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 proposed that plants use phytoestrogens as part of their natural defence against the overpopulation of herbivore animals by controlling male 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, it was noticed for the first time that red clover (a phytoestrogens-rich plant) pastures had effects on the fecundity of grazing sheep. 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,
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, 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.
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.
There are conflicting studies, and it is unclear if phytoestrogens have any effect on the cause or prevention of cancer in females. Epidemiological studies showed a protective effect against breast cancer. 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 since 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. 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. Recent epidemiologic studies suggest that consumption of soy estrogens is safe for patients with breast cancer and that it may in fact decrease mortality and recurrence rates. 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. It has been 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. 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. 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, Fatih (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 (June 1988). "Phytochemical mimicry of reproductive hormones and modulation of herbivore fertility by phytoestrogens". Environ. Health Perspect. 78: 171–4. doi:10.1289/ehp.8878171. PMC 1474615. PMID 3203635.
- Mascie-Taylor, C. G. N.; Bentley, Gillian R. (2000). Infertility in the modern world: present and future prospects. Cambridge, UK: Cambridge University Press. pp. 99–100. ISBN 0-521-64387-2.
- Varner, J E, Bonner, J (1966). Plant Biochemistry. Academic Press. ISBN 978-0-12-114856-0.
- JOHNSTON, I (2003). Phytochem Functional Foods. CRC Press Inc. pp. 66–68. ISBN 978-0-8493-1754-5.
- Adlercreutz H (June 2002). "Phyto-oestrogens and cancer.". Lancet Oncol. 3 (6): 364–73. doi:10.1016/S1470-2045(02)00777-5. PMID 12107024.
- Zhao E, Mu Q (March 2011). "Phytoestrogen biological actions on Mammalian reproductive system and cancer growth". Sci Pharm 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.
- Naz, Rajesh K. (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 (August 2007). "Molecular aspects of phytoestrogen selective binding at estrogen receptors". J Pharm Sci 96 (8): 1879–1885. doi:10.1002/jps.20987. PMID 17518366.
- Dang ZC, Lowik C (July 2005). "Dose-dependent effects of phytoestrogens on bone". Trends Endocrinol. Metab. 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". Obes Rev 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 (January 2003). "Peroxisome proliferator-activated receptor gamma (PPARgamma ) as a molecular target for the soy phytoestrogen genistein". J. Biol. Chem. 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". J. Bone Miner. Res. 19 (5): 853–61. doi:10.1359/jbmr.040120. PMID 15068509.
- Richard C. Leegood, Per Lea (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. Identification of Xenoestrogens in Food Additives by an Integrated in Silico and in Vitro Approach. Chemical Research in Toxicology 2008;22:52–63
- Korach, Kenneth S. (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 (January 1976). "Phytoestrogens: adverse effects on reproduction in California quail". Science 191 (4222): 98–100. doi:10.1126/science.1246602. PMID 1246602. Retrieved 2008-12-20.
- 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): 191–199. 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 (January 2004). "Rapid dereplication of estrogenic compounds in pomegranate (Punica granatum) using on-line biochemical detection coupled to mass spectrometry". Phytochemistry 65 (2): 233–241. doi:10.1016/j.phytochem.2003.07.001. PMID 14732284. Retrieved 2008-12-19.
- Chadwick LR, Nikolic D, Burdette JE, Overk CR, Bolton JL, van Breemen RB, Fröhlich R, Fong HH, Farnsworth NR, Pauli GF (December 2004). "Estrogens and congeners from spent hops (Humulus lupulus)". Journal of Natural Products 67 (12): 2024–2032. doi:10.1021/np049783i. PMID 15620245.
- 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): 1207–1209. doi:10.1111/j.1530-0277.1993.tb05230.x. PMID 8116832. Retrieved 2008-12-19.
- Albert-Puleo M (December 1980). "Fennel and anise as estrogenic agents". J Ethnopharmacol 2 (4): 337–344. 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 (June 2001). "Intake of dietary phytoestrogens is low in postmenopausal women in the United States: the Framingham study(1–4)". J. Nutr. 131 (6): 1826–1832. PMID 11385074.
