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  1. 1. INTRODUCTION:<br />Phytoestrogens are plant-derived xenoestrogens functioning as the primary female sexhormone estrogen not generated within the endocrine system but consumed by eating phytoestrogonic plants. Also called "dietary estrogens", 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.<br />ESTROGEN:<br />Estrogen is a hormone that comprises a group of compounds, including estrone, estradiol and estriol. It is the main sex hormone in women and is essential to the menstrual cycle. Estrone is produced during menopause, estradiol is the predominant form in non-pregnant females and estriol is the primary estrogen of pregnancy. Although estrogen exists in men as well as women, it is found in higher amounts in women, especially those capable of reproducing. Estrogen contributes to the development of secondary sex characteristics, which are the defining differences between men and women that don’t relate to the reproductive system. In women, these characteristics include breasts, a widened pelvis, and increased amounts of body fat in the buttock, thigh and hip region. Estrogen also contributes to the fact that women have less facial hair and smoother skin then men. Estrogen is an essential part of a woman’s reproductive process. It regulates the menstrual cycle and prepares the uterus for pregnancy by enriching and thickening the endometrium. Two hormones, the luteinizing hormone (LH) and the follicle stimulating hormone (FSH), help to control how the body produces estrogen in women who ovulate. Estrogen is manufactured mostly in the ovaries, by developing egg follicles. In addition, estrogen is produced by the corpus luteum in the ovary, as well as by the placenta. The liver, breasts and adrenal glands may also contribute to estrogen production, although in smaller quantities. Estrogen can be broken down into three distinct compounds: estrone, estradiol and estriol. During a woman’s reproductive life, which starts with the onset of menstruation and continues until menopause, the main type of estrogen produced is estradiol. Enzymatic actions produce estradiol from androgens. Testosterone contributes to the production of estradiol, while <br />the estrogen estrone is made from andostenedione. Estrogen is important to a woman’s health, not only as it relates to her reproductive cycle. Although it can cause women to retain fluid, and early exposure through early menses can increase a woman's risk of developing breast cancer, estrogen has its benefits. It can contribute to increasing high density lipoprotein (HDL), which is considered the “good” cholesterol, and lower the low density lipoprotein (LDL), which is the “bad” cholesterol. After menopause, women experience a reduction in estrogen. This can lead to vaginal dryness, memory problems, hot flashes, fatigue, irritability and possibly one of the most devastating problems, a decrease in bone density.<br />BIOSYNTHESIS:<br />In females, synthesis of estrogens starts in theca interna cells in the ovary, by the synthesis of androstenedione from cholesterol. Androstenedione is a substance of moderate androgenic activity. This compound crosses the basal membrane into the surrounding granulosa cells, where it is converted to oestrone or oestradiol, either immediately or through testosterone. The conversion of testosterone to oestradiol, and of androstenedione to oestrone, is catalyzed by the enzyme aromatase.<br />Oestradiol levels vary through the menstrual cycle, with levels highest just before ovulation.<br />MECHANISM OF ACTION:<br />Estrogens readily diffuse across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors which in turn modulate the expression of many genes. Additionally, estrogens have been shown to activate a G protein-coupled receptor, GPR30.<br />ESTROGEN RECEPTORS:<br />There are two different forms of estrogen receptors ER alpha(ER-α ) and beta (ER-β).<br />LOCATION:<br />ER-α<br />Uterus, Testis, Pituitary, Ovary, Epidydimis, and adrenal gland.<br />ER-β<br />Brain, Kidney, Prostate, Ovary, lung, Bladder, Intestine, and epididymis.