Phytoestrogen

A phytoestrogen is a plant-derived xenoestrogen (see estrogen) not generated within the endocrine system, but consumed by eating phytoestrogenic plants. 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 and/or antiestrogenic effects.^[1] 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.^[1]

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 defence against the overpopulation of herbivore animals by controlling female fertility.^[2][3]

The similarities, at molecular level, of an estrogen and a phytoestrogen allow them to mildly mimic and sometimes act as an antagonist of estrogen.^[1] Phytoestrogens were first observed in 1926,^[1][4] 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.^[1][5][6][7]

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.^[1] Mycoestrogens have similar structures and effects, but are not components of plants; these are mold metabolites of Fusarium, especially common on cereal grains,^[8][9][10] but also occurring elsewhere, e.g. on various forages.^[11] Although mycoestrogens are rarely taken into account in discussions about phytoestrogens, these are the compounds that initially generated the interest on the topic.^[12]

Mechanism of action

Phytoestrogens exert their effects primarily through binding to estrogen receptors (ER).^[13] 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.^[13]

The key structural elements that enable phytoestrogens to bind with high affinity to estrogen receptors and display estradiol-like effects are:^[1]

• 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).^[7]

Emerging evidence shows that some phytoestrogens bind to and transactivate peroxisome proliferator-activated receptors (PPARs).^[14][15] In vitro studies show an activation of PPARs at concentrations above 1 μM, which is higher than the activation level of ERs.^[16][17] 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.^[14][15][16]

Ecology

These compounds in plants are an important part of their defense system, mainly against fungi.^[18]

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^[19] 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.^[20]

Avian studies

The consumption of plants with unusual content of phytoestrogens, under drought conditions, has been shown to decrease fertility in quail.^[21] 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.^[22]

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.^[23] 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:

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.^[29]

Effects on humans

In human beings, 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.^[20]

A wide range of beneficial effects of phytoestrogens on the cardiovascular, metabolic, central nervous systems as well as reduction of risk of cancer and post menopausal symptoms have been claimed. However, there is also concern that phytoestrogens may act as endocrine disruptors that adversely affect health. Based on currently available evidence, it is not clear whether the potential health benefits of phytoestrogens outweigh their risks.^[30]

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.^[49] Plants used that have been shown to contain phytoestrogens include Pueraria mirifica,^[50] and its close relative, kudzu,^[51] Angelica,^[52] fennel,^[27] 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^[53] (black cohosh is also used for menopausal symptoms, but does not contain phytoestrogens.^[54])

See also

References