Chemistry:Phytoestrogen

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Short description: Plant-derived xenoestrogen

A phytoestrogen is a plant-derived xenoestrogen (a type of estrogen produced by organisms other than humans) not generated within the endocrine system, but consumed by eating plants or manufactured foods.[1] Also called a "dietary estrogen", it is a diverse group of naturally occurring nonsteroidal plant compounds that, because of its structural similarity to estradiol (17-β-estradiol), have the ability to cause estrogenic or antiestrogenic effects.[2] Phytoestrogens are not essential nutrients because their absence from the diet does not cause a disease, nor are they known to participate in any normal biological function.[2] Common foods containing phytoestrogens are soy protein, beans, oats, barley, rice, coffee, apples, carrots (see Food Sources section below for bigger list).

Its name comes from the Greek phyto ("plant") and estrogen, the hormone which gives fertility to female mammals. The word "estrus" (Greek οίστρος) means "sexual desire", and "gene" (Greek γόνο) is "to generate". It has been hypothesized that plants use a phytoestrogen as part of their natural defense against the overpopulation of herbivore animals by controlling female fertility.[3][4]

The similarities, at molecular level, of an estrogen and a phytoestrogen allow them to mildly mimic and sometimes act as an antagonist of estrogen.[2] Phytoestrogens were first observed in 1926,[2][5] but it was unknown if they could have any effect in human or animal metabolism. In the 1940s and early 1950s, it was noticed that some pastures of subterranean clover and red clover (phytoestrogen-rich plants) had adverse effects on the fecundity of grazing sheep.[2][6][7][8]

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

Structure

Phytoestrogens mainly belong to a large group of substituted natural phenolic compounds: the coumestans, prenylflavonoids and isoflavones are three of the most active in estrogenic effects in this class.[1] 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.[2] Mycoestrogens have similar structures and effects, but are not components of plants; these are mold metabolites of Fusarium, especially common on cereal grains,[9][10][11] but also occurring elsewhere, e.g. on various forages.[12] Although mycoestrogens are rarely taken into account in discussions about phytoestrogens, these are the compounds that initially generated the interest on the topic.[13]

Mechanism of action

Phytoestrogens exert their effects primarily through binding to estrogen receptors (ER).[14] There are two variants of the estrogen receptor, alpha (ER-α) and beta (ER-β) and many phytoestrogens display somewhat higher affinity for ER-β compared to ER-α.[14]

The key structural elements that enable phytoestrogens to bind with high affinity to estrogen receptors and display estradiol-like effects are:[2]

  • 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 depressing or stimulating the synthesis of sex hormone-binding globulin (SHBG).[8]

Emerging evidence shows that some phytoestrogens bind to and transactivate peroxisome proliferator-activated receptors (PPARs).[15][16] In vitro studies show an activation of PPARs at concentrations above 1 μM, which is higher than the activation level of ERs.[17][18] At the concentration below 1 μM, activation of ERs may play a dominant role. At higher concentrations (>1 μM), both ERs and PPARs are activated. Studies have shown that both ERs and PPARs influence each other and therefore induce differential effects in a dose-dependent way. The final biological effects of genistein are determined by the balance among these pleiotrophic actions.[15][16][17]


Ecology

Phytoestrogens are involved in the synthesis of antifungal benzofurans and phytoalexins, such as medicarpin (common in legumes), and sesquiterpenes, such as capsidiol in tobacco.[19] Soybeans naturally produce isoflavones, and are therefore a dietary source for isoflavones.

Phytoestrogens are ancient naturally occurring substances, and as dietary phytochemicals they are considered to have coevolved with mammals. In the human diet, phytoestrogens are not the only source of exogenous estrogens. Xenoestrogens (novel, man-made), are found as food additives[20] 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.[21]

Avian studies

The consumption of plants with unusual content of phytoestrogens, under drought conditions, has been shown to decrease fertility in quail.[22] Parrot food as available in nature has shown only weak estrogenic activity. Studies have been conducted on screening methods for environmental estrogens present in manufactured supplementary food, with the purpose of aiding reproduction of endangered species.[23]

Food sources

According to one study 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 soybeans and tofu.[24] The highest concentrations of isoflavones are found in soybeans and soybean products followed by legumes, whereas lignans are the primary source of phytoestrogens 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 soybean used. Legumes (in particular soybeans), whole grain cereals, and some seeds are high in phytoestrogens.

