phytoestrogen phytoestrogen a phytoestrogen is a plant-derived xenoestrogen (see estrogen) not generated within the endocrine system, but consumed by eating plants or manufactured foods. also called a "dietary estrogen", it is a diverse group of naturally occurring nonsteroidal plant compounds that, because of its structural similarity with estradiol (17-β-estradiol), have the ability to cause estrogenic or antiestrogenic effects. 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. 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. the similarities, at molecular level, of an estrogen and a phytoestrogen allow them to mildly mimic and sometimes act as an antagonist 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. 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. 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. affinities of estrogen receptor ligands for the erα and erβ ligandother namesrelative binding affinities (rba, %)aabsolute binding affinities (ki, nm)aaction erαerβerαerβ estradiole2; 17β-estradiol1001000.115 (0.04–0.24)0.15 (0.10–2.08)estrogen estronee1; 17-ketoestradiol16.39 (0.7–60)6.5 (1.36–52)0.445 (0.3–1.01)1.75 (0.35–9.24)estrogen estriole3; 16α-oh-17β-e212.65 (4.03–56)26 (14.0–44.6)0.45 (0.35–1.4)0.7 (0.63–0.7)estrogen estetrole4; 15α,16α-di-oh-17β-e24.03.04.919estrogen alfatradiol17α-estradiol20.5 (7–80.1)8.195 (2–42)0.2–0.520.43–1.2metabolite 16-epiestriol16β-hydroxy-17β-estradiol7.795 (4.94–63)50 ? ?metabolite 17-epiestriol16α-hydroxy-17α-estradiol55.45 (29–103)79–80 ? ?metabolite 16,17-epiestriol16β-hydroxy-17α-estradiol1.013 ? ?metabolite 2-hydroxyestradiol2-oh-e222 (7–81)11–352.51.3metabolite 2-methoxyestradiol2-meo-e20.0027–2.01.0 ? ?metabolite 4-hydroxyestradiol4-oh-e213 (8–70)7–561.01.9metabolite 4-methoxyestradiol4-meo-e22.01.0 ? ?metabolite 2-hydroxyestrone2-oh-e12.0–4.00.2–0.4 ? ?metabolite 2-methoxyestrone2-meo-e1<0.001–<1<1 ? ?metabolite 4-hydroxyestrone4-oh-e11.0–2.01.0 ? ?metabolite 4-methoxyestrone4-meo-e1<1<1 ? ?metabolite 16α-hydroxyestrone16α-oh-e1; 17-ketoestriol2.0–6.535 ? ?metabolite 2-hydroxyestriol2-oh-e32.01.0 ? ?metabolite 4-methoxyestriol4-meo-e31.01.0 ? ?metabolite estradiol sulfatee2s; estradiol 3-sulfate<1<1 ? ?metabolite estradiol disulfateestradiol 3,17β-disulfate0.0004 ? ? ?metabolite estradiol 3-glucuronidee2-3g0.0079 ? ? ?metabolite estradiol 17β-glucuronidee2-17g0.0015 ? ? ?metabolite estradiol 3-gluc. 17β-sulfatee2-3g-17s0.0001 ? ? ?metabolite estrone sulfatee1s; estrone 3-sulfate<1<1>10>10metabolite estradiol benzoateeb; estradiol 3-benzoate10 ? ? ?estrogen estradiol 17β-benzoatee2-17b11.332.6 ? ?estrogen estrone methyl etherestrone 3-methyl ether0.145 ? ? ?estrogen ent-estradiol1-estradiol1.31–12.349.44–80.07 ? ?estrogen equilin7-dehydroestrone13 (4.0–28.9)13.0–490.790.36estrogen equilenin6,8-didehydroestrone2.0–157.0–200.640.62estrogen 17β-dihydroequilin7-dehydro-17β-estradiol7.9–1137.9–1080.090.17estrogen 17α-dihydroequilin7-dehydro-17α-estradiol18.6 (18–41)14–320.240.57estrogen 17β-dihydroequilenin6,8-didehydro-17β-estradiol35–6890–1000.150.20estrogen 17α-dihydroequilenin6,8-didehydro-17α-estradiol20490.500.37estrogen δ8-estradiol8,9-dehydro-17β-estradiol68720.150.25estrogen δ8-estrone8,9-dehydroestrone19320.520.57estrogen ethinylestradiolee; 17α-ethynyl-17β-e2120.9 (68.8–480)44.4 (2.0–144)0.02–0.050.29–0.81estrogen mestranolee 3-methyl ether ?2.5 ? ?estrogen moxestrolru-2858; 11β-methoxy-ee35–435–200.52.6estrogen methylestradiol17α-methyl-17β-estradiol7044 ? ?estrogen diethylstilbestroldes; stilbestrol129.5 (89.1–468)219.63 (61.2–295)0.040.05estrogen