Phytoestrogens are plant-derived xenoestrogens (see estrogen) not generated within the endocrine system but consumed by eating phytoestrogenic plants. Also called "dietary estrogens", they are a diverse group of naturally occurring nonsteroidal plant compounds that, because of their structural similarity with estradiol (17-β-estradiol), have the ability to cause estrogenic or/and antiestrogenic effects, by sitting in and blocking receptor sites against estrogen.
Their 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 phytoestrogens as part of their natural defence against the overpopulation of herbivore animals by controlling female fertility.
The similarities, at molecular level, of estrogens and phytoestrogens allow them to mildly mimic and sometimes act as antagonists of estrogen. Phytoestrogens were first observed in 1926, 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. Researchers are exploring the nutritional role of phytoestrogens 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,
Phytoestrogens cannot be considered nutrients, given that the lack of these in the diet does not produce any characteristic deficiency syndrome nor do they participate in any essential biological function.
Analytical methods are available to determine phytoestrogen content in plants and food.
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. 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. Mycoestrogens have similar structures and effects, but are not components of plants; these are mold metabolites of Fusarium, especially common on cereal grains, but also occurring elsewhere, e.g. on various forages. Although mycoestrogens are rarely taken into account in discussions about phytoestrogens, these are the compounds that initially generated the interest on the topic.
Mechanism of action
Phytoestrogens exert their effects primarily through binding to estrogen receptors (ER). 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.
The key structural elements that enable phytoestrogens to bind with high affinity to estrogen receptors and display estradiol-like effects are:
- 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).
Emerging evidence shows that some phytoestrogens bind to and transactivate peroxisome proliferator-activated receptors (PPARs). In vitro studies show an activation of PPARs at concentrations above 1 μM, which is higher than the activation level of ERs. 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.
These compounds in plants are an important part of their defense system, mainly against fungi.
Phytoestrogens are ancient naturally occurring substances, and as dietary phytochemicals they are considered as co-evolutive with mammals. In the human diet, phytoestrogens are not the only source of exogenous estrogens. Xenoestrogens (novel, man-made), are found as food additives 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.
The consumption of plants with unusual content of phytoestrogens under drought conditions, has been shown to decrease fertility in quail. 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 to enable reproduction of endangered species.
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 soybeans and tofu. 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:
- Soybeans and soy products
- Linseed (flax)
- Sesame seeds
- Fenugreek (contains diosgenin, but also used to make Testofen®, a compound taken by men to increase testosterone).
- Mung beans
- Wheat germ
- Rice bran
- Licorice root
- Fennel and
- Red clover (sometimes a constituent of green manure).
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.
Effects on humans
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.
A 2010 meta-analysis of fifteen placebo-controlled studies said that "neither soy foods nor isoflavone supplements alter measures of bioavailable testosterone concentrations in men." Furthermore, isoflavone supplementation has no effect on sperm concentration, count or motility, and it leads to no observable changes in testicular or ejaculate volume. A 2010 review suggested that the sperm count decline and the increasing rate of testicular cancers in the West could be linked to a higher presence of isoflavone phytoestrogens in the diet, even if this is not proved and must still be debated.
It is unclear if phytoestrogens have any effect on the cause or prevention of cancer in females. Some epidemiological studies have suggested a protective effect against breast cancer. But a recent in vitro study concluded that females with current or past breast cancer may risk of tumor growth by consuming soy products, since they can stimulate the growth of estrogen receptor-positive cells in vitro. Low levels of genistein and daidzein, the phytoestrogens in soybeans, showed the potential to stimulate tumors, while protective effects were found at larger concentrations of the same phytoestrogen. A 2006 review article concluded that not enough information is available on the effects of phytoestrogens to justify drawing conclusions. While preliminary in vitro results suggest that isoflavins inhibit tumor growth, more research is needed to evaluate how isoflavones affect breast tissue in females at high risk for breast cancer. A more recent epidemiologic study argued that consumption of soy estrogens is safe for patients with breast cancer and that it may in fact decrease mortality and recurrence rates. Thus, even review studies have failed to produce consensus on the relationship between phytoestrogens and breast cancer.
It also remains unclear if phytoestrogens can minimize some of the deleterious effects of low estrogen levels (hypoestrogenism) resulting from oophorectomy, menopause, or other causes. A Cochrane Review of the use of phytoestrogens to relieve the vasomotor symptoms of menopause (hot flashes) concluded that there was no evidence to suggest any benefit to their use. Another study reported that phytoestrogens such as genistein may help prevent photoaging in human skin and promote formation of hyaluronic acid.
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.
