Phytoestrogen

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.<ref name="lpi">Template:Cite web</ref> 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 both estrogenic or antiestrogenic effects.<ref name=lpi/><ref name= "Yil">Template:Cite book</ref>

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.<ref name=lpi/><ref name= "Yil"/> Common foods containing phytoestrogens are soybeans and soy protein concentrate, miso, tempeh, and tofu.<ref name=lpi/> Some soy-based infant formulas manufactured with soy protein contain isoflavones.<ref name=lpi/>

Its name comes from the Greek phyto ("plant") and estrogen, the hormone which gives fertility to female mammals.<ref name=lpi/> 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.<ref name="pmid3203635">Template:Cite journal</ref><ref name="isbn0-521-64387-2">Template:Cite book</ref>

The similarities, at the molecular level, of an estrogen and a phytoestrogen allow them to mildly mimic and sometimes act as an antagonist of estrogen.<ref name=lpi/> Phytoestrogens were first observed in 1926,<ref name= "Yil"/><ref>Template:Cite book</ref> 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.<ref name= "Yil"/><ref name="pmid21028682">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name= "Jon">Template:Cite book</ref>

File:Phytoestrogens2.png

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.<ref name=lpi/> 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.<ref name= "Yil"/> Mycoestrogens have similar structures and effects, but are not components of plants; these are mold metabolites of Fusarium, especially common on cereal grains,<ref>Template:Cite journalTemplate:Dead linkTemplate:Cbignore</ref><ref name="pmid2961013">Template:Cite journal</ref><ref name="pmid17045381">Template:Cite journal</ref> but also occurring elsewhere, e.g. on various forages.<ref name="pmid26274974">Template:Cite journal</ref> Although mycoestrogens are rarely taken into account in discussions about phytoestrogens, these are the compounds that initially generated the interest on the topic.<ref>Template:Cite book</ref>

Mechanism of action

Phytoestrogens exert their effects primarily through binding to estrogen receptors (ER).<ref name="pmid17518366">Template:Cite journal</ref> 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.<ref name="pmid17518366"/>

The key structural elements that enable phytoestrogens to bind with high affinity to estrogen receptors and display estradiol-like effects are:<ref name= "Yil"/>

• 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).<ref name= "Jon"/>

Emerging evidence shows that some phytoestrogens bind to and transactivate peroxisome proliferator-activated receptors (PPARs).<ref name="pmid15922618">Template:Cite journal</ref><ref name="pmid19207876">Template:Cite journal</ref> In vitro studies show an activation of PPARs at concentrations above 1 μM, which is higher than the activation level of ERs.<ref name="pmid12421816">Template:Cite journal</ref><ref name="pmid15068509">Template:Cite journal</ref> 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.<ref name="pmid15922618"/><ref name="pmid19207876"/><ref name="pmid12421816"/>

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.<ref>Template:Cite book</ref> Soybeans naturally produce isoflavones, and are therefore a dietary source for isoflavones.<ref name=lpi/>

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<ref name="pmid19063592">Template:Cite journal</ref> 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.<ref name= "Repro">Template:Cite book</ref>

Avian studies

The consumption of plants with unusual content of phytoestrogens, under drought conditions, has been shown to decrease fertility in quail.<ref name="pmid1246602">Template:Cite journal</ref> 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.<ref name="pmid11302429">Template:Cite journal</ref>

Food sources

Soy-based food products, such as soybeans, miso, tempeh, tofu, meatless soy burgers, and soy protein infant foods contain the highest amounts of isoflavones.<ref name=lpi/>

According to a 2006 study of nine common phytoestrogens in Canadian foods, 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.<ref name="thompson">Template:Cite journal</ref> 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.<ref name=thompson/> 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.<ref name=thompson/>

Food content of phytoestrogens is highly variable, and accurate estimates of intake are therefore difficult and depends on the databases used.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref name= "Repro"/>

As of 2020, there is insufficient clinical evidence to determine that phytoestrogens have effects in humans.<ref>Template:Cite journal</ref>

Females

It is unclear if phytoestrogens have any effect on the cause or prevention of cancer in women.<ref name=lpi/><ref name="bilal">Template:Cite journal</ref> Some epidemiological studies have suggested a protective effect against breast cancer.<ref name=lpi/><ref name=bilal/><ref name="pmid9329514">Template:Cite journal</ref> 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.<ref name=lpi/><ref name="pmid19996398">Template:Cite journal</ref><ref name="fritz">Template:Cite journal</ref> It remains unclear if phytoestrogens can minimize some of the deleterious effects of low estrogen levels (hypoestrogenism) resulting from oophorectomy, menopause, or other causes.<ref name=bilal/> 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.<ref name="Lethaby_2013">Template:Cite journal</ref>

Males

It is unclear if phytoestrogens have any effect on male physiology, with conflicting results about the potential effects of isoflavones originating from soy.<ref name=lpi/> Some studies showed that isoflavone supplementation had a positive effect on sperm concentration, count, or motility, and increased ejaculate volume.<ref name= "tox">Template:Cite book</ref><ref name="pmid11352776">Template:Cite journal</ref> 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.<ref name="pmid20347861">Template:Cite journal</ref> Furthermore, while there is some evidence that phytoestrogens may affect male fertility Template:Citation needed, more recent reviews of available studies found no link,<ref name=":0">Template:Cite journal</ref><ref name=":1">Template:Cite journal</ref> and instead suggests that healthier diets such as the Mediterranean diet might have a positive effect on male fertility.<ref name=":1" /> Neither isoflavones nor soy have been shown to affect male reproductive hormones in healthy individuals.<ref name=":0" /><ref name="pmid33383165">Template:Cite journal</ref>

Infant formula

Infant formulas made with soy protein phytoestrogens are considered safe alternatives to formulas containing dairy ingredients, which may be excluded for infants with galactosemia and hereditary lactose intolerance.<ref name=lpi/>

Some reviews express the opinion that more research is needed to answer the question of what effect phytoestrogens may have on infants,<ref name="pmid14599051">Template:Cite journal</ref><ref name="pmid15189112">Template:Cite journal</ref> 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.<ref name=lpi/><ref name="pmid11497534">Template:Cite journal</ref><ref name="pmid15055353">Template:Cite journal</ref><ref name= "Nutri">Template:Cite journal</ref> 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."<ref name="pmid18450914">Template:Cite journal</ref>

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.<ref>Template:Cite book</ref> Plants used that have been shown to contain phytoestrogens include Pueraria mirifica<ref name="pmid12819377">Template:Cite journal</ref> and its close relative kudzu.<ref name="pmid16915857">Template:Cite journal</ref>

See also

• Ethnopharmacology
• Mycoestrogens
• Phytoandrogens
• Plant hormone