<br />Benefits and Functions of Estrogen:<br />Helps maintain memory<br />Increases sexual interest and joy<br />Improves mood and happiness<br />Improves sleep quality<br />Relieves hot flashes<br />Increases vaginal secretions<br />Increases concentration and cognitive abilities<br />Enhances energy<br />Increases reasoning and ideation -- richer language<br />Prevents joint pains in the fingers, hands and large joints associated with aging<br />Increases eye (lacrimal) secretions that otherwise lead to dry, itchy  eye syndrome<br />Decreases wrinkles<br />Stops those tell-tale aging lines of the upper lip<br />Maintains the amount of collagen and elasticity in the skin<br />Maintains bone density along with progesterone and testosterone<br />Increases the water content of skin and is responsible for its thickness and softness<br />Reduces the overall risk of heart disease by 40 to 50%<br />Helps with fine motor skills<br />Helps maintain muscle <br />Decreases blood pressure -- natural vasodilator<br />Increases metabolic rate<br />Reduces risk of cataracts<br />Protects against macular degeneration<br />Increases HDL by 10 to 15%<br />Decreases LDL and prevents its oxidation<br />Decreases lipoprotein(a) -- Lp(a) -- a highly atherogenic substance<br />Improves insulin sensitivity -- thereby preventing type II diabetes<br />Decreases the accumulation of plaque on arteries<br />Regulates body temperature<br />Stimulates the production of cholineacetyltransferase, an enzyme which prevents Alzheimer's Disease<br />Improves serotonin formation, a anti-depressant brain neurotransmitter, which decreases depression, irritability, anxiety, and pain sensitivity<br />Helps maintain the elasticity of arteries<br />Dilates small arteries<br />Inhibits platelet adhesiveness -- preventing heart attacks and strokes<br />Enhances magnesium uptake and utilization<br />Enhances the production of nerve-growth factor<br />Acts as a natural calcium channel blocker to keep arteries open<br />Reduces homocysteine<br />Decreases risk of colon cancer<br />Helps prevent tooth loss<br />MENOPAUSE:<br />Menopause is the transition period in a woman’s life when her ovaries stop producing eggs, body produces less estrogen and progesterone. Menopause is a natural event that normally occurs between ages of 45 and 55.<br />PREMATURE MENOPAUSE:<br />Menopause is more likely to occur at a slight earlier age in women who smoke, have never been pregnant or live at high altitudes.<br />PERIMENOPAUSE:<br />The hormonal changes associated with menopause actually begin prior to the last menstrual period, during a 3-5 year period called the perimenopause.<br />SURGICAL MENOPAUSE:<br />Surgical menopause is menopause induced by the removal of the ovaries. Women who have had surgical menopause often have a sudden and more severe onset of symptoms of menopause.<br />As estrogen levels decrease during menopause the following symptoms occur:<br />Hot flashes<br />Sleep disturbances<br />Urogenital atrophy<br />Osteoporosis<br />Skin dryness<br />Aging<br />CLINICAL USES OF ESTROGENS:<br />Oral contraceptives:<br />Since estrogen circulating in the blood can negatively feed-back to reduce circulating levels of FSH and LH, most oral contraceptives contain a synthetic estrogen, along with a synthetic progestin. Even in men, the major hormone involved in LH feedback is estradiol, not testosterone.<br /> Hormone replacement therapy:<br />Estrogen and other hormones are given to postmenopausal women in order to prevent osteoporosis as well as treat the symptoms of menopause such as hot flushes, vaginal dryness, urinary stress incontinence, chilly sensations, dizziness, fatigue, irritability, and sweating. Fractures of the spine, wrist, and hips decrease by 50-70% and spinal bone density increases by ~5% in those women treated with estrogen within 3 years of the onset of menopause and for 5–10 years thereafter.<br />Before the specific dangers of conjugated equine estrogens were well understood, standard therapy was 0.625 mg/day of conjugated equine estrogens (such as Premarin). There are, however, risks associated with conjugated equine estrogen therapy. Among the older postmenopausal women studied as part of the Women's Health Initiative (WHI), an orally administered conjugated equine estrogen supplement was found to be associated with an increased risk of dangerous blood clotting. The WHI studies used one type of estrogen supplement, a high oral dose of conjugated equine estrogens (Premarin alone and with medroxyprogesterone acetate as PremPro).<br />In a study by the NIH, esterified estrogens were not proven to pose the same risks to health as conjugated equine estrogens. Hormone replacement therapy has favorable effects on serum <br />cholesterol levels, and when initiated immediately upon menopause may reduce the incidence of cardiovascular disease, although this hypothesis has yet to be tested in randomized trials. Estrogen appears to have a protector affect on atherosclerosis it lowers LDL and triglycerides, it raises HDL levels and has endothelial vasodilatation properties plus an anti-inflammatory component.<br />Research is underway to determine if risks of estrogen supplement use are the same for all methods of delivery. In particular, estrogen applied topically may have a different spectrum of side-effects than when administered orally, and transdermal estrogens do not affect clotting as they are absorbed directly into the systemic circulation, avoiding first-pass metabolism in the liver. This route of administration is thus preferred in women with a history of thrombo-embolic disease.