A more comprehensive list of foods known to contain phytoestrogens includes:


Food content of phytoestrogens is very variable and accurate estimates of intake are therefore difficult and depends on the databases used.[30] Data from the European Prospective Investigation into Cancer and Nutrition found intakes between 1 mg/d in Mediterranean Countries and more than 20 mg/d in the United Kingdom .[31] The high intake in the UK is partly explained by the use of soy in the Chorleywood bread process.[32] 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.[33]

Effects on humans

In humans, phytoestrogens are digested in the small intestine, poorly absorbed into the circulatory system, 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.[21]

As of 2020, there is sufficient clinical evidence to determine that phytoestrogens have effects in humans.[34]

Females

It is unclear if phytoestrogens have any effect on the cause or prevention of cancer in women.[1][35] Some epidemiological studies have suggested a protective effect against breast cancer.[1][35][36] Additionally, other epidemiological studies found that consumption of soy estrogens is safe for patients with breast cancer, and that it may decrease mortality and recurrence rates.[1][37][38] It remains unclear if phytoestrogens can minimize some of the deleterious effects of low estrogen levels (hypoestrogenism) resulting from oophorectomy, menopause, or other causes.[35] A Cochrane review of the use of phytoestrogens to relieve the vasomotor symptoms of menopause (hot flashes) stated that there was no conclusive evidence to suggest any benefit to their use, although genistein effects should be further investigated.[39]

Males

It is unclear if phytoestrogens have any effect on male sexuality, with conflicting results about the potential effects of isoflavones originating from soy.[1] Some studies showed that isoflavone supplementation had a positive effect on sperm concentration, count, or motility, and increased ejaculate volume.[40][41] Sperm count decline and increasing rate of testicular cancers in the West may be linked to a higher presence of isoflavone phytoestrogens in the diet while in utero, but such a link has not been definitively proven.[42] Furthermore, while there is some evidence that phytoestrogens may affect male fertility, more recent reviews of available studies found no link,[43][44] and instead suggests that healthier diets such as the Mediterranean diet might have a positive effect on male fertility.[44] Neither isoflavones nor soy have been shown to affect male reproductive hormones in healthy individuals.[43][45]

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.[46] Some reviews express the opinion that more research is needed to answer the question of what effect phytoestrogens may have on infants,[47][48] but their authors did not find any adverse effects. 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.[49][50][51] The American Academy of Pediatrics states: "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."[52]

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.[53] Plants used that have been shown to contain phytoestrogens include Pueraria mirifica[54] and its close relative kudzu,[55] Angelica,[56] fennel,[28] and anise. In a rigorous study, the use of one such source of phytoestrogen, red clover, has been shown to be safe, but ineffective in relieving menopausal symptoms[57] (black cohosh is also used for menopausal symptoms, but does not contain phytoestrogens[58]).

