The Secret of Soy,What is Soy Isoflavones?...Function of Natural Genistein?

  seminal trace...soy isoflavones,Genistein 90%98%M.F.C15 H10O5.CAS.NO:446-72-0,Daidzein 98%M.F.C15 H10O4.CAS.NO:486-66-8.soy isoflavone,Glycine max L.extract...

 


 Basic Info of Soy Isoflavones:
 Introduction and Brief Benefits of Soy Isoflavones:
 Actions and Pharmacology:
 Women's health and Isoflavones:
 Suggestions and Administration:
 Soy Isoflavones Research Update:
  Soy Isoflavones Metabolism:
  Soy Isoflavones Estrogenic and Anti-Estrogenic Activities:
  Soy Isoflavones Estrogen Receptor-Independent Activities:
  Soy Isoflavones Prevent Cardiovascular Disease:
  Soy Isoflavones and Hormone-associated Cancers:
  Soy Isoflavones Prevent Osteoporosis:
  Soy Isoflavones Help Prevent Cognitive Decline:
  Soy Isoflavones Treatment Menopausal Symptoms:
  Soy isoflavone glycitein protects against beta amyloid-induced toxicity and oxidative stress in transgenic Caenorhabditis elegans.:
  Pharmacokinetics of isoflavones, daidzein and genistein, after ingestion of soy beverage compared with soy extract capsules in postmenopausal Thai women.:
 What is genistein?
 Genistein mimics human estrogens:
 Actions of the soy phytoestrogen genistein in models of human chronic disease: potential involvement of transforming growth factor Beta
 Estrogenic Effects of Genistein:
 Effect of genistein to control postmenopausal symptoms and bone loss:
 How Search engine think about Genistein:
 Safety and Acute toxicity:
 Research Update and latest findings of Soy Isoflavones.Daidzein.Daidzin.Genistein.Genistin related.:


   Basic Info of Soy Isoflavones:

 Bio-Chemical : Soy Isoflavones
 Local Name : Soybeans
 Scientific Name:Soy
 Other Names:Glycine max, Glycine soja , Soya
 Genus:Glycine
 Species:max
 Parts Used : Beans
 Actives: genistein, daidzein and glycetin
 Distribution : Soybeans plant is cultivated throughout India.
 

  What are isoflavones?

 Isoflavones are secondary vegetable substances,which can act as estrogens in the body and have protective functions. The estrogen effects of isoflavones are much less powerful than the estrogen hormones (it's effectiveness represents around 1/1000 of the estrogen hormones). This is why isoflavones and phyto-estrogens exercise a balancing effect when the level of estrogens is low, such as during the menopause, and cause less menopause symptoms. Isoflavones can also reduce the effect of the estrogen on cells and skin layers when the hormone levels are high, and then essentially reduce the risk of estrogen linked cancers.

 As nutrition related observations have shown, diseases and troubles mentioned above are uncommon in countries where a lot of soybeans are consumed, because soybeans bring to the organism isoflavones. Scientific literature contains data about the synergy effects. Within the isoflavones we find daidzein and genistein.

  Digestion of isoflavones:

 Isoflavones are transformed by bacteria in the intestinal flora during digestion. It is only once this transformation has been completed that the isoflavones exercise their beneficial effects in the body. Lower absorption in the intestine has been observed following a lengthy intake of antibiotics or in the case of diarrhea. This can result in a reduction of the protective functions of these substances for the body.In order to obtain a regular absorption of isoflavones, the intake isoflavones rich foods or isoflavones supplements must be spread during the day.

  Major Constituents: Daidzein, Daidzin, Genistein, Genistin, Glycitein, Glycitin

 Soy Isoflavone,a sort of bioflavonoid,mainly located in the cotyledon and hypocotyl of the bean seeds. Soy Isoflavone is a combination,12 kinds of Isoflavone have been discovered due to present research, they are divided into two categories: free aglycon and compound glucoside. Aglycon makes 2%-3% of the whole,including genistein(G), daidzein(D) and glycitein(Gly), while glucoside makes 97-98%,mainly existing in the forms of 6"-O-malonygenistin, 6"-O-malonydaidzin, 6"-O-malonyglycitin , genistin, daidzin and glycitin. The four core ingredients in Soy Isoflavone are: daidzein, daidzin, genistein and genistin.

 Soy Isoflavone is the metabolic byproduct generated by bean's up-growing. In 1931,Soy Isoflavone was extracted from bean for the first time. In 1962,Setchell and Adlercreutz made the first proof that Soy Isoflavone has the similar structure with that of the mammals' feminine hormone,and the possible anti-cancer function of Soy Isoflavone was put forward. A great deal of research after 1980 indicates that Soy Isoflavone is most effective for preventing and curing cancer, symptoms of women's menopause and aged women's osteoporosis. Since the 90's of last century,Soy Isoflavone has been widely used in the healthy food and cosmetics.