<br />Estrogen is also used in the therapy of vaginal atrophy, hypoestrogenism (as a result of hypogonadism, castration, or primary ovarian failure), amenorrhea, dysmenorrhea, and oligomenorrhea. Estrogens can also be used to suppress lactation after child birth.<br />Breast cancer<br />About 80% of breast cancers, once established, rely on supplies of the hormone estrogen to grow: they are known as hormone-sensitive or hormone-receptor-positive cancers. Suppression of production of estrogen in the body is a treatment for these cancers.<br />Hormone-receptor-positive breast cancers are treated with drugs which suppress production of estrogen in the body. This technique, in the context of treatment of breast cancer, is known variously as hormonal therapy, hormone therapy, or anti-estrogen therapy (not to be confused with hormone replacement therapy). Certain foods such as soy may also suppress the proliferative effects of estrogen and are used as an alternative to hormone therapy.<br /> Prostate cancer<br />Under certain circumstances, estrogen may also be used in males for treatment of prostate cancer.<br /> Miscellaneous<br />In humans and mice, estrogen promotes wound healing.<br />At one time, estrogen was used to induce growth attenuation in tall girls. Recently, estrogen-induced growth attenuation was used as part of the controversial Ashley Treatment to keep a developmentally disabled girl from growing to adult size.<br />Most recently, estrogen has been used in experimental research as a way to treat patients suffering from bulimia nervosa, in addition to Cognitive Behavioral Therapy, which is the established standard for treatment in bulimia cases. The estrogen research hypothesizes that the disease may be linked to a hormonal imbalance in the brain.<br />Estrogen has also been used in studies which indicate that it may be an effective drug for use in the treatment of traumatic liver injury.<br />ESTROGEN PREPARATIONS:<br />Ethinyl Estradiol<br />Hormone Replacement: 0.005 to 0.02 mg/day<br />Oral Contraceptive: 0.03 to 0.10 mg/day<br />Micronized estradiol (1-2 mg/day)<br />Estradiol Cypionate (2-5 mg every 3-4 weeks)<br />Estradiol valerate (2-20 mg every other week)<br />Estropipate (1.25-2.5 mg/day)<br />Conjugated Estrogen (e.g. Premarin)<br />Oral (0.3-1.25 mg/day)<br />Injectable (0.2-2 mg/day)<br />Transdermal<br />Diethylstilbestrol (0.1-0.5 mg/day)<br />Quinestrol (0.1-0.2 mg/week)<br />Chlorotrianisene (12-25 mg/day)<br />Methallenestril (3-9 mg/day)<br />Esterified Estrogen (Menest): 0.3 to 1.25 mg/day<br />Estrogen replacement therapy has been widely used by women in menopause. It provides relief from acute menopausal symptoms and in the later stage, it prevents complications like osteoporosis. But long term use of estrogens may produce the following side effects:<br />Women can experience side effects during hormone therapy; these can be divided into more minor side effects, and more serious side effects. The more minor side effects are more common than the serious side effects, and are generally perceived by women as "annoying." These symptoms include:<br />Nausea, vomiting <br />Pain, cramps or tenderness in the abdomen <br />Yellowing of the skin and/or whites of the eyes <br />Breast tenderness or enlargement <br />Enlargement of benign (fibroid) tumors <br />Irregular bleeding or spotting <br />Change in amount of cervical secretion <br />Vaginal yeast infections <br />Retention of excess fluid. (This may make some conditions worsen, such as asthma, epilepsy, migraine, heart disease, or kidney disease) <br />A spotty darkening of the skin, particularly on the face <br />Reddening of the skin <br />Skin rashes <br />Worsening of porphyria <br />Headache, migraines <br />Dizziness, faintness <br />Changes in vision (including intolerance to contact lenses) <br />Mental depression <br />Involuntary muscle spasms <br />Hair loss or abnormal hairiness <br />Changes in weight. (Most women experience weight gain instead of weight loss) <br />Changes in sex drive. (Most women experience decreased libido)  <br />Possible changes in blood sugar <br />Shortness of breath <br />Coughing up blood <br />Severe stomach pain or swelling <br />Acne <br />Allergies <br />Fatigue <br />High blood pressure <br />Gallstones <br />Loss of libido <br />Asthma <br />Numbness, tingling, itching of feet and hands <br />Heaviness of the chest <br />It is still controversial which of these side effects are due to the estrogen component as compared to the progesterone component. Therefore, if side effects persist for a few months, the doctor will often alter either the progesterone or the estrogen part of the hormone therapy (HT). <br />Contrary to common belief, recent research has confirmed that women