Some reviews express the opinion that more research is needed to answer the question of what effect phytoestrogens may have on infants, 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. Soy formula presents no more risk than cow-milk formula. One of these studies, published at the Journal of Nutrition, concludes that:
Comprehensive literature reviews and clinical studies of infants fed SBIFs [soy-based infant formulas] have resolved questions or raise 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."
In some countries, phytoestrogenic plants have been used for centuries in the treatment of menstrual and menopausal problems, as well as for fertility problems. Plants used that have been shown to contain phytoestrogens include Pueraria mirifica, and its close relative, kudzu, Angelica, fennel 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 (black cohosh is also used for menopausal symptoms, but does not contain phytoestrogens.) Panax Ginseng contains phytoestrogens and has been used for menopausal symptoms .
- Phytoestrogen food sources
- Phytoestrogen content in food
- Phytoestrogens at e.hormone, a website of the Tulane/Xavier Center for Bioenvironmental Research
- Yildiz F (2005). Phytoestrogens in Functional Foods. Taylor & Francis Ltd. pp. 3–5, 210–211. ISBN 978-1-57444-508-4.
- Theresa L. Crenshaw and James P. Goldberg: Sexual Pharmacology.
- Hughes CL (Jun 1988). "Phytochemical mimicry of reproductive hormones and modulation of herbivore fertility by phytoestrogens". Environmental Health Perspectives 78: 171–4. doi:10.1289/ehp.8878171. PMC 1474615. PMID 3203635.
- Bentley GR, Mascie-Taylor CG (2000). Infertility in the modern world: present and future prospects. Cambridge, UK: Cambridge University Press. pp. 99–100. ISBN 0-521-64387-2.
- Varner JE, Bonner J (1966). Plant Biochemistry. Academic Press. ISBN 978-0-12-114856-0.
- Bennetts HW, Underwood EJ, Shier FL (1946). "A specific breeding problem of sheep on subterranean clover pastures in Western Australia". Australian Veterinary Journal 22: 2–12. doi:10.1111/j.1751-0813.1946.tb15473.x. PMID 21028682.
- Cunningham IJ, Hogan KG (1954). "Oestrogens in New Zealand pasture plants.". N. Z. Vet. J. 2 (4): 128–134. doi:10.1080/00480169.1954.33166.
- Johnston I (2003). Phytochem Functional Foods. CRC Press Inc. pp. 66–68. ISBN 978-0-8493-1754-5.
- Adlercreutz H (Jun 2002). "Phyto-oestrogens and cancer". The Lancet. Oncology 3 (6): 364–73. doi:10.1016/S1470-2045(02)00777-5. PMID 12107024.
- Zhao E, Mu Q (Mar 2011). "Phytoestrogen biological actions on Mammalian reproductive system and cancer growth". Scientia Pharmaceutica 79 (1): 1–20. doi:10.3797/scipharm.1007-15. PMC 3097497. PMID 21617769.
- Committee on Toxicity Group on Phytoestrogens. "Chemistry and Analysis of Phytoestrogens". Draft Report. United Kingdom Food Standards Agency. Retrieved 2011-11-11.
- Bennett GA, Shotwell OI (1979). "Zearalenone in cereal grains.". J. Amer. Oil. Chemists Soc. 56: 812–819. doi:10.1007/bf02909525.
- Kuiper-Goodman T, Scott PM, Watanabe H (1987). "Risk assessment of the mycotoxin zearalenone". Regul. Toxicol. Pharmacol. 7 (3): 253–306. doi:10.1016/0273-2300(87)90037-7. PMID 2961013.
- Zinedine A, Soriano JM, Moltó JC, Mañes J (2007). "Review on the toxicity, occurrence, metabolism, detoxification, regulations and intake of zearalenone: an oestrogenic mycotoxin". Food Chem. Toxicol. 45 (1): 1–18. doi:10.1016/j.fct.2006.07.030. PMID 17045381.
- Gallo A, Giuberti G, Frisvad JC, Bertuzzi T, Nielsen KF (2015). "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. doi:10.3390/toxins7083057. PMID 26274974.
- Naz RK (1999). Endocrine Disruptors: Effects on Male and Female Reproductive Systems. CRC Press Inc. p. 90. ISBN 978-0-8493-3164-0.
- Turner JV, Agatonovic-Kustrin S, Glass BD (Aug 2007). "Molecular aspects of phytoestrogen selective binding at estrogen receptors". Journal of Pharmaceutical Sciences 96 (8): 1879–85. doi:10.1002/jps.20987. PMID 17518366.
- Dang ZC, Lowik C (Jul 2005). "Dose-dependent effects of phytoestrogens on bone". Trends in Endocrinology and Metabolism 16 (5): 207–13. doi:10.1016/j.tem.2005.05.001. PMID 15922618.