  


 Genistein: Formula:C₁₅ H₁₀O₅. CAS RN:446-72-0
 Daidzein: Formula: C₁₅ H₁₀O₄. CAS RN:486-66-8
 Glycitein: Formula: C₁₆ H₁₂O₅. CAS RN:
 Genistin: Formula: C₂₁ H₂₀O₁₀. CAS RN:529-59-9
 Daidzin: Formula: C₂₁ H₂₀O₉. CAS RN:552-66-9
 Glycitin: Formula: C₂₂ H₂₂O₁₀. CAS RN:
  


   Introduction and Brief Benefits of Soy Isoflavones:

 Isoflavones are polyphenolic compounds that are capable of exerting estrogen-like effects. For this reason, they are classified as phytoestrogens,compounds with estrogenic activity derived from plants. Legumes, particularly soybeans, are the richest sources of isoflavones in the human diet. In soybeans, isoflavones are present as glycosides (bound to a sugar molecule). Fermentation or digestion of soybeans or soy products results in the release of the sugar molecule from the isoflavone glycoside, leaving an isoflavone aglycone. Soy isoflavone glycosides are called genistin, daidzin, and glycitin, while the aglycones are called genistein, daidzein, and glycitein, respectively (chemical structures of isoflavone aglycones). Unless otherwise indicated, quantities of isoflavones specified in this article refer to aglycones,not glycosides.

  Introduction and Brief Benefits of Soy Isoflavones:

 Soy Isoflavones are derived from Soybeans. Isoflavones belong to a class of compounds known as flavonoids. The highest amounts of Isoflavones can be found in soy nuts and tempeh. Isoflavones are fairly stable; they are not destroyed under normal cooking methods. Soy Isoflavones is a promising nutraceutical with potentially significant health benefits.

 Benefits of using Soy Isoflavones :
 Soy isoflavones provide beneficial effects for the prevention and treatment of breast, colon and prostate cancers.
 Soy isoflavones are also known as phytoestrogens (plant estrogens), signifying their mild estrogenic activity.
 Soy isoflavones reduce the bioavailability of sex hormones that may stimulate tumor growth capacity in both men and women.
 Soy isoflavones are beneficial in preventing osteoporosis and autoimmune conditions.
 Special soy isoflavones supplements are also available in capsules and tablets. Some provide added digestive enzymes.
 

  Properties of Isoflavones:

 Phyto-estrogens are dietary nonsteroidal plant compounds of diverse structure that produce estrogenic responses. They vary greatly in both their potency and physiological effects. There are three main classes of phyto-estrogens: isoflavones, coumestans and lignans, which are present in either plants or their seeds. Isoflavones in four chemical forms: the aglycons daidzein, genistein and glycitein; the glucosides daidzin, genistin and glycitin; the acetyiglucosides and the malonylglucosides. Isoflavones are structurally similar to the mammalian estrogen, estradiol. The principal compounds within these classes of phyto-estrogens have been shown to have weak estrogenic activity, ranging from 0.002 to 0.001 the activity of estradiol. Their effect can both be agonistic and antagonistic to 17-Beta estradiol when they act simultaneously at target tissues. Antagonistic compounds normally compete for 17-Beta estradiol receptors but fail to exert a similar estrogenic effect.

  Health Effects of Isoflavones:

 The above raises the interest in isoflavones as protective agent for hormone-related diseases, as menopause, osteoporosis and coronary heart disease and breast cancer.Research in several areas of healthcare has shown that consumption of isoflavones may play a role in lowering risk for disease. They can fight disease on several fronts. The following potential health benefits are attributed to isoflavones:
 

  Ease menopause symptoms:

 The hot flush is the most common and disruptive symptom of the menopause. Estrogen replacement therapy eliminates 60% of flushes within three months. Hormone replacement generally alleviates the condition, as well as the vaginitis occurring at the menopause due to atrophy. However, due to increasingly suggested and reported negative side effect of hormone replacement therapies, women today request dietary and natural' options for symptom management. The rarity of the problem in soy consuming countries has prompted some investigations to determine whether phyto-estrogens have a similar effect. Human studies have shown that soy isoflavone supplementation resulted in significant reduction in the frequency and intensity of hot flushes and increases serum levels of SHBG, which in turn may alleviate symptoms such as hot flushes and vaginal dryness.

 Recent studies have found that soy isoflavones can reduce menopause symptoms such as hot flushes and increase bone density in women. Indeed, many menopausal and post-menopausal health problems may result from a lack of isoflavones in the typical Western diet. Although study results are not entirely consistent, isoflavones from soy or red clover may be helpful for symptoms of menopause. A study carried out by "Health Test" in 2004 investigated the prescription behaviour of 27 doctors for women with menopause symptoms. It showed that isoflavones were recommended twice (44%) as often as hormonal treatment (22%). The prescribed supplements were mainly based on the following plants: soy, black cohosh and hops.


  Isoflavones improve bone health:Soy and Osteoporosis:

 Soy Isoflavones help in the preservation of the bone substance and fight osteoporosis. This is the reason why people in China very rarely have osteoporosis, despite their low consumption of dairy products, whereas in Europe and North America the contrary happens. Unlike estrogen, which helps prevent the destruction of bone, evidence suggests that isoflavones may also assist in creating new bone. Other studies are not entirely consistent, but evidence suggests that genistein and other soy isoflavones can help prevent osteoporosis.

 Osteoporosis in women is particularly associated with menopause, since the loss of estrogen accelerates bone loss. The hormonal effect of phyto-estrogens, coupled with the comparative rarity of the disease in populations consuming soy, has also prompted investigation of their effects on osteoporosis. Dietary effects have been investigated for achieving peak bone mass and preventing bone loss in later life. It has even been showed that isoflavones do not only prevent the loss of bone, but even allow significant increases in both mineral content and bone mineral density in the lumbar spine region. Similar trends were notes for other skeletal areas. An important role in this effect is ascribed to daidzein. More human studies are currently conducted.

