Phytoestrogens are plant-derived xenoestrogens functioning as the primary female sex hormone (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.
Their name comes from the Greek phyto = plant and estrogen, the hormone which gives fertility to the female mammals. The word "estrus" -Greek οίστρος- means sexual desire and "gene" -Greek γόνο- is "to generate". It has been proposed that plants use the phytoestrogens as part of their natural defence against the overpopulation of the herbivore animals by controlling the 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, though there is no evidence to support their use in alleviating the symptoms of menopause.
Phytoestrogens cannot be considered as nutrients, given that the lack of these in 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, tempeh, linseed (flax), sesame seeds, wheatberries, fenugreek, 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, beer, fennel and anise.
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 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, as 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 may 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 also 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.
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