hexestroldihydrodiethylstilbestrol153.6 (31–302)60–2340.060.06estrogen dienestroldehydrostilbestrol37 (20.4–223)56–4040.050.03estrogen benzestrol (b2)–114 ? ? ?estrogen chlorotrianisenetace1.74 ?15.30 ?estrogen triphenylethylenetpe0.074 ? ? ?estrogen triphenylbromoethylenetpbe2.69 ? ? ?estrogen tamoxifenici-46,4743 (0.1–47)3.33 (0.28–6)3.4–9.692.5serm afimoxifene4-hydroxytamoxifen; 4-oht100.1 (1.7–257)10 (0.98–339)2.3 (0.1–3.61)0.04–4.8serm toremifene4-chlorotamoxifen; 4-ct ? ?7.14–20.315.4serm clomifenemrl-4125 (19.2–37.2)120.91.2serm cyclofenilf-6066; sexovid151–152243 ? ?serm nafoxidineu-11,000a30.9–44160.30.8serm raloxifene–41.2 (7.8–69)5.34 (0.54–16)0.188–0.5220.2serm arzoxifenely-353,381 ? ?0.179 ?serm lasofoxifenecp-336,15610.2–16619.00.229 ?serm ormeloxifenecentchroman ? ?0.313 ?serm levormeloxifene6720-cdri; nnc-460,0201.551.88 ? ?serm ospemifenedeaminohydroxytoremifene0.82–2.630.59–1.22 ? ?serm bazedoxifene– ? ?0.053 ?serm etacstilgw-56384.3011.5 ? ?serm ici-164,384–63.5 (3.70–97.7)1660.20.08antiestrogen fulvestrantici-182,78043.5 (9.4–325)21.65 (2.05–40.5)0.421.3antiestrogen propylpyrazoletriolppt49 (10.0–89.1)0.120.4092.8erα agonist 16α-le216α-lactone-17β-estradiol14.6–570.0890.27131erα agonist 16α-iodo-e216α-iodo-17β-estradiol30.22.30 ? ?erα agonist methylpiperidinopyrazolempp110.05 ? ?erα antagonist diarylpropionitriledpn0.12–0.256.6–1832.41.7erβ agonist 8β-ve28β-vinyl-17β-estradiol0.3522.0–8312.90.50erβ agonist prinaberelerb-041; way-202,0410.2767–72 ? ?erβ agonist erb-196way-202,196 ?180 ? ?erβ agonist erteberelserba-1; ly-500,307 ? ?2.680.19erβ agonist serba-2– ? ?14.51.54erβ agonist coumestrol–9.225 (0.0117–94)64.125 (0.41–185)0.14–80.00.07–27.0xenoestrogen genistein–0.445 (0.0012–16)33.42 (0.86–87)2.6–1260.3–12.8xenoestrogen equol–0.2–0.2870.85 (0.10–2.85) ? ?xenoestrogen daidzein–0.07 (0.0018–9.3)0.7865 (0.04–17.1)2.085.3xenoestrogen biochanin a–0.04 (0.022–0.15)0.6225 (0.010–1.2)1748.9xenoestrogen kaempferol–0.07 (0.029–0.10)2.2 (0.002–3.00) ? ?xenoestrogen naringenin–0.0054 (<0.001–0.01)0.15 (0.11–0.33) ? ?xenoestrogen 8-prenylnaringenin8-pn4.4 ? ? ?xenoestrogen quercetin–<0.001–0.010.002–0.040 ? ?xenoestrogen ipriflavone–<0.01<0.01 ? ?xenoestrogen miroestrol–0.39 ? ? ?xenoestrogen deoxymiroestrol–2.0 ? ? ?xenoestrogen β-sitosterol–<0.001–0.0875<0.001–0.016 ? ?xenoestrogen resveratrol–<0.001–0.0032 ? ? ?xenoestrogen α-zearalenol–48 (13–52.5) ? ? ?xenoestrogen β-zearalenol–0.6 (0.032–13) ? ? ?xenoestrogen zeranolα-zearalanol48–111 ? ? ?xenoestrogen taleranolβ-zearalanol16 (13–17.8)140.80.9xenoestrogen zearalenonezen7.68 (2.04–28)9.45 (2.43–31.5) ? ?xenoestrogen zearalanonezan0.51 ? ? ?xenoestrogen bisphenol abpa0.0315 (0.008–1.0)0.135 (0.002–4.23)19535xenoestrogen endosulfaneds<0.001–<0.01<0.01 ? ?xenoestrogen keponechlordecone0.0069–0.2 ? ? ?xenoestrogen o,p'-ddt–0.0073–0.4 ? ? ?xenoestrogen p,p'-ddt–0.03 ? ? ?xenoestrogen methoxychlorp,p'-dimethoxy-ddt0.01 (<0.001–0.02)0.01–0.13 ? ?xenoestrogen hptehydroxychlor; p,p'-oh-ddt1.2–1.7 ? ? ?xenoestrogen testosteronet; 4-androstenolone<0.0001–<0.01<0.002–0.040>5000>5000androgen dihydrotestosteronedht; 5α-androstanolone0.01 (<0.001–0.05)0.0059–0.17221–>500073–1688androgen nandrolone19-nortestosterone; 19-nt0.010.2376553androgen dehydroepiandrosteronedhea; prasterone0.038 (<0.001–0.04)0.019–0.07245–1053163–515androgen 5-androstenediola5; androstenediol6173.60.9androgen 4-androstenediol–0.50.62319androgen 4-androstenedionea4; androstenedione<0.01<0.01>10000>10000androgen 3α-androstanediol3α-adiol0.070.326048androgen 3β-androstanediol3β-adiol3762androgen