 Many soy foods are naturally high in calcium as this mineral is added as a coagulating agent. In addition, soy also contains magnesium and boron, which are important in bone health.
 In addition, isoflavones in soy foods may inhibit the breakdown of bones. Daidzein, a type of isoflavone, is actually very similar to the drug ipriflavone, which is used throughout Europe and Asia to treat osteoporosis.

 A study completed by Erdman in the early 1990's inspired the many studies that followed to investigate the possible benefits of soy on bone health. Erdman's study focused on post-menopausal women who consumed 40 g of isolated soy protein daily for 6 months. Erdman found that these women had significantly increased bone mineral density as compared to the controls.

 A recent study published in 2003 by the Oklahoma State University showed that soy protein was more effective in bone formation and retention of calcium inside the body (excreting less calcium in urine) compared to milk protein. In addition, researchers also found that the benefits of soy on bone health were more pronounced in postmenopausal women who were not on hormone replacement therapy.

 There is no doubt that soy has a role in maintaining healthy bones and may even help to prevent bone loss in postmenopausal women. However, it is still not clear whether the benefits are due to its soy protein, or its isoflavones daidzein and genistein, or the combination of them. The best approach is to include soy foods such as tofu, tempeh, soy milk, edamame etc in your diet instead of taking isolated soy supplements. Many brands of soy milk are now fortified with calcium. Hence, one glass of fortified soy milk provides an equivalent amount of calcium from a glass of cow's milk.With the increasing public concerns regarding genetically modified foods, look for soy products which use non-genetically modified soy crops in their production.
   

  Cancer/Immune Function:

 High soy consumption leading to high exposures of soy isoflavones has been associated with a reduced risk of cancers at many sites. Several studies on experimental animals and cell cultures have demonstrated cancer chemo-preventive effects of soy isoflavones. In addition to weak estrogenic activities, isoflavones possess a variety of characteristics such as antioxidant, anti-proliferative and differentiation-inducing abilities. A recent study shows that isoflavones might also increase the metabolism of endogenous estrogens to the protective 2-hydroxylated estrogens in women, and this may play an important role in lowering 1 7Beta-estradiol levels and the long-term risk for breast cancer. Also the role of the immune function has become increasingly important in our understanding of the mechanisms underlying the body's ability to prevent cancer. At high doses, especially daidzein was shown to enhance several immuno-regulatory functions.

 Isoflavones seem to be protect agains tumors because thet act against cancer cells in a way similar to many common cancer-treating drugs. Population-based studies show a strong association between consumption of isoflavones and a reduced risk of breast and endometrial cancer. Women who ate the most soy products and other foods rich in isoflavones reduced their risk of endometrial cancer by 54%.

  Bio-activity:

 Diet derived health protectants, like the isoflavones, need sufficient systemic bio-availability to exert the beneficial effects. Determinants of isoflavone bio-activity are structural differences between the isoflavones, gut micro-floral metabolism and mammalian phase-II metabolism. Gut micro-floral influences seems a major factor in inter-individual variation in isoflavones blo-availability. Individuals who excrete larger amounts of faecal isoflavones have much higher urinary and plasma isoflavone levels than individuals who excrete small amounts of isoflavones in faeces. Moreover, these high excreters experience more prolonged plasma diadzein and genistein. Research has shown that glycitein and daidzein are more blo-available than genistein. Urinary recovery of glycitein and daidzein was about 47% and 52% respectively after a single soy dose, whereas the recovery of genistein was 37%. Genistein's lower bio-availability may be due to its more rapid degradation in the gut compared with daidzein and glycitein.
 

  Protect against prostate problems:

 Isoflavones may be benificial for men's health because they may protect against enlargement of the male prostate gland. Studies show isoflavones slowed prostate cancer growth and caused prostate cancer cells to die. Isoflavones act against cancer cells in a way similar to many common cancer-treating drugs.

  Isoflavones are natural plant hormones:

 Isoflavones can be found in many foods but the best known source is the soy bean (Glycine max). The soy isoflavones are responsible for most of the soy health benefits. The Soy bean is a plant cultivated as foodstuff whose health properties have recently been discovered. Thorough studies have revealed that the consumption of the soy beans have favourable effects on people's health. Another source of isoflavones is red clover. As opposed to soy beans, red clover is normally not eaten but the isoflavones are extracted in industrial processes and used to make isoflavones supplements.

  Isoflavones are natural antioxidants:

 A recent study has demonstrated that isoflavones have potent antioxidant properties, comparable to that of the well known antioxidant vitamin E. The antioxidant powers of isoflavones can reduce the long-term risk of cancer by preventing free radical damage to DNA. Genistein is the most potent antioxidant among the soy isoflavones, followed by daidzein.

  Soy infant formula:

 Research on infant formula made with soy is beyond the scope of this article. I'd like to point out, however, that infant formula with soy has been around since the 1960's and fed to babies who were not breastfed and who were allergic to cow's milk. Soy allergies appear to be much less common than allergies to cow's milk, and fewer than 10% of infants allergic to cow milk are also allergic to soy formula. As of today, there would appear to be no obvious detrimental effect, but formulas are constantly changing and research is ongoing into the effects on children's thyroid, sexual, immune and intestinal health.

  Soy and heart disease:

 Soy isoflavones also appear to reduce cardiovascular disease risk via several distinct mechanisms. Isoflavones inhibit the growth of cells that form artery clogging plaque. These arteries usually form blood clots which can lead to a heart attack. A review of 38 controlled studies on soy and heart disease concluded that soy is definitely effective for improving cholesterol profile. There is some evidence that isoflavones are the active ingredients in soy responsible for improving cholesterol profile.