- Hamilton-Reeves JM, Vazquez G, Duval SJ, Phipps WR, Kurzer MS, Messina MJ (2010). "Clinical studies show no effects of soy protein or isoflavones on reproductive hormones in men: results of a meta-analysis". Fertil Steril. 94 (3): 997–1007. doi:10.1016/j.fertnstert.2009.04.038. PMID 19524224.
- Dabrowski, Waldemar M. (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 (June 2001). "Effect of a phytoestrogen food supplement on reproductive health in normal males". Clin. Sci. 100 (6): 613–618. doi:10.1042/CS20000212. PMID 11352776. Retrieved 2008-12-20.
- Cornell veterinary medicine website on phytoestrogens and cancer
- Cancer Care Ontario
- Ingram D, Sanders K, Kolybaba M, Lopez D (October 1997). "Case-control study of phyto-oestrogens and breast cancer". Lancet 350 (9083): 990–994. doi:10.1016/S0140-6736(97)01339-1. PMID 9329514. Retrieved 2008-12-20.
- de Lemos ML (September 2001). "Effects of soy phytoestrogens genistein and daidzein on breast cancer growth". Ann Pharmacother 35 (9): 1118–1121. doi:10.1345/aph.10257. PMID 11573864. Retrieved 2008-12-20.
- Messina M, McCaskill-Stevens W, Lampe JW (September 2006). "Addressing the soy and breast cancer relationship: review, commentary, and workshop proceedings". J. Natl. Cancer Inst. 98 (18): 1275–1284. doi:10.1093/jnci/djj356. PMID 16985246. Retrieved 2008-12-20.
- Shu XO, Zheng Y, Cai H, Gu K, Chen Z, Zheng W, Lu W (December 2009). "Soy food intake and breast cancer survival". JAMA 302 (22): 2437–2443. 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". Cochrane Database Syst Rev (4): CD001395. doi:10.1002/14651858.CD001395.pub3. PMID 17943751.
- Estrogen and Hormonal Treatments - The Ageing Skin
- Chen AC, Donovan SM (June 2004). "Genistein at a concentration present in soy infant formula inhibits Caco-2BBe cell proliferation by causing G2/M cell cycle arrest". J. Nutr. 134 (6): 1303–1308. PMID 15173388.
- Miniello VL, Moro GE, Tarantino M, Natile M, Granieri L, Armenio L (September 2003). "Soy-based formulas and phyto-oestrogens: a safety profile". Acta Paediatr Suppl 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". Annu. Rev. Nutr. 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 (August 2001). "Exposure to soy-based formula in infancy and endocrinological and reproductive outcomes in young adulthood". JAMA 286 (7): 807–814. doi:10.1001/jama.286.7.807. PMID 11497534.
- Giampietro PG, Bruno G, Furcolo G, Casati A, Brunetti E, Spadoni GL, Galli E (February 2004). "Soy protein formulas in children: no hormonal effects in long-term feeding". J. Pediatr. Endocrinol. Metab. 17 (2): 191–196. 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". J. Nutr. 134 (5): 1220S–1224S. PMID 15113975.
- Haffejee IE (February 1990). "Cow's milk-based formula, human milk, and soya feeds in acute infantile diarrhea: a therapeutic trial". J. Pediatr. Gastroenterol. Nutr. 10 (2): 193–198. 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): 1062–1068. doi:10.1542/peds.2008-0564. PMID 18450914. Retrieved 2008-12-20.
- Muller-Schwarze, Dietland (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 (December 2002). "Requirement of metabolic activation for estrogenic activity of Pueraria mirifica". J. Vet. Sci. 3 (4): 273–277. PMID 12819377. Retrieved 2008-12-20.
- Delmonte P, Rader JI (2006). "Analysis of isoflavones in foods and dietary supplements". J AOAC Int 89 (4): 1138–1146. PMID 16915857.
- D.E. Brown, N.J. Walton, (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 et al. (2009). "Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms: a randomized controlled trial". Menopause 16 (6): 1156–1166. 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 (2002). "Analysis of thirteen populations of black cohosh for formononetin". Phytomedicine 9 (5): 461–467. doi:10.1078/09447110260571733. PMID 12222669.