who take commonly prescribed doses of hormone therapy (HT) are no more likely to gain weight than women not taking hormone therapy (HT). This is probably because menopause or aging itself is associated with weight gain, regardless of hormone therapy. <br />The more serious health concerns for women undergoing hormone therapy (HT) include:<br />Hormone therapy (HT) increases the risk of vein clots in the legs (deep vein thrombosis) and blood clots in the lungs (pulmonary embolus) by about 2 or 3 fold. However, it is important to remember that these conditions are extremely rare in healthy women. Thus, the true increase in risk for healthy women is minimal. Women with a personal or family history of these clots should review this issue when considering hormone therapy (HT).<br />Uterine Cancer (endometrial cancer): Research shows that women who have their uterus and use estrogen alone are at risk for endometrial cancer. Today, however, most doctors prescribe the combination of estrogen and progestin. Women without a uterus (including women who have had a hysterectomy) have no risk of endometrial cancer.<br />Breast cancer: Recent research indicates that hormone therapy (HT), and especially EPT, increases the risk of breast cancer, although the increase in risk is very small. For example, the Women's Health Initiative, a reliable large study of hormone therapy (HT) in menopausal women, predicted that there were approximately 8 extra cases per 10,000 women who took hormone therapy (HT) for 1 year, compared to women taking a placebo pill. The increase in risk of breast cancer associated with hormone therapy (HT) likely increases with duration of use and is especially increased with 5 or more years of use.<br />Heart disease: Even though hormone therapy (HT) lowers the bad LDL cholesterol and raises the good HDL cholesterol, hormone therapy (HT) increases the risk of heart attacks in women who already have heart disease, as well as in women who do not have known heart disease. Hormone therapy (HT) does not prevent heart attack based on recent research from the Women's Health Initiative.<br />Abnormal vaginal bleeding: Women on hormone therapy (HT) are more likely than other postmenopausal women to experience abnormal vaginal bleeding. What is called "abnormal bleeding" depends on the type of hormone therapy (HT). With cyclic therapy, in which 5monthly bleeding is expected, bleeding is abnormal if it occurs when it is not <br />expected or is excessively heavy or long in duration. With daily continuous therapy, irregular bleeding can last for 6 months to a year, therefore, irregular bleeding that lasts for more than a year is considered abnormal. <br />Stroke: Hormone therapy (HT) slightly increased the risk of stroke in women Because of the possibility of increased breast cancer, stroke, and heart disease risks, women who have no major menopause symptoms may choose to avoid hormone therapy (HT). <br />These adverse effects diverted the attention from conventional estrogens and increased the interest in phytoestrogens. The result of Women’s health initiative demonstrated that many of the ill-effects of conventional estrogen therapy are due to the late age (63 years) of women taking this treatment. The great promise of phytoestrogen use is that they are natural and basically derived from food products; they can be successfully used in all stages of menopause, without any serious harmful effects reported so far. However, the efficacy of conventional estrogens in treating acute vasomotor and psychometric symptoms is much superior to that of the weaker phyoestrogens. The rule of the thumb is to use conventional estrogen for the alleviation of greater efficacy. Conversely, phytoestrogens should be used for long-term prevention as they are slow-acting, but safer on extended use.<br />PHYTOESTROGENS:<br />Phytoestrogens are plant-derived xenoestrogens functioning as the primary female sexhormone estrogen not generated within the endocrine system but consumed by eating phytoestrogonic plants. Also called "dietary estrogens", 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.<br />ADVANTAGES OVER ESTROGENS:<br />These substances are estrogenic compounds which occur naturally in plants such as soy, black cohosh, dong quai, licorice root, etc.  In countries where large amounts of phyto-estrogens are consumed, women suffer very few menopausal symptoms.  Phyto-estrogens differ remarkably from synthetic estrogens in that they are easily broken down, are not stored in the tissues and spend very little time in the body, thus they are unlikely to cause cancer. And because humans have spent millions of years eating plants and herbs, our bodies easily accept plant estrogens and find them both effective and beneficial.