 Early Eastern texts prescribed soy as good for digestion, detoxification, and basic good health and well being.These data were then extrapolated into an assumption that soy had almost magical abilities and the "miracle" of soy blossomed in the 1990's. Advocates claimed it was the answer to all kinds of ills, from high cholesterol to low bone density to cancer, but failed to underscore the fact that a traditional Eastern diet uses much less processed soy than many Westernized soy products. In 1999, the FDA allowed soy food manufacturers to advertise the health claim that 25 grams of soy protein a day could reduce bad cholesterol (LDL) levels. (It should be noted that this claim did not extend to isolated isoflavones.) A backlash of research then came out purporting that soy was a dangerous allergen, created thyroid problems and caused cancer.

 However, a well-balanced August 2005 report from the Agency for Healthcare Research and Quality reviewed hundreds of studies with support from the National Institute of Health. In the 68 studies examining the impact of soy on cholesterol levels, they found that it did indeed reduce LDL and triglyceride levels. They found insufficient data among 200 human studies to suggest that soy had an effect~ negative or positive~on bone health, cancer, kidney disease, endocrine function, reproductive health, neurocognitive function, or glucose metabolism. They hinted that soy isoflavones may protect against fractures after menopause.

 Coronary Heart Disease (CHD) The importance of lowering serum cholesterol in reducing the risk of CHD, and total mortality, is now well established.As CHD is a multi-factorial disease, many dietary factors are involved in affecting risk. LDL-lipoproteins are normally taken up by the liver, thus maintaining levels of serum cholesterol, but if they are oxidatively damaged they are taken up by macrophages to form foam cells in the lining of arteries, initiating the first stages of atherosclerosis. In soy, the positive role of soy proteins is strongly recognised. The Food and Drug Administration in the US has approved a health claim for cholesterol lowering effect when consuming 25g of soy protein per day. The isoflavones may prevent oxidative damage through their antioxidant activities, and are believed to support an improved HDL/LDL ratio. Furthermore because of its effects on tyrosine kinases, genistein may have a role in suppression of the cellular processes which lead to atherosclerosis.


   Actions and Pharmacology:

  How do isoflavones work?

 In the eighties, scientists discovered the alpha- and beta-receptors for estrogens. Estrogens, like all hormones, act by using receptors located on the cell, which provokes some reaction. The alpha-receptors are linked with a risk of estrogen related cancers. On the other hand, the beta-receptors initiate only favourable effects. The repartition of these two types of receptors in the cells and organs is different. Different tissues appear to have different ratios of each receptor type. This discovery allowed us to understand why isoflavones can act differently than estrogens even though the structure of isoflavones is similar to estrogens.

  The isoflavones mechanism:Mechanism of Action:

 How can we explain that isoflavones have an estrogenic effect and an anti-estrogenic effect? When the natural levels of estrogens are low, isoflavones can help the estrogens by activating the beta-receptors.
 When the natural levels of estrogen are high, for example during Adolescence , the isoflavones bind with the alpha-receptors and prevent the natural estrogens from binding with these receptors.
 Soy isoflavones have weak estrogenic activity. The order of activity in in vivo assays is glycitein greater than genistein greater than daidzein. They bind to estrogen receptors-alpha and beta. They appear to bind better to estrogen receptor-beta than to estrogen receptor-alpha.

 The most studied of the soy isoflavones is genistein. Genistein has been found to have a number of antioxidant activities. It is a scavenger of reactive oxygen species and inhibits lipid peroxidation. It also inhibits superoxide anion generation by the enzyme xanthine oxidase. In addition, genistein, in animal experiments, has been found to increase the activities of the antioxidant enzymes superoxide dismutase, glutathionine peroxidase, catalase and glutathione reductase. Daidzein and glycitein also appear to have reactive oxygen scavenging activity. However, these isoflavones have not been studied as much as genistein has.

 Regarding possible anticarcinogenic activity, again genistein has been the most studied of the soy isoflavones. Several mechanisms have been proposed for genistein's possible anticarcinogenic activity. These include upregulation of apoptosis, inhibition of angiogenesis, inhibition of DNA topoisomerase II and inhibition of protein tyrosine kinases. Genistein's weak estrogenic activity may be involved in its putative activity against prostate cancer. Other possible anti-prostate cancer mechanisms include inhibition of NF (nuclear factor)-kappa B in prostate cancer cells, downregulation of TGF (transforming growth factor)-beta and inhibition of EGF (epidermal growth factor)- stimulated growth. Genistein's anti-estrogenic action may be another possible mechanism to explain its putative activity against breast cancer. Additional possible anti-breast cancer mechanisms include inhibition of aromatase activity and stimulation of sex hormone binding globulin, both of which might lower endogenous estrogen levels.

 The possible anti-atherogenic activity of soy isoflavones may be accounted for, in part, by their possible antioxidant activity, particularly with regard to inhibition of lipid peroxidation and oxidation of LDL. Soy isoflavones may have some cholesterol-lowering activity, but the mechanism of this possible effect is unclear.
 Soy isoflavone's weak estrogenic effect may help protect against osteoporosis by preventing bone resorption and promoting bone density. However, the mechanism of this possible effect is entirely speculative at this time.
 

  How do isoflavones influence health?:

 Isoflavones activate the beta-receptor and reinforce the favourable estrogenic properties. On the other hand, isoflavones protect the estrogen alpha-receptors. Consequently the proneness to estrogen-related cancers is lower.
 The beta-receptors, which exercise favourable effects for health, can be found mainly in the blood cells, the lungs, the prostate, the bladder, bones and thymus. Isoflavones stimulate their function even after the level of estrogens has decreased.

