesis of sex hormone binding globuline (SHBG).[3]

[edit] Ecology

These compounds in plants are an important part of their defense system mainly against fungi.[9]

Phytoestrogens are considered archiestrogens (ancient, naturally occurring) and as dietary phytochemicals they are considered as co-evolutive with mammals. In human diet, phytoestrogens are not the only source of exogenous estrogens. Xenoestrogens (novel, man-made), are found as food additives [10] and ingredients, and also in cosmetics, plastics, and insecticides. Environmentally, they have similar effects as phytoestrogens, making it difficult to clearly separate the action of these two kind of agents in studies done on populations.[11]

[edit] Avian studies

The consumption of plants with unusual content of phytoestrogens under drought conditions, have shown to decrease fertility in quail.[12] Parrot food as available in nature has shown only weak estrogenic activity. Studies on screening methods for environmental estrogens present in manufactured supplementary food, with the purpose to enable reproduction of endangered species. have been researched.[13]

[edit] Food sources

According to a study by Canadian researchers about the content of nine common phytoestrogens in a Western diet, foods with the highest relative phytoestrogen content were nuts and oilseeds, followed by soy products, cereals and breads, legumes, meat products, and other processed foods that may contain soy, vegetables, fruits, alcoholic, and nonalcoholic beverages. Flax seed and other oilseeds contained the highest total phytoestrogen content, followed by soy bean and tofu.[14] The highest concentrations of Isoflavones are found in soy bean and soy bean products followed by legumes, whereas lignans are the primary source of phytoestrogen found in nuts and oilseeds (e.g. flax) and also found in cereals, legumes, fruits and vegetables.

Phytoestrogen content varies in different foods, and may vary significantly within the same group of foods (e.g. soy beverages, tofu) depending on processing mechanisms and type of soy bean used.[15] Legumes (in particular soybeans), whole grain cereals, and some seeds are high in phytoestrogen. A more comprehensive list of foods known to contain phytoestrogens includes: soy beans, tofu, tempeh, soy beverages, linseed (flax), sesame seeds, wheat, berries, oats, barley, dried beans, lentils, yams, rice, alfalfa, mung beans, apples, carrots, pomegranates,[16] wheat germ, ricebran, soy linseed bread, ginseng, hops[17] bourbon and beer[18] fennel and anise.[19]

An epidemiological study of women in the United States found that the dietary intake of phytoestrogens in healthy post-menopausal Caucasian women is less than one milligram daily.[20]

[edit] Health risks and benefits

In human beings, phytoestrogens are readily absorbed, circulate in plasma and are excreted in the urine. Metabolic influence is different from that of grazing animals due to the differences between ruminant versus monogastric digestive systems.[11]

[edit] Males

In the last few years, there has been a great deal of research into the possible beneficial effects of phytoestrogens in both diabetes and coronary heart disease.

The use of phytoestrogens (as soy protein) in fast food meals and other processed foods as a low-cost substitute for meat products may lead to excessive consumption of isoflavonoids by fast food eaters. A research team at the Queen's University in Belfast, in a review article, speculate that such intake may lead to a slight decrease in male fertility, including a decrease in reproductive capability if isoflavones are taken in excess during childhood.[21]

In theory, exposure to high levels of phytoestrogens in males could alter their hypothalamic-pituitary-gonadal axis. However, studies have shown that such a hormonal effect is minor.[22] Isoflavones supplementation has no effect in sperm concentration, count or motility and show no changes in testicular or ejaculate volume.[23][24] Phytoestrogens may have health benefits for males. Researchers are studying if phytoestrogens can prevent prostate cancer.[25][26]

[edit] Females

There are conflicting studies, and it is unclear if phytoestrogens have any effect on the cause or prevention of cancer in females.[27][28] Epidemiological studies showed a protective effect against breast cancer.[29] In vitro studies concluded that females with current or past breast cancer should be aware of the risks of potential tumor growth when taking soy products, as they can stimulate the growth of estrogen receptor-positive cells in vitro. The potential for tumor growth was found related only with small concentration of genistein and protective effects were found with larger concentrations of the same phytoestrogen.[30] A 2006 review article stated the opinion that not enough information is available, and that even if isoflavones have mechanisms to inhibit tumor growth, in vitro results justify the need to evaluate, at cellular level, the impact of isoflavones on breast tissue in females at high risk for breast cancer.[31] A Cochrane Review of the use of phytoestrogens to relieve the vasomotor symptoms of menopause (hot flashes) demonstrated that there was no evidence to suggest any benefit to their use.[32]

HRT may also be effective at reversing the effects of aging on muscle. A future aim is to target therapy to molecular mechanisms that work specifically in selected tissues.[33]

[edit] Infant formula

Some studies have found that some concentrations of isoflavones may have effects on intestinal cells. At low doses, genistein acted as a weak estrogen and stimulated cell growth; at high doses, it inhibited proliferation and altered cell cycle dynamics. This biphasic response correlates with how genistein is thought to exert its effects.[34]

Some reviews express the opinion that more research is needed to answer the question of what effect phytoestrogens may have on infants,[35][36] but their authors did not find any adverse effects. Multiple studies conclude there are no adverse effects in human growth, development, or reproduction as a result of the consumption of soy-based infant formula compared to conventional cow-milk formula.[37][37][38][39] While it should be noted that all infant formulas are inferior to human milk, soy formula presents no more risk than cow-milk formula.[40] One of these studies, published at the Journal of Nutrition,[39] concludes that:

"...there is no clinical concerns with respect to nutritional adequacy, sexual development, neurobehavioral development, immune development, or thyroid disease. SBIFs provide complete nutrition that adequately supports normal infant growth and development. FDA has accepted SBIFs as safe for use as the sole source of nutrition"

Clinical guidelines from the American Academy of Pediatrics state: "although isolated soy protein-based formulas may be used to provide nutrition for normal growth and development, there are few indications for their use in place of cow milk-based formula. These indications include (a) for infants with galactosemia and hereditary lactase deficiency (rare) and (b) in situations in which a vegetarian diet is preferred."[41]

[edit] Ethnopharmacology

In some countries, phytoestrogenic plants have been used for centuries in the treatment of menstrual and menopausal problems as well as for fertility problems.[42] Plants most that have shown to contain phytoestrogens include Pueraria mirifica,[43] and its close relative, kudzu,[44] Angelica,[45] fennel and anise.[19]

[edit] See also

[edit] External links

[edit] References

  1. ^ a b c d e f g h Yildiz, Fatih (2005). Phytoestrogens in Functional Foods. Taylor & Francis Ltd. pp. 3–5, 210-211. ISBN 978-1574445084. 
  2. ^ Varner, J E, Bonner, J (1966). Plant Biochemistry. Academic Press. ISBN 978-0121148560. 
  3. ^ a b c JOHNSTON, I (2003). Phytochem Functional Foods. CRC Press Inc. pp. 66–68. ISBN 978-0849317545. 
  4. ^ Adlercreutz H (June 2002). "Phyto-oestrogens and cancer". Lancet Oncol. 3 (6): 364–73. PMID 12107024. http://linkinghub.elsevier.com/retrieve/pii/S1470204502007775. Retrieved 2008-12-20. 
  5. ^ Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J (2007). "Phytoestrogens for vasomotor menopausal symptoms". Cochrane Database Syst Rev (4): CD001395. doi:10.1002/14651858.CD001395.pub3. PMID 17943751. 
  6. ^ Foods Standards Agency UK
  7. ^ Naz, Rajesh K. (1999). Endocrine Disruptors: Effects on Male and Female Reproductive Systems. CRC Press Inc. p. 90. ISBN 978-0849331640. 
  8. ^ a b Turner JV, Agatonovic-Kustrin S, Glass BD (August 2007). "Molecular aspects of phytoestrogen selective binding at estrogen receptors". J Pharm Sci 96 (8): 1879–85. doi:10.1002/jps.20987. PMID 17518366. 
  9. ^ Richard C. Leegood, Per Lea (1998). Plant Biochemistry and Molecular Biology. John Wiley & Sons. p. 211. ISBN 978-0471976837. 
  10. ^ Amadasi A, Mozzarelli A, Meda C, Maggi A, Cozzini P. Identification of Xenoestrogens in Food Additives by an Integrated in Silico and in Vitro Approach. Chemical Research in Toxicology 2008;22:52-63
  11. ^ a b Korach, Kenneth S. (1998). Reproductive and Developmental Toxicology. Marcel Dekker Ltd. pp. 278–279. ISBN 978-0824798574. 
  12. ^ Leopold AS, Erwin M, Oh J, Browning B (January 1976). "Phytoestrogens: adverse effects on reproduction in California quail". Science 191 (4222): 98–100. PMID 1246602. http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=1246602. Retrieved 2008-12-20. 
  13. ^ Fidler AE, Zwart S, Pharis RP, Weston RJ, Lawrence SB, Jansen P, Elliott G, Merton DV (2000). "Screening the foods of an endangered parrot, the kakapo (Strigops habroptilus), for oestrogenic activity using a recombinant yeast bioassay". Reprod. Fertil. Dev. 12 (3-4): 191–9. PMID 11302429. 
  14. ^ Thompson LU, Boucher BA, Liu Z, Cotterchio M, Kreiger N (2006). "Phytoestrogen content of foods consumed in Canada, including isoflavones, lignans, and coumestan". Nutrition and Cancer 54 (2): 184–201. doi:10.1207/s15327914nc5402_5. PMID 16898863. 
  15. ^ Fermented soy products have lower phytoestrogen content. Phytoestrogens and Menopause [1]
  16. ^ van Elswijk DA, Schobel UP, Lansky EP, Irth H, van der Greef J (January 2004). "Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry". Phytochemistry 65 (2): 233–41. PMID 14732284. http://linkinghub.elsevier.com/retrieve/pii/S0031942203006241. Retrieved 2008-12-19. 
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  18. ^ Rosenblum ER, Stauber RE, Van Thiel DH, Campbell IM, Gavaler JS (December 1993). "Assessment of the estrogenic activity of phytoestrogens isolated from bourbon and beer". Alcohol. Clin. Exp. Res. 17 (6): 1207–9. PMID 8116832. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0145-6008&date=1993&volume=17&issue=6&spage=1207. Retrieved 2008-12-19. 
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  25. ^ Heald CL, Ritchie MR, Bolton-Smith C, Morton MS, Alexander FE (August 2007). "Phyto-oestrogens and risk of prostate cancer in Scottish males". Br. J. Nutr. 98 (2): 388–96. doi:10.1017/S0007114507700703. PMID 17403269. http://journals.cambridge.org/abstract_S0007114507700703. Retrieved 2008-12-20. 
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  27. ^ Cornell veterinary medicine website on phytoestrogens and cancer
  28. ^ Cancer Care Ontario
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  45. ^ D.E. Brown, N.J. Walton, (1999). Chemicals from Plants: Perspectives on Plant Secondary Products. World Scientific Publishing. pp. 21, 141. ISBN 978-9810227739. 
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