<br />Phyto-estrogens appear to exert a natural balancing action in the body. If estrogen is low, phyto-estrogens will increase estrogen activity in the body.  When estrogen levels are high, phyto-estrogens will compete for estrogen receptor sites, causing a decrease in the estrogen effects.  The result is a chemo protecting action.  Numerous studies have indicated that high intake of phyto-estrogenic substances may reduce the risk of breast cancer.<br />The US National Institutes of Health announced.  In fact, years-long use of synthetic estrogens and progestin increased otherwise healthy women's risk of a stroke by 41 percent, a heart attack by 29 percent and breast cancer by 24 percent<br />STRUCTURE:<br />Phytoestrogens mainly belong to a large group of substituted natural phenolic compounds: the coumestans, prenylated flavonoids 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.<br />FOOD SOURCES:<br />Phytoestrogen can be also found in wide variety of food products (including herbs), even though the level varies depending on the source. Below is a short list of phytoestrogen food sources.<br />Table 1. Foods high in phytoestrogen content.<br />Phytoestrogen food sourcesPhytoestrogen content (µg/100g)Flax seed379380Soy beans103920Tofu27150.1Soy yogurt10275Sesame seed8008.1Flax bread7540Multigrain bread4798.7Soy milk2957.2Hummus993Garlic603.6Mung bean sprouts495.1Dried apricots444.5Alfalfa sprouts441.4Dried dates329.5Sunflower seed216Chestnuts210.2Olive oil180.7Almonds131.1Green bean105.8Peanuts34.5Onion32Blueberry17.5Corn9Coffee, regular6.3Watermelon2.9Milk, cow1.2<br />Total phytoestrogen and lignin content in vegetables, fruits, nuts and drinks.<br />Food items Lignan content (µg/100g)Total phytoestrogen (µg/100g)VegetablesSoy bean sprouts2.2789.6Garlic583.2603.6Winter squash113.3113.7Green beans66.8105.8Collards97.8101.3Broccoli93.994.1Cabbage79.180FruitsDried prunes177.5183.5Peaches61.864.5Strawberry48.951.6Raspberry37.747.6Watermelon2.92.9Nuts and other legume seedsPistachios198.9382.5Chestnuts186.6210.2Walnuts85.7139.5Cashews99.4121.9Hazel nuts77.1107.5Lentils26.636.5BeveragesWine, red37.353.9Tea, green1213Wine, white812.7Tea, black8.18.9Coffee, decaf4.85.5Beer1.12.7OtherBlack bean source10.55330.3Black licorice415.1862.7Bread, rye142.9146.3<br />Epidomological studies give evidence that Asian women experience milder menopausal symptoms and this because of high intake of soy products in the Asian diet.<br />Soy foods and flax seed have the highest amount of phytoestrogens however all pant foods contain some.<br />EXTRACTION OF PHYTOESTROGENS FROM FOODS:<br />Several methods for the extraction of phytoestrogens, especially isoflavones, have been proposed. Some methods are used to determine the various conjugated forms of phytoestrogens, whereas others are used to determine total phytoestrogens within foods. To determine the individual phytoestrogen composition in foods, extractions are done without a hydrolysis step. To determine total phytoestrogen content, enzymatic hydrolytic with Aspergillums nigercellulase is carried out. <br /> Acidified Solvent Extraction of Phytoestrogens:<br />A general procedure that is suitable for the extraction of phytoestrogens. Raw soybean seeds (2 g) with their seed coats are ground, mixed with 2 ml 0.1N HCl and 10 ml of acetonitrile, stirred <br />for 2 h at room temperature, and filtered through Whatman No. 42 filter paper. The filtrate is taken to dryness under vacuum at a temperature below 300c. The dried material is redissolved in 10 ml of 80% aqueous methanol and then filtered through a 0.45m filter unit. An aliquot of the <br />filtrate (20μ l) is analyzed by reversed phase HPLC. Although this extraction method preserves the isoflavone conjugates, degradation of the O-malonylglycosides in aqueous methanol occur seven at room temperature. Coward et al. (1998) have shown that extraction of isoflavones at 40c, where degradation is minimized, is possible if an internal standard such as fluorescein is used. In this latter method, the extract is not concentrated prior to HLPC analysis, but instead analyzed directly. Flavones and p-hydroxybenzoic acid have also been used as internal standards.