 The alpha-receptor can be mainly found in the breast tissue, the uterus, the ovaries, the testicles and the liver. In those places, isoflavones protect the receptor against estrogens and help reduce the proneness to tumors.
 Regulation of the hormonal balance during menopause:
 Isoflavones regulate the estrogen levels in the body. Isoflavones play a role when the estrogen level is low. The typical symptoms of the menopause, such as hot flushes and night sweat become less severe.
 When taking daily 40-50mg of isoflavones, the symptoms of menopause will decrease after 2 to 3. This treatment will also reduce the risk of hormones related tumors, osteoporosis and arterio-sclerosis. In the long term the health benefits are really high.

  Other isoflavones actions:

 Soy isoflavones have estrogenic activity. Soy isoflavones may have antioxidant activity. They may also have anticarcinogenic, anti-atherogenic, hypolipidemic and anti-osteoporotic activities. Most interest in isoflavones has been generated by their potential hormonal effects. But isoflavones have other physiological effects. There are indications that isoflavones can stop the growth of cancer cells through inhibition of DNA replication and reduction in the activity of various enzymes. Isoflavones also have antioxidant effects and inhibit the actions of various growth factors.
 

  Metabolism of isoflavones:

  Formation of aglycones:

 Isoflavones occur in foods in the form of glucosides which means that the isoflavones are bound to sugar (conjugated isoflavones). These glycosides are very water soluble. These conjugated isoflavones have to undergo further changes. When ingested, these conjugated isoflavones undergo hydrolysis by ?-glucosidases in the intestine, releasing the principal bioactive aglycones (daidzein, genistein and glycitein). These aglycones may be absorbed and further metabolized to many specific metabolites such as equol.

  Influence of diet on isoflavones metabolism:

 Further metabolism of aglycones seems to be strongly influenced by the diet. A high carbohydrate environment, which causes increased intestinal fermentation, results in more phytoestrogens being transformed in equol. This may be relevant because the potency of equol is higher than that of its plant precursor, daidzein. Also, the intestinal microflora has an effect on the metabolism of isoflavones. When intestinal flora is low (antibiotics, germfree animals, newborn babies) metabolism falls down too. When the dietary intake of fat is high, intestinal microflora has difficulty in synthesizing equol from isoflavones.

 Like endogenous estrogens (estradiol), isoflavones are metabolized in the intestines and liver. Absorption happens along the entire length of the intestine and they are secreted in bile and urine. Excretion of isoflavones metabolites can vary strongly between individuals. This may be influenced by the fact that each person has his own specific intestinal microflora population.

 Once absorbed equol shows less affinity to be bound to serum proteins and therefore has a greater availability than estradiol. When soy is consumed on a regular basis (50 mg isoflavones/day), plasma isoflavone levels far exceed normal estradiol concentrations. This observation led to the hypothesis that isoflavone would be biologically active, conferring health benefits that could explain the relatively low incidence of hormone-dependent diseases in countries in which soy is a dietary staple.


   Women's health and Isoflavones:

  Women's health is much influenced by the female hormone estrogen:

 When estrogen levels drop during menopause, many women resort to hormone therapy. Hormone therapy can help women with hot flashes, mood swings, vaginal dryness and osteoporosis, but it also has some risks. Hormone therapy may increase their chance of heart attack, stroke, breast cancer and dementia. Isoflavones do not seem to have these risks. Isoflavones have an influence on the women's health during menopause but also before and during the reproductive years, or pre-menopause period. A study showed that of the 1172 women participating in a six year study, the hysterectomy rate was lowest among the women whose diets contained the most soy foods. This study suggests that consuming soy foods, which contain isoflavones, seems to reduce the risk of fibroids and endometriosis.

  Isoflavones and girls:

 The consumption of isoflavones during the puberty, when the female breast develops, appears to protect the woman later in life against cancer. Studies show that women who ate weekly more than 3 portions of soy during adolescence showed a 40% reduced risk of breast cancer compared to those who did not consume soy. That's why it's important for girls to consume soy products or isoflavones supplements.

  Isoflavones and menstrual cycle:

 Isoflavones could increase the length of the menstrual cycle and moderate alter steroid hormone levels. A British study found that women who were given 60 grams of soy a day had longer menstrual cycles. Asian women, who ingest more soy on a daily basis, generally have longer menstrual cycles than Western women. Research suggests that the low Chinese breast cancer mortality rate may, in part, be due to consumption of food containing soy isoflavones. Levels of steroid hormones and menstrual cycle duration are known risk factors for breast cancer. An increased menstrual cycle is beneficial because this results in less time that the breast cells are exposed to higher estrogen levels.

  Isoflavones and menopause:

 During menopause the level of estrogen drops and causes common symptoms of menopause: hot flushes, insomnia, heavy sweating, mood swings, vaginal dryness and headaches.
 


   Suggestions and Administration:

  Recommendations:

 In adults, 25 grams per day of soy protein may reduce the risk of heart disease.Soy foods and soy-based infant formula are widely used in children, but there are no studies that have determined whether isolated soy protein or isoflavone supplements are useful or safe in this population. Therefore, isolated soy products are not recommended for children at this time.