See also


References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Isoflavones". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis. October 2016. https://lpi.oregonstate.edu/mic/dietary-factors/phytochemicals/soy-isoflavones. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Yildiz, Fatih (2005). Phytoestrogens in Functional Foods. Taylor & Francis Ltd. pp. 3–5, 210–211. ISBN 978-1-57444-508-4. 
  3. ↑ "Phytochemical mimicry of reproductive hormones and modulation of herbivore fertility by phytoestrogens". Environmental Health Perspectives 78: 171–4. Jun 1988. doi:10.1289/ehp.8878171. PMID 3203635. 
  4. ↑ Bentley, Gillian R.; Mascie-Taylor, C. G. N. (2000). Infertility in the modern world: present and future prospects. Cambridge, UK: Cambridge University Press. pp. 99–100. ISBN 978-0-521-64387-0. https://archive.org/details/infertilitymoder00bent. 
  5. ↑ Varner, JE; Bonner, J (1966). Plant Biochemistry. Academic Press. ISBN 978-0-12-114856-0. 
  6. ↑ "A specific breeding problem of sheep on subterranean clover pastures in Western Australia". Australian Veterinary Journal 22 (1): 2–12. 1946. doi:10.1111/j.1751-0813.1946.tb15473.x. PMID 21028682. 
  7. ↑ "Oestrogens in New Zealand pasture plants.". N. Z. Vet. J. 2 (4): 128–134. 1954. doi:10.1080/00480169.1954.33166. 
  8. ↑ 8.0 8.1 Johnston, I (2003). Phytochem Functional Foods. CRC Press Inc. pp. 66–68. ISBN 978-0-8493-1754-5. 
  9. ↑ "Zearalenone in cereal grains". J. Amer. Oil. Chemists Soc. 56 (9): 812–819. 1979. doi:10.1007/bf02909525. https://naldc-legacy.nal.usda.gov/naldc/download.xhtml?id=26065&content=PDF. [yes|permanent dead link|dead link}}]
  10. ↑ "Risk assessment of the mycotoxin zearalenone". Regul. Toxicol. Pharmacol. 7 (3): 253–306. 1987. doi:10.1016/0273-2300(87)90037-7. PMID 2961013. 
  11. ↑ "Review on the toxicity, occurrence, metabolism, detoxification, regulations and intake of zearalenone: an oestrogenic mycotoxin". Food Chem. Toxicol. 45 (1): 1–18. 2007. doi:10.1016/j.fct.2006.07.030. PMID 17045381. 
  12. ↑ "Review on Mycotoxin Issues in Ruminants: Occurrence in Forages, Effects of Mycotoxin Ingestion on Health Status and Animal Performance and Practical Strategies to Counteract Their Negative Effects". Toxins (Basel) 7 (8): 3057–111. 2015. doi:10.3390/toxins7083057. PMID 26274974. 
  13. ↑ Naz, Rajesh K. (1999). Endocrine Disruptors: Effects on Male and Female Reproductive Systems. CRC Press Inc. p. 90. ISBN 978-0-8493-3164-0. 
  14. ↑ 14.0 14.1 "Molecular aspects of phytoestrogen selective binding at estrogen receptors". Journal of Pharmaceutical Sciences 96 (8): 1879–85. Aug 2007. doi:10.1002/jps.20987. PMID 17518366. 
  15. ↑ 15.0 15.1 "Dose-dependent effects of phytoestrogens on bone". Trends in Endocrinology and Metabolism 16 (5): 207–13. Jul 2005. doi:10.1016/j.tem.2005.05.001. PMID 15922618. 
  16. ↑ 16.0 16.1 "Dose-dependent effects of soy phyto-oestrogen genistein on adipocytes: mechanisms of action". Obesity Reviews 10 (3): 342–9. May 2009. doi:10.1111/j.1467-789X.2008.00554.x. PMID 19207876. 
  17. ↑ 17.0 17.1 "Peroxisome proliferator-activated receptor gamma (PPARgamma ) as a molecular target for the soy phytoestrogen genistein". The Journal of Biological Chemistry 278 (2): 962–7. Jan 2003. doi:10.1074/jbc.M209483200. PMID 12421816. 
  18. ↑ "The balance between concurrent activation of ERs and PPARs determines daidzein-induced osteogenesis and adipogenesis". Journal of Bone and Mineral Research 19 (5): 853–61. May 2004. doi:10.1359/jbmr.040120. PMID 15068509. 
  19. ↑ Leegood, Richard C.; Lea, Per (1998). Plant Biochemistry and Molecular Biology. John Wiley & Sons. pp. 204,211–213. ISBN 978-0-471-97683-7. 
  20. ↑ "Identification of xenoestrogens in food additives by an integrated in silico and in vitro approach". Chem. Res. Toxicol. 22 (1): 52–63. 2009. doi:10.1021/tx800048m. PMID 19063592. 
  21. ↑ 21.0 21.1 Korach, Kenneth S. (1998). Reproductive and Developmental Toxicology. Marcel Dekker Ltd. pp. 278–279. ISBN 978-0-8247-9857-4. 