androstanedione5α-androstanedione<0.01<0.01>10000>10000androgen etiocholanedione5β-androstanedione<0.01<0.01>10000>10000androgen methyltestosterone17α-methyltestosterone<0.0001 ? ? ?androgen ethinyl-3α-androstanediol17α-ethynyl-3α-adiol4.0<0.07 ? ?estrogen ethinyl-3β-androstanediol17α-ethynyl-3β-adiol505.6 ? ?estrogen progesteronep4; 4-pregnenedione<0.001–0.6<0.001–0.010 ? ?progestogen norethisteronenet; 17α-ethynyl-19-nt0.085 (0.0015–<0.1)0.1 (0.01–0.3)1521084progestogen norethynodrel5(10)-norethisterone0.5 (0.3–0.7)<0.1–0.221453progestogen tibolone7α-methylnorethynodrel0.5 (0.45–2.0)0.2–0.076 ? ?progestogen δ4-tibolone7α-methylnorethisterone0.069–<0.10.027–<0.1 ? ?progestogen 3α-hydroxytibolone–2.5 (1.06–5.0)0.6–0.8 ? ?progestogen 3β-hydroxytibolone–1.6 (0.75–1.9)0.070–0.1 ? ?progestogen footnotes: a = (1) binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. the full sets of values within the ranges can be found in the wiki code. (2) binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human erα and erβ proteins (except the erβ values from kuiper et al. (1997), which are rat erβ). sources: see template page. ecology 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. avian studies 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 of aiding reproduction of endangered species. 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. 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 tempeh linseed (flax) sesame seeds wheat berries fenugreek (contains diosgenin, but also used to make testofen, a compound taken by men to increase testosterone). oats barley beans lentils yams rice alfalfa mung beans apples carrots pomegranates wheat germ rice bran lupin kudzu coffee licorice root mint ginseng hops, bourbon whiskey beer, fennel anise. red clover (sometimes a constituent of green manure). spinach food content of phytoestrogens is very variable and accurate estimates of intake therefore difficult and depends on the databases used. 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. the high intake in the uk is partly explained by the use of soy in the chorleywood bread process. 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 humans, phytoestrogens are readily 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. as of 2020, there is sufficient clinical evidence to determine that phytoestrogens have effects in humans. females 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. 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. it 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) stated that there was no conclusive evidence to suggest any benefit to their use, although genistein effects should be further investigated. males it is unclear if phytoestrogens have any effect on male sexuality, with conflicting results about the potential effects of isoflavones originating from soy. some studies showed that isoflavone supplementation had a positive effect on sperm concentration, count, or motility, and increased ejaculate volume. 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. furthermore, while there is some evidence that phytoestrogens may affect male fertility, more recent reviews of available studies found no link, and instead suggests that healthier diets such as the mediterranean diet might have a positive effect on male fertility. neither isoflavones nor soy have been shown to affect male reproductive hormones in healthy individuals. 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. 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. 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.