- Dang ZC (May 2009). "Dose-dependent effects of soy phyto-oestrogen genistein on adipocytes: mechanisms of action". Obesity Reviews 10 (3): 342–9. doi:10.1111/j.1467-789X.2008.00554.x. PMID 19207876.
- Dang ZC, Audinot V, Papapoulos SE, Boutin JA, Löwik CW (Jan 2003). "Peroxisome proliferator-activated receptor gamma (PPARgamma ) as a molecular target for the soy phytoestrogen genistein". The Journal of Biological Chemistry 278 (2): 962–7. doi:10.1074/jbc.M209483200. PMID 12421816.
- Dang Z, Löwik CW (May 2004). "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. doi:10.1359/jbmr.040120. PMID 15068509.
- Leegood RC, Lea P (1998). Plant Biochemistry and Molecular Biology. John Wiley & Sons. p. 211. ISBN 978-0-471-97683-7.
- Amadasi A, Mozzarelli A, Meda C, Maggi A, Cozzini P (2009). "Identification of xenoestrogens in food additives by an integrated in silico and in vitro approach". Chem. Res. Toxicol. 22 (1): 52–63. doi:10.1021/tx800048m. PMC 2758355. PMID 19063592.
- Korach KS (1998). Reproductive and Developmental Toxicology. Marcel Dekker Ltd. pp. 278–279. ISBN 978-0-8247-9857-4.
- Leopold AS, Erwin M, Oh J, Browning B (Jan 1976). "Phytoestrogens: adverse effects on reproduction in California quail". Science 191 (4222): 98–100. doi:10.1126/science.1246602. PMID 1246602.
- 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". Reproduction, Fertility, and Development 12 (3-4): 191–9. doi:10.1071/RD00041. PMID 11302429.
- 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.
- Fermented soy products have lower phytoestrogen content. Phytoestrogens and Menopause 
- van Elswijk DA, Schobel UP, Lansky EP, Irth H, van der Greef J (Jan 2004). "Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry". Phytochemistry 65 (2): 233–41. doi:10.1016/j.phytochem.2003.07.001. PMID 14732284.
- Chadwick LR, Nikolic D, Burdette JE, Overk CR, Bolton JL, van Breemen RB, Fröhlich R, Fong HH, Farnsworth NR, Pauli GF (Dec 2004). "Estrogens and congeners from spent hops (Humulus lupulus)". Journal of Natural Products 67 (12): 2024–32. doi:10.1021/np049783i. PMID 15620245.
- Rosenblum ER, Stauber RE, Van Thiel DH, Campbell IM, Gavaler JS (Dec 1993). "Assessment of the estrogenic activity of phytoestrogens isolated from bourbon and beer". Alcoholism: Clinical and Experimental Research 17 (6): 1207–9. doi:10.1111/j.1530-0277.1993.tb05230.x. PMID 8116832.
- Albert-Puleo M (Dec 1980). "Fennel and anise as estrogenic agents". Journal of Ethnopharmacology 2 (4): 337–44. doi:10.1016/S0378-8741(80)81015-4. PMID 6999244.
- de Kleijn MJ, van der Schouw YT, Wilson PW, Adlercreutz H, Mazur W, Grobbee DE, Jacques PF (Jun 2001). "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. PMID 11385074.
- Hamilton-Reeves JM, Vazquez G, Duval SJ, Phipps WR, Kurzer MS, Messina MJ (Aug 2010). "Clinical studies show no effects of soy protein or isoflavones on reproductive hormones in men: results of a meta-analysis". Fertility and Sterility 94 (3): 997–1007. doi:10.1016/j.fertnstert.2009.04.038. PMID 19524224.
- Dabrowski WM (2004). Toxins in Food. CRC Press Inc. p. 95. ISBN 978-0-8493-1904-4.
- Mitchell JH, Cawood E, Kinniburgh D, Provan A, Collins AR, Irvine DS (Jun 2001). "Effect of a phytoestrogen food supplement on reproductive health in normal males". Clinical Science 100 (6): 613–8. doi:10.1042/CS20000212. PMID 11352776.
- Patisaul, HB; Jefferson, W (October 2010). "The pros and cons of phytoestrogens.". Front Neuroendocrinol 31 (4): 400–419. PMC 3074428. PMID 20347861.
- Cornell veterinary medicine website on phytoestrogens and cancer
- Cancer Care Ontario
- Ingram D, Sanders K, Kolybaba M, Lopez D (Oct 1997). "Case-control study of phyto-oestrogens and breast cancer". Lancet 350 (9083): 990–4. doi:10.1016/S0140-6736(97)01339-1. PMID 9329514.