  22. ↑ "Phytoestrogens: adverse effects on reproduction in California quail". Science 191 (4222): 98–100. January 1976. doi:10.1126/science.1246602. PMID 1246602. Bibcode: 1976Sci...191...98S. 
  23. ↑ "Screening the foods of an endangered parrot, the kakapo (Strigops habroptilus), for oestrogenic activity using a recombinant yeast bioassay". Reproduction, Fertility, and Development 12 (3–4): 191–9. 2000. doi:10.1071/RD00041. PMID 11302429. 
  24. ↑ "Phytoestrogen content of foods consumed in Canada, including isoflavones, lignans, and coumestan". Nutrition and Cancer 54 (2): 184–201. 2006. doi:10.1207/s15327914nc5402_5. PMID 16898863. 
  25. ↑ "Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry". Phytochemistry 65 (2): 233–41. Jan 2004. doi:10.1016/j.phytochem.2003.07.001. PMID 14732284. Bibcode: 2004PChem..65..233V. 
  26. ↑ "Estrogens and congeners from spent hops (Humulus lupulus)". Journal of Natural Products 67 (12): 2024–32. Dec 2004. doi:10.1021/np049783i. PMID 15620245. 
  27. ↑ "Assessment of the estrogenic activity of phytoestrogens isolated from bourbon and beer". Alcoholism: Clinical and Experimental Research 17 (6): 1207–9. Dec 1993. doi:10.1111/j.1530-0277.1993.tb05230.x. PMID 8116832. 
  28. ↑ 28.0 28.1 "Fennel and anise as estrogenic agents". Journal of Ethnopharmacology 2 (4): 337–44. Dec 1980. doi:10.1016/S0378-8741(80)81015-4. PMID 6999244. 
  29. ↑ Bacciottini, Lucia; Falchetti, Alberto; Pampaloni, Barbara; Bartolini, Elisa; Carossino, Anna Maria; Brandi, Maria Luisa (2007). "Phytoestrogens: food or drug?". Clinical Cases in Mineral and Bone Metabolism 4 (2): 123–130. ISSN 1724-8914. PMID 22461212. 
  30. ↑ Kuhnle, Gunter G.C.; Dell’Aquila, Caterina; Runswick, Shirley A.; Bingham, Sheila A. (2008). "Variability of phytoestrogen content in foods from different sources" (in en). Food Chemistry 113 (4): 1184–1187. doi:10.1016/j.foodchem.2008.08.004. https://linkinghub.elsevier.com/retrieve/pii/S0308814608009679. 
  31. ↑ Zamora-Ros, R; Knaze, V; Luján-Barroso, L; Kuhnle, G G C; Mulligan, A A; Touillaud, M; Slimani, N; Romieu, I et al. (2012). "Dietary intakes and food sources of phytoestrogens in the European Prospective Investigation into Cancer and Nutrition (EPIC) 24-hour dietary recall cohort" (in en). European Journal of Clinical Nutrition 66 (8): 932–941. doi:10.1038/ejcn.2012.36. ISSN 0954-3007. PMID 22510793. 
  32. ↑ Cauvain, Stanley P. (2006). The Chorleywood bread process. Linda S. Young. Boca Raton, FL: CRC Press. ISBN 1-84569-143-1. OCLC 236341936. https://www.worldcat.org/oclc/236341936. 
  33. ↑ "Intake of dietary phytoestrogens is low in postmenopausal women in the United States: the Framingham study(1-4)". The Journal of Nutrition 131 (6): 1826–32. Jun 2001. doi:10.1093/jn/131.6.1826. PMID 11385074. http://jn.nutrition.org/cgi/content/abstract/131/6/1826. 
  34. ↑ Domínguez-López, Inés; Yago-Aragón, Maria; Salas-Huetos, Albert; Tresserra-Rimbau, Anna; Hurtado-Barroso, Sara (August 2020). "Effects of Dietary Phytoestrogens on Hormones throughout a Human Lifespan: A Review" (in en). Nutrients 12 (8): 2456. doi:10.3390/nu12082456. ISSN 2072-6643. PMID 32824177. 
  35. ↑ 35.0 35.1 35.2 "Phytoestrogens and prevention of breast cancer: The contentious debate". World Journal of Clinical Oncology 5 (4): 705–12. 2014. doi:10.5306/wjco.v5.i4.705. PMID 25302172. 
  36. ↑ "Case-control study of phyto-oestrogens and breast cancer". Lancet 350 (9083): 990–4. Oct 1997. doi:10.1016/S0140-6736(97)01339-1. PMID 9329514. 
  37. ↑ "Soy food intake and breast cancer survival". JAMA 302 (22): 2437–43. Dec 2009. doi:10.1001/jama.2009.1783. PMID 19996398. 
  38. ↑ "Soy, red clover, and isoflavones and breast cancer: a systematic review". PLOS ONE 8 (11): e81968. 2013. doi:10.1371/journal.pone.0081968. PMID 24312387. Bibcode: 2013PLoSO...881968F. 
  39. ↑ "Phytoestrogens for menopausal vasomotor symptoms". The Cochrane Database of Systematic Reviews 2013 (12): CD001395. 2013. doi:10.1002/14651858.CD001395.pub4. PMID 24323914. 