  Dosage and Administration:

 Soy isoflavone supplements containing genistin, daidzin and glycitin are available with much smaller amounts of the aglycones genistein, daidzein and glycitein. The percentages of the soy isoflavones present in a standard soy isoflavone supplement reflect the percentages of these substances as found in soybeans and are: genistin, about 50%; daidzin, about 38%;and glycitin, about 12%.A 50-mg dose of soy isoflavones~a typical daily dose~delivers 25 mg of genistin, 19 mg of daidzin and about 6 mg of glycitin. Usually, 40% of the formula is comprised of soy isoflavones. Therefore,to get a dose of 50 milligrams of soy isoflavones, 125 mg daily of soy isoflavones are required. Various observational and epidemiological studies suggest 50 mg daily of soy isoflavones approximates the dose that may have health benefits.Soy isoflavones are also available in some functional food products.

  Contradications:  Soy isoflavones are contraindicated in those who are hypersensitive to any component of a soy isoflavone-containing product.

  Precautions:  Pregnant women and nursing mothers should avoid the use of soy isoflavone supplements pending long-term safety studies. Men with prostate cancer should discuss the advisability of the use of soy isoflavones with their physicians before deciding to use them.Women with estrogen receptor-positive tumors should exercise caution in the use of soy isoflavones and should only use them if they are recommended and monitored by a physician.Soy isoflavone intake has been associated with hypothyroidism in some.

  Side Effects:  For individuals who are not allergic to soy, no serious short-term or long-term side effects have been reported from eating soy foods. Common mild side effects include stomach upset and digestive problems, including constipation and diarrhea.
 


   What is genistein?

 Isoflavonoids are a group of diphenolic hormone-like compounds of dietary origin that are of great interest particularly because of their anti-carcinogenic potency, but also because of their association with other Western diseases like coronary heart disease.
 These isoflavonoids are derived mainly from soy-protein products, while clover seeds and leaves are a rich source of Biochanin A and Formononetin.
 Genistein precursors such as Genistin and Biochainin A are converted by the intestinal microflora to Genistein into gut.
 


   Genistein mimics human estrogens:

 In research collaborations with scientists in the Department of Medicinal Chemistry here at Ohio State, we are investigating the nature of these potentially conserved signaling and signal transduction pathways. So far evidence suggests possible parallels in apoptotic cell death, estrogen-like and interleukin signaling pathways.
 Shown at left is the soybean isoflavone genistein (the small grey structure with red hydroxy groups) binding to the human estrogen receptor ER-Alfa.
 Genistein is one of the most potent phytoestrogens. It mimics human estrogens by binding to both ER-Alfa and ER-Beta and has promising anti-breast cancer activity.
 Genistein is also a central signal in soybean for the potentiation of defense responses. Interestingly, human estrogens such as estradiol also activate defense potentiation in soybean, possibly by acting as a genistein mimic.
 


   Actions of the soy phytoestrogen genistein in models of human chronic disease: potential involvement of transforming growth factor Beta

 The structural similarity, but non-identity, between 17b-oestradiol and the soy phytoestrogen genistein suggests that the two compounds will have actions that may be identical in some target biological systems, but different in others. Epidermal growth factor (EGF)-stimulated proliferation of human mammary epithelial cells (that do not express the oestrogen receptor) was significantly suppressed at genistein concentrations (5¨C10 ¦ÌM) that are attainable physiologically.
 Others have shown previously that transforming growth factor b (TGFBeta) has similar growth-inhibitory effects on human cells. Analysis of the conditioned medium of human mammary epithelial cells exposed to genistein plus EGF showed increased levels of TGFBeta relative to those in the medium of cells exposed to EGF or genistein alone. Related experiments in a primate model of menopause demonstrated that ingestion of soy containing isoflavones was correlated with the suppression of neurodegeneration-relevant phosphorylation of the microtubule-associated protein tau, while intake of Premarin (a hormone replacement therapy that is commonly prescribed for women) was not correlated. The results discussed here indicate that genistein, and probably other related phytoestrogens, have pleiotropic actions, some of which may involve TGFBeta activity.
 


   Estrogenic Effects of Genistein:

 The phytoestrogen genistein is present naturally as several ?-glucosides, which are metabolized by intestinal microflora to genistein. Genistein, a planar molecule with an aromatic A ring, has a chemical structure similar to steroidal estrogens, and its ability to behave as an estrogen in various tissues has been widely described. Observations of phytoestrogens' estrogenic properties date back to the 1950s, when it was discovered that the diadezan metabolite equol was the compound responsible for reduced reproductive capacity in sheep grazing on clover. Subsequently, countless studies have been conducted to characterize the hormonal effects of phytoestrogens including genistein's estrogenic and presumed antiestrogenic properties.

 Genistein has significant estrogenic properties in both in vitro and in vivo models. Genistein binds to the estrogen receptor (ER), although its binding affinity is several-fold weaker than that of estradiol. Genistein can also activate a number of estrogen-responsive genes in vitro, including pS2 and c-fos. Furthermore, when administered at low doses, genistein stimulates the growth of ER-positive (ER+) breast cancer cells. Findings in other tissue systems support the estrogenicity of genistein. For example, genistein is uterotrophic in a variety of species, resulting in impaired reproductive activity and increases in uterine wet weights. It is important to note that some studies have failed to see any effect of genistein on the uterus, including alterations in wet weight. Furthermore, findings with coumestrol, a more estrogenic phytoestrogen than genistein, indicate that although coumestrol increases uterine wet weights, it does not increase uterine DNA content or alter other indicators of more true estrogenic activity. Thus, an increase in uterine wet weight alone does not necessarily indicate that genistein has estrogenic properties.