<br />Solvent Extraction of Phytoestrogens:<br />Isoflavones in solid foods are extracted into 80% aqueous methanol (10 ml/g) by stirring for 1 h at 600c. Other soy products (miso, soy milk, soy paste, and tofu) are freeze-dried and extracted whole. The mixture is centrifuged at 2500g for 10 min and the supernatant is transferred to a round bottom flask. The pellet is extracted twice more in 5 ml each and centrifuged. Supernatants are combined in the round-bottom flask and evaporated to dryness in a rotary evaporator. The dried extracts are resolubilized in 5 ml of 50% aqueous methanol and then defatted by partitioning the neutral lipids into hexane (4 20 ml). The aqueous methanol is taken to dryness in a rotary evaporator, and the resulting dried residue is resolubilized in 10 ml 80% aqueous methanol. An aliquot is centrifuged at 14,000gfor 2 min and analyzed by HPLC as described by Coward et al. (1993).While Coward et al. (1993) used aqueous methanol, Griffith and Collison (2001) used acetonitrile for isoflavone extraction: soy foods (1 g) are dispersed into a 10ml volume of acetonitrile followed by the addition of 6 ml double de ionized water and 0.5 ml apigenin [2000 g/ml in dimethylsulfoxide (DMSO)]. Samples are shaken to mix and extracted on a rotary mixer for 2 h, after which the sample is recovered and the acetonitrile concentration is adjusted to 50% (v/v) with the addition of deionized water. Samples are centrifuged at 2000g for 10 min to pellet insoluble matter and eliminate foam. An aliquot is filtered through a 0.45 μ m PVDF filter and analyzed by HPLC.<br />Extraction Followed by Enzymatic Hydrolysis :<br />Phytoestrogen-containing materials (2.5 g) are mixed with a minimum of 5 ml of 80% aqueous methanol. If the material under study is particularly enriched in phytoestrogens, then the amount taken for analysis should be reduced, as phytoestrogens have a limited solubility in aqueous <br />methanol, which would thereby lead to an erroneously low result. Sonication for10 min solubilizes the phytoestrogen glycosides in the methanol by breaking up cellular material. It is followed by a further hour of soaking in the solvent. Insoluble material is removed by filtration through a double layer of filter paper (Whatman No. 4 and then No. 1), and any adsorbed phytoestrogens are washed through with fresh 80% aqueous methanol (>5ml). The methanol in the filtrate is evaporated, and 100 Fishman units of cellulase from A. Niger are added to the sample in 5 ml of 0.1 M sodium acetate buffer, pH 5. Samples are sonicated and subsequently incubated overnight in a shaking water bath at 37. The hydrolyzed phytoestrogen aglycones usually precipitate because of their reduced aqueous solubility. They are extracted from the aqueous hydrolyzes by the addition of 100%ethyl acetate. Three 2 μ ml extracts with ethyl acetate are combined; a 1 μ ml aliquot of the combined extract is pipetted into a separate vial and taken to dryness at 600c under nitrogen prior to chromatographic analysis of the phytoestrogen aglycones.<br />Extraction of Lignans:<br />Milder et al. (2004) developed an assay to extract lignans from a variety of foods, including flaxseed, broccoli, whole wheat bread, and tea. Previous extraction methods allowed for the quantitation of the major lignans secoisolarici resinol and matairesinol but were lacking for pinoresinol and lariciresinol. To allow for quantification, the lignans need to be extracted from their food matrices. This can be difficult due to their ability to oligomerize with 3-hydroxy-3-methylglutaric acid through ester bonding. Therefore, lignan extractions require the use of alkaline hydrolysis to release the lignan glycosides from the 3-hydroxy-3-methylglutaric acid. There are many unknown lignan glycosides; therefore, lignan extraction methods typically have <br />a hydrolysis step to allow for the release of the glycosides. This results in an estimate of the total lignan content in foods. The following describes the current extraction and analysis methods for <br />lignans from foods. Alkaline extraction of 1.0 g of dry food is performed with 24.0 ml of methanol/water (70/30, v/v) containing 0.3Msodium hydroxide in a shaking water bath for 1 h at 150 rpm and 600c. After extraction, the pH is adjusted to 5–6 with 750 μ l of 100% glacial acetic acid and the extract is centrifuged at 4,500g for 10 min at 100c.An aliquot (1 ml) is transferred to a pre weighed test-tube. Methanol is evaporated from this aliquot at 600c, under nitrogen, until the residual weight is< 0.30 g. The volume is adjusted to approximately 1.2ml with 0.05 M sodium acetate buffer, pH 5, and the extract is weighed again to calculate the dilution compared to the original aliquot of 1 ml. A 1-ml aliquot of the weighed extract or 1 ml of beverage is hydrolyzed by the addition of Helix pomatia β glucuronidase/sulfatase (0.83 mg in 1 ml0.05 M sodium acetate buffer, pH 5). The samples are incubated overnight at 370c. Samples are extracted twice with 2 ml diethyl ether, and the two organic phases are combined. The diethyl ether is evaporated, and the dried samples are redissolved in 0.3 ml of methanol, mixed, and 0.7 ml water is added. A 240- μ l aliquot of sample is added to 10 μ l of internal standard solution containing 50 ng of secoisolariciresinol-d8 and 50 ng of matairesinol-d6 in 30% aqueous methanol. Samples are mixed and transferred to HPLC vials for LC-MRM-MS analysis.<br />MECHANISM OF ACTION:<br />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.