Phytoestrogen supplements by Ray Sahelian, M.D. Health benefit of Phytoestrogen supplements and phytoestrogen side effects

 Phytoestrogens are a group of plant-derived compounds which include mainly isoflavones, lignans, coumestanes, stilbenes and the flavonoids quercetin and kaempherol. Phytoestrogens are non-steroidal plant molecules whose structure differs from gonadal hormones, but with an estrogen-type activity: they are capable of interacting with estrogen receptors, showing both agonist and antagonist methods of action. The beneficial effects of various classes of phytoestrogens present in nature are now known, but the main isoflavone present in soy, genistein, appears to be particularly effective. Interest in genistein is concentrated in particular on its therapeutic role in menopause. A diet rich in isoflavones is