 In addition to directly binding to the ER, genistein may indirectly affect estrogenicity through inhibition of the cytochrome P450 enzyme CYP1A1. It has recently been shown that genistein is a noncompetitive inhibitor of the CYP1A1 enzyme, which apart from playing a role in the metabolism of carcinogens, is responsible for the metabolic degradation of 17Beta-estradiol. Thus, it is possible that genistein-mediated inhibition of estradiol degradation could result in higher levels of circulating estradiol and thus elevated ER activity.

 Genistein has estrogenic effects on the hypothalamic/pituitary axis in ovariectomized Sprague-Dawley rats. Human studies indicate that high soy intake can disrupt the hypothalamic/pituitary/gonadal axis in premenopausal women similar to that seen in animal models. This perturbation is not seen in postmenopausal women, suggesting a differential effect of soy/genistein on pre- and postmenopausal women. Finally, genistein may exert beneficial effects on bone, cardiovasculature, and lipid profiles, all of which are effects characteristic of estrogen. Taken together, these studies indicate that genistein can behave as an estrogen and can mediate mitogenic effects via the ER.

 Estrogens have long been identified as important mitogens in the breast and thus are associated with an increase in breast cancer risk. This is evidenced by the link between reproductive factors, including ages of first menarche, first pregnancy, and menopause, and breast cancer risk. This is further supported by studies showing that elevated concentrations of estrogens in serum and urine are associated with increased postmenopausal breast cancer risk. Additionally, estrogens induce mitogenic effects in both in vitro and in vivo models of breast cancer. The role of estrogen in this disease is supported by the fact that removal of ovarian estrogens by bilateral ovariectomy or use of tamoxifen (which blocks ER in the mammary gland) significantly reduces breast cancer risk. Because estrogen exposure presumably increases breast cancer risk, evidence showing that genistein acts in an estrogenic fashion is puzzling in light of the in vitro reports of genistein as an anticancer agent. To address studies that demonstrate the protective effects of genistein in in vitro and in vivo breast cancer models, it is important to determine whether genistein has antiestrogenic properties as well.
 


   Effect of genistein to control postmenopausal symptoms and bone loss:

 Post-menopausal women suffer symptoms like hot flushes and they are also at a higher risk of bone fractures due to osteoporosis.?This is attributable to a lower level of estrogen secretion by the ovaries of these women.Albertazzi P et al conducted a clinical study in 1998 whereby 104 post-menopausal women were given a daily supplement of 60 g of isolated soy protein or placebo (casein) (Albertazzi P., et al 1998).

 By the fourth week of the clinical trial, subjects that were given soy supplement showed a significant reduction in the mean number of hot flushes per 24 hours. By week 12, there was a 15% (p<0.01) decrease in the number of hot flushes in soy group subjects compared to the control.

 This study confirms that genistein which has weak estrogenic property is able to counteract the natural loss of estrogen in post-menopausal women.?Genistein is now commercially available as health food to combat such symptoms and bone loss.A note of caution however; genistein at high concentration in the body can work the reverse; it exhibits anti-estrogenic activity.This activity may be linked to genistein anti-tumour effect on breast cancer
 


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   Safety and Acute toxicity:

  Genistein:

 Chemical Name: Isoflavone,4',5,7-trihydroxy-
 CAS: 446-72-0.Molecular Formula: C15-H10-O5.Weight: 270.25
 Synonyms: 4H-1-Benzopyran-4-one,5,7-dihydroxy-3-(4-hydroxyphenyl)-;C.I.75610;Differenol A;Genistein;Genisteol;Genisterin;Prunetol;Sophoricol;4',5,7-Trihydroxyisoflavone;5,7,4'-Trihydroxyisoflavone.

 Acute toxicity(LD50):

 LD-Lethal dose,Intraperitoneal.Rodent-mouse.>500mg/kg.
 Details of toxic effects not reported other than lethal dose value.
 Reference: JANTAJ Journal of Antibiotics.V.2-5,1948-52;V.21-1968-Volume(issue)/page/year:39,606,1986.

 Reproductive Data:

 TDLo-Lowest published toxic dose.Subcutaneous.Rodent-rat.125mg/kg.
 Sex/Duration:female 16~20days(s) after conception.
 Toxic Effects: Reproductive-Specific Development Abnormalities-urogenital system.
 Reference: PSEBAA Proceedings of the Society for Experimental Biology and Medicine.(Academic Press, Inc.,1E. First St.Duluth,MN55802)V.1-1903/04-Volume(issue)/page/year:208.60.1995.

 TDLo-Lowest published toxic dose.subcutaneous.Rodent-rat.625mg/kg.
 Sex/Duration:female 16~20 day(s) after conception.
 Toxic Effects: Reproductive-Effects on Newborn-growth statistics(e.g.%,reduced weight gain).
 Reference: PSEBAA Proceedings of the Society for Experimental Biology and Medicine.(Academic Press, Inc.,1E. First St.Duluth,MN55802)V.1-1903/04-Volume(issue)/page/year:208.60.1995.

 TDLo-Lowest published toxic dose.Oral.Rodent-mouse.1680mg/kg.
 Sex/Duration:female 21 day(s) pre-mating.
 Toxic Effects:Reproductive.Maternal Effects.other effects.
 Reference:JOENAK Journal of Endocrinology.(Biochemical Soc.Book Depot,POB32,Commerce Way,Colchester,Essex CO2 8HP,UK)V.1-1939-Volume(issue)/page/year:13.94.1955.