<br />The key structural elements that enable phytoestrogens to bind with high affinity to estrogen receptors and display estradiol-like effects are:<br />The phenolic ring that is indispensable for binding to estrogen receptor<br />The ring of isoflavones mimicking a ring of estrogens at the receptors binding site<br />Low molecular weight similar to estrogens (MW=272)<br />Distance between two hydroxyl groups at the isoflavones nucleus similar to that occurring in estradiol<br />Optimal hydroxylation pattern<br />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 binding or stimulating the synthesis of sex hormone binding globulin (SHBG).<br />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 dominate 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.<br />METABOLISM:<br />The two main isoflavonoids (genistien and diadzen) are present in all soy bean foods either as aglycone or as beta-glycoside(conjugated). The malonyl and acetyl glycosides are also present, but they are susceptible to heat and are readily converted into more stable beta-glycoside. These glycosides are readily hydrolysed to estrogenically active aglycones either as result of processing and preparation of soy food or as result of the metabolism by intestinal microflora. Genistien is further metabolized in gut to p-ethyl phenol, diadzein to equol, dihydrodiadzien to o-methylangolensin.<br />The diadzein metabolite equol may exert significant biological effects, having greater antioxidant activity than other phytoestrogens, and is often found in highest concentration in the blood and urine in humans. Further metabolism of isoflavonoids takes place by conjugating the aglycone with glucouronic acid and to lesser extent sulfuric acid. Coumestol is found in medicago sativa, clovers and in low levels in beans and peas. It is least studied for biological activity and metabolism. Linseed(flax seed) is a rich source of lignans. The two precursors of lignans namely secoisolariciresinol and matairesinol occur in the aleuronic layer of the grain close to the fibre layer. After fermentation by colonic microflora, two diphenols namely enterodiol and enterolactone are formed, which structurally similar to estradiol.<br />After absorption these are excreted in urine. Urinary isoflavonoid excretions range from about <br />0.3-30 μM/day. Though phytoestrogens can be measured in urine , plasma, feces, semen, bile, saliva, and breast milk, the concentration of their metabolites differ widely among individuals even after administration of controlled quantity of food supplements. This is due to gut microflora, antibiotic use, gender difference and concamitent dietary intake. Urinary secretions of vegetarians may contain 1000 times higher phytoestrogens than total urinary steroid estrogens.<br />CLINICAL USES:<br />Phytoestrogen supplements have a number of uses which mainly focus on increasing estrogen levels and balancing hormone levels within the body. <br />Menopause: <br />Menopause can cause a number of uncomfortable side effects and there are a range of treatments available for women during this time. Hormone replacement therapy (HRT) and Estrogen replacement therapy (ERT) can both relieve menopausal symptoms and are recommended for women who are post menopausal. As well as reducing hot flashes and mood swings, both HRT and ERT can also help prevent cardiovascular disease and osteoporosis.<br />As both treatments include prescription estrogens, many people view them as being unnatural and therefore potentially dangerous. Phytoestrogen supplements are currently being used as a natural alternative and are proving to be extremely popular among menopausal women. <br />Osteoporosis:<br /> Osteoporosis is a common condition which affects people as they mature and the result is painful and debilitating swelling of the joints. Low estrogen levels are thought to contribute to osteoporosis as post menopausal women often see their bones weaken. Phytoestrogen for osteoporosis can be an effective treatment. <br />Phytoestrogens Reduce Risk for Stroke:<br />Stroke is the third most common cause of death for middle-aged and older women. A 50-year-old woman has about a one in five chance of suffering a stroke in her remaining lifetime. One of the most common causes of stroke is blockage due to atherosclerosis of the carotid arteries in the neck the arteries responsible for a major portion of the blood flow to the brain. Phytoestrogens have been shown to improve a women's lipid profile to prevent strokes, similar to Premarin without the harmful side-effects associated with such drugs.<br />Phytoestrogens Reduce Risk for Cancer :<br />In a study published in Environmental Health Perspectives, researchers reported that, in addition to their benefits for the glandular system, phytoestrogens have been shown to have antioxidant activity and can influence intracellular enzymes, protein synthesis, growth factor action, and cell proliferation in a way that makes them "strong candidates for a role as natural cancer-protective compounds."