  40. ↑ Dabrowski, Waldemar M. (2004). Toxins in Food. CRC Press Inc. p. 95. ISBN 978-0-8493-1904-4. 
  41. ↑ "Effect of a phytoestrogen food supplement on reproductive health in normal males". Clinical Science 100 (6): 613–8. Jun 2001. doi:10.1042/CS20000212. PMID 11352776. http://www.clinsci.org/content/100/6/613. 
  42. ↑ "The pros and cons of phytoestrogens". Frontiers in Neuroendocrinology 31 (4): 400–19. 2010. doi:10.1016/j.yfrne.2010.03.003. PMID 20347861. 
  43. ↑ 43.0 43.1 Messina, Mark; Mejia, Sonia Blanco; Cassidy, Aedin; Duncan, Alison; Kurzer, Mindy; Nagato, Chisato; Ronis, Martin; Rowland, Ian et al. (2021-03-27). "Neither soyfoods nor isoflavones warrant classification as endocrine disruptors: a technical review of the observational and clinical data". Critical Reviews in Food Science and Nutrition 62 (21): 5824–5885. doi:10.1080/10408398.2021.1895054. ISSN 1040-8398. PMID 33775173. 
  44. ↑ 44.0 44.1 Nassan, Feiby L.; Chavarro, Jorge E.; Tanrikut, Cigdem (2018-09-01). "Diet and men's fertility: does diet affect sperm quality?" (in English). Fertility and Sterility 110 (4): 570–577. doi:10.1016/j.fertnstert.2018.05.025. ISSN 0015-0282. PMID 30196939. https://www.fertstert.org/article/S0015-0282(18)30426-6/abstract. 
  45. ↑ "Neither soy nor isoflavone intake affects male reproductive hormones: An expanded and updated meta-analysis of clinical studies". Reproductive Toxicology 100: 60–67. 2020. doi:10.1016/j.reprotox.2020.12.019. PMID 33383165. 
  46. ↑ "Genistein at a concentration present in soy infant formula inhibits Caco-2BBe cell proliferation by causing G2/M cell cycle arrest". The Journal of Nutrition 134 (6): 1303–8. Jun 2004. doi:10.1093/jn/134.6.1303. PMID 15173388. 
  47. ↑ "Soy-based formulas and phyto-oestrogens: a safety profile". Acta Paediatrica 91 (441): 93–100. Sep 2003. doi:10.1111/j.1651-2227.2003.tb00655.x. PMID 14599051. 
  48. ↑ "Isoflavones in soy infant formula: a review of evidence for endocrine and other activity in infants". Annual Review of Nutrition 24 (1): 33–54. 2004. doi:10.1146/annurev.nutr.24.101603.064950. PMID 15189112. https://zenodo.org/record/1235043. 
  49. ↑ "Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood". JAMA 286 (7): 807–14. Aug 2001. doi:10.1001/jama.286.7.807. PMID 11497534. 
  50. ↑ "Soy protein formulas in children: no hormonal effects in long-term feeding". Journal of Pediatric Endocrinology & Metabolism 17 (2): 191–6. Feb 2004. doi:10.1515/JPEM.2004.17.2.191. PMID 15055353. 
  51. ↑ "Safety of soy-based infant formulas containing isoflavones: the clinical evidence". The Journal of Nutrition 134 (5): 1220S–1224S. May 2004. doi:10.1093/jn/134.5.1220S. PMID 15113975. 
  52. ↑ "Use of soy protein-based formulas in infant feeding". Pediatrics 121 (5): 1062–8. May 2008. doi:10.1542/peds.2008-0564. PMID 18450914. http://pediatrics.aappublications.org/cgi/pmidlookup?view=long&pmid=18450914. 
  53. ↑ Muller-Schwarze, Dietland (2006). Chemical Ecology of Vertebrates. Cambridge University Press. p. 287. ISBN 978-0-521-36377-8. 
  54. ↑ "Requirement of metabolic activation for estrogenic activity of Pueraria mirifica". Journal of Veterinary Science 3 (4): 273–277. Dec 2002. doi:10.4142/jvs.2002.3.4.273. PMID 12819377. 
  55. ↑ "Analysis of isoflavones in foods and dietary supplements". Journal of AOAC International 89 (4): 1138–1146. 2006. doi:10.1093/jaoac/89.4.1138. PMID 16915857. 
  56. ↑ Brown, D.E.; Walton, N.J. (1999). Chemicals from plants: Perspectives on plant secondary products. World Scientific Publishing. pp. 21, 141. ISBN 978-981-02-2773-9. 
  57. ↑ "Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: A randomized controlled trial". Menopause 16 (6): 1156–1166. 2009. doi:10.1097/gme.0b013e3181ace49b. PMID 19609225. 
  58. ↑ "Analysis of thirteen populations of black cohosh for formononetin". Phytomedicine 9 (5): 461–467. Jul 2002. doi:10.1078/09447110260571733. PMID 12222669. 



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