 TDLo-Lowest published toxic dose.Oral.Rodent-mouse.13200mg/kg.
 Sex/Duration:male 22 day(s) pre-mating.
 Toxic Effects: Reproductive-fertility-male fertility index(e.g.#males impregnating females per#males exposed to fertile nonpregnant females).
 Reference:JOENAK Journal of Endocrinology.(Biochemical Soc.Book Depot,POB32,Commerce Way,Colchester,Essex CO2 8HP,UK)V.1-1939-Volume(issue)/page/year:13.94.1955.

 TDLo-Lowest published toxic dose.Oral.Rodent-mouse.18600mg/kg.
 Sex/Duration:male 31 day(s) pre-mating.
 Toxic Effects: Reproductive-Effects on Newborn-stillbirth.
 Reference:JOENAK Journal of Endocrinology.(Biochemical Soc.Book Depot,POB32,Commerce Way,Colchester,Essex CO2 8HP,UK)V.1-1939-Volume(issue)/page/year:13.94.1955.

 Mutagenic Data.

 DNA damage.Test system:Human Cells-not otherwise specified.50mg/L.
 Reference: CNREA8 Cancer Research.(Public Ledger Building,Suit 816,6th&Chestnut Sts.,Philadelphia,PA 19106)V.1-1941-Volume(issue)/page/year:50,2618,1990.

 DNA damage.Test system:Human Cells-not otherwise specified.50umol/L.
 Reference: CNCMET Cancer Communications.(Pergamon Press, Inc.,Maxwell House,Fairview Park,Elmsford,New York,10523) V.1-1989-Volume(issue)/page/year:2,271,1990.

 Mutation test systems-not otherwise specified.Test system:Human Cells-not otherwise specified.45 umol/L.
 Reference: CNCMET Cancer Communications.(Pergamon Press, Inc.,Maxwell House,Fairview Park,Elmsford,New York,10523) V.1-1989-Volume(issue)/page/year:2,271,1990.

 Micronucleus test.Test sytem:Rodent-hamster Lung.18 umol/L.
 Reference:FCTOD7 Food and Chemical Toxicology.(Pergamon Press Inc.Maxwell House,Fairview Park,Elmsford,NY 10523) V.20-1982-Volume(issue)/page/year:35,605,1997.

  Daidzein:

 Chemical Name: 4H-1-Benzopyran-4-one,7-hydroxy-3-(4-hydroxyphenyl)-
 CAS: 486-66-8.Molecular Formula: C15-H10-O4.Weight: 254.25
 Beilstein No.:0231523(5-18-04-00089.Beilstein Handbook Reference)
 Synonyms: Daidzein;Daidzeol;4'7-Dihydroxyisoflavone;7,4'-Dihydroxyisoflavone;7-Hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one;Isoflavone,4'7-dihydroxy-;K251b.

 Acute toxicity(LD50):

 LD-Lethal dose,Intraperitoneal.Rodent-mouse.>2gm(2000mg)/kg.
 Details of toxic effects not reported other than lethal dose value.
 Reference: PCJOAU Pharmaceutical Chemistry Journal(English Translation).Translation of KHFZAN.(Plenum Pub.Corp.,233 Spring St.,New York,NY 10013) No.1-1967-Volume(issue)/page/year:13,51,1979.

  Genistin:

 Chemical Name:4H-1-Benzopyran-4-one,7-(beta-D-glucopyranosyloxy)-3-(4-hydroxyphenyl)-
 CAS: 4529-59-9.Molecular Formula: C21-H20-O10.Weight: 432.41
 Beilstein No.:0064479(4-18-00-02732.Beilstein Handbook Reference)
 Synonyms:Genistein,7-beta-D-glucopyranoside;Genistein,7-O-beta-D-glucoside;Genistin;Genistine;Genistoside.

 Acute toxicity(LD50):

 LD50-Lethal dose,50 percent kill.Intraperitoneal.Rodent-mouse.>2gm(2000mg)/kg.
 Details of toxic effects not reported other than lethal dose value.
 Reference: PCJOAU Pharmaceutical Chemistry Journal(English Translation).Translation of KHFZAN.(Plenum Pub.Corp.,233 Spring St.,New York,NY 10013) No.1-1967-Volume(issue)/page/year:13,51,1979.

  Daidzin:

 Chemical Name:4H-1-Benzopyran-4-one,7-(beta-D-glucopyranosyloxy)-3-(4-hydroxyphenyl)-5-hydroxy-
 CAS: 552-66-9.Molecular Formula: C21-H20-O9.Weight: 416.41
 Beilstein No.:0059741(4-18-00-01808.Beilstein Handbook Reference)
 Synonyms:Daidzein 7-glucoside;Daidzein 7-O-glucoside;Daidzin;Daidzoside;7-(beta-D-Glucopyranosyloxy)-3-(4-hydroxyphenyl)-5-hydroxy-4H-1-benzopyran-4-one.

 Acute toxicity(LD50):

 LD50-Lethal dose,50 percent kill.Intraperitoneal.Rodent-mouse.>2gm(2000mg)/kg.
 Details of toxic effects not reported other than lethal dose value.
 Reference: PCJOAU Pharmaceutical Chemistry Journal(English Translation).Translation of KHFZAN.(Plenum Pub.Corp.,233 Spring St.,New York,NY 10013) No.1-1967-Volume(issue)/page/year:13,51,1979.


  Scientific References:

  1.The Secret of Soy,What is Soy Isoflavones?...Function of Natural Genistein?