<br />PHYTOESTROGEN PRODUCTS:<br />Emerita PhytoEstrogen Cream:<br />Emerita phytoestrogen cream is a remedy for: <br />Hot Flashes <br />Night Sweats <br />Mood Swings <br />Vaginal Dryness <br />Urinary Incontinence <br />Skin Conditions <br />Low Libido <br />Hair Loss <br />Sleeping Difficulties <br />Instructions:Massage 1/4 to 1/2 teaspoon of Emerita phytoestrogen cream into skin. Suggested application sites of Emerita phytoestrogen cream include the palms, inner arms, abdomen, chest, insides of the thighs, and backs of the knees. Emerita Phytoestrogen Cream may be used daily. Individual needs may vary. Cautions:Emerita phytoestrogen cream is not recommended when pregnant or breastfeeding unless your health care provider specifically recommends it. <br />PHYTOESTROGEN PLUS (capsules):<br />Contains plant source ingredients with known phytoestrogen activity, including black cohosh, chaste berry, dong quai, red clover, and soy isoflavones. All these plant source ingredients are in the form of standardized extracts in order to guarantee potency. The ingredients are contained in a preservative-free gelatin capsule.<br /> Phytoestrogen Plus also contains gamma oryzanol (a substance derived from rice bran that has the proven ability to reduce hot flashes) and Vitamin E, providing a broader range of nutrients that can support body function.<br />Phytoestrogen Plus should be used primarily to support women's health during perimenopause and menopause, and also may be helpful for women experiencing post menopausal symptoms.<br />Chattem - Rejuvex (Disc), 30 caplets:<br />The unique Rejuvex formula combines dong quai (a Chinese herb), magnesium, boron and glandular powders to support a woman's health during and after the menopause years. These ingredients, combined with synergistic levels of other vitamins and minerals, provide a woman with nutrients she needs for a comfortable menopause and continuation of a full, active life.<br />Healthy bonesRejuvex supplies 500mg of magnesium - essential for the support of strong healthy bones.<br />PHYTOESTROGEN &IPRIFLAVONES:<br />PhytoEstrogen & Ipriflavones Dosage:Use only as directed. Take two capsules daily with a meal or glass of water. Store in a cool, dry place.<br />PhytoEstrogen & Ipriflavones Caution:Do not use if safety seal is broken or missing. Keep out of reach of children.<br />ESTROSOY REPLENISH LIFT<br />Gives forty-plus skin a new lease on life. Phytoestrogen works to combat the effects of hormonal changes. Brings back a youthful firmness, resilience and smoothness. <br />SIDE EFFECTS OF USING PHYTOESTROGEN:<br />The side effects of phytoestrogens differ depending on the plant from which the chemical is sourced. Soy, for instance, may have different phytoestrogenic side effects to black cohosh<br />Phytoestrogen acne: is one possible side effect and although not life threatening, it can be embarrassing and uncomfortable.<br /> Soy intoxication: If a person starts to eat soy beans as a way of introducing phytoestrogens into their diet it important to be aware that the plant chemicals in these beans can be toxic and act as anti-nutrients. The beans must be cooked slowly or fermented to ensure that these harmful chemicals are not ingested. <br />Lost of Zinc absorption: Phytate, found in phytoestrogen, affects the body by binding to Zinc to estrogen receptors. This can cause Zinc absorption in the body to decrease, potentially damaging cell functions in the bones, skin, muscles, eyes, and kidneys. <br /> Phytochemicals found in soy: Some phytochemicals slow down the enzymes that digest protein into simple building blocks of amino acids, which does not occur in phytoestrogen-free products. <br />Other hormone medication: Such as the contraceptive pill or HRT, should not be taken alongside phytoestrogens. Side effects may include these treatments becoming ineffective. <br />Genistein inhibits an enzyme called GLUT-1: This enzyme transports glucose used in brain cells and red blood cell.<br /> <br /> CONCLUSION<br />Because of the adverse effects caused by harmone replacement therapy now a days there is diversion in attention from conventional estrogens and increase in interest in phytoestrogens. The great promise of phytoestrogen use is that they are natural and basically derived from food products; they can be successfully used in all stages of menopause, without any serious harmful effects. Today more and more people are turning to these naturally-occurring compounds as an alternative to man-made and potentially dangerous hormone replacement treatments.<br /> REFRENCES<br /><ul><li>WWW.WIKIPEDIA.ORG
  10. 10. WWW.MENOPAUSERX.COM</li></ul> <br />