- de Lemos ML (Sep 2001). "Effects of soy phytoestrogens genistein and daidzein on breast cancer growth". The Annals of Pharmacotherapy 35 (9): 1118–21. doi:10.1345/aph.10257. PMID 11573864.
- Messina M, McCaskill-Stevens W, Lampe JW (Sep 2006). "Addressing the soy and breast cancer relationship: review, commentary, and workshop proceedings". Journal of the National Cancer Institute 98 (18): 1275–84. doi:10.1093/jnci/djj356. PMID 16985246.
- Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W (Dec 2009). "Soy food intake and breast cancer survival". JAMA 302 (22): 2437–43. doi:10.1001/jama.2009.1783. PMC 2874068. PMID 19996398.
- Lethaby AE, Brown J, Marjoribanks J, Kronenberg F, Roberts H, Eden J (2007). "Phytoestrogens for vasomotor menopausal symptoms". The Cochrane Database of Systematic Reviews (4): CD001395. doi:10.1002/14651858.CD001395.pub3. PMID 17943751.
- Estrogen and Hormonal Treatments - The Ageing Skin
- Chen AC, Donovan SM (Jun 2004). "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. PMID 15173388.
- Miniello VL, Moro GE, Tarantino M, Natile M, Granieri L, Armenio L (Sep 2003). "Soy-based formulas and phyto-oestrogens: a safety profile". Acta Paediatrica 91 (441): 93–100. doi:10.1111/j.1651-2227.2003.tb00655.x. PMID 14599051.
- Chen A, Rogan WJ (2004). "Isoflavones in soy infant formula: a review of evidence for endocrine and other activity in infants". Annual Review of Nutrition 24 (1): 33–54. doi:10.1146/annurev.nutr.24.101603.064950. PMID 15189112.
- Strom BL, Schinnar R, Ziegler EE, Barnhart KT, Sammel MD, Macones GA, Stallings VA, Drulis JM, Nelson SE, Hanson SA (Aug 2001). "Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood". JAMA 286 (7): 807–14. doi:10.1001/jama.286.7.807. PMID 11497534.
- Giampietro PG, Bruno G, Furcolo G, Casati A, Brunetti E, Spadoni GL, Galli E (Feb 2004). "Soy protein formulas in children: no hormonal effects in long-term feeding". Journal of Pediatric Endocrinology & Metabolism 17 (2): 191–6. doi:10.1515/JPEM.2004.17.2.191. PMID 15055353.
- Merritt RJ, Jenks BH (May 2004). "Safety of soy-based infant formulas containing isoflavones: the clinical evidence". The Journal of Nutrition 134 (5): 1220S–1224S. PMID 15113975.
- Haffejee IE (Feb 1990). "Cow's milk-based formula, human milk, and soya feeds in acute infantile diarrhea: a therapeutic trial". Journal of Pediatric Gastroenterology and Nutrition 10 (2): 193–8. doi:10.1097/00005176-199002000-00009. PMID 2406406.
- Bhatia J, Greer F (May 2008). "Use of soy protein-based formulas in infant feeding". Pediatrics 121 (5): 1062–8. doi:10.1542/peds.2008-0564. PMID 18450914.
- Muller-Schwarze D (2006). Chemical Ecology of Vertebrates. Cambridge University Press. p. 287. ISBN 978-0-521-36377-8.
- Lee YS, Park JS, Cho SD, Son JK, Cherdshewasart W, Kang KS (Dec 2002). "Requirement of metabolic activation for estrogenic activity of Pueraria mirifica". Journal of Veterinary Science 3 (4): 273–7. PMID 12819377.
- Delmonte P, Rader JI (2006). "Analysis of isoflavones in foods and dietary supplements". Journal of AOAC International 89 (4): 1138–46. PMID 16915857.
- Brown D, Walton N (1999). Chemicals from Plants: Perspectives on Plant Secondary Products. World Scientific Publishing. pp. 21, 141. ISBN 978-981-02-2773-9.
- Geller SE, Shulman LP, van Breemen RB, Banuvar S, Zhou Y, Epstein G, Hedayat S, Nikolic D, Krause EC, Piersen CE, Bolton JL, Pauli GF, Farnsworth NR (2009). "Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial". Menopause 16 (6): 1156–66. doi:10.1097/gme.0b013e3181ace49b. PMC 2783540. PMID 19609225.
- Kennelly EJ, Baggett S, Nuntanakorn P, Ososki AL, Mori SA, Duke J, Coleton M, Kronenberg F (Jul 2002). "Analysis of thirteen populations of black cohosh for formononetin". Phytomedicine 9 (5): 461–7. doi:10.1078/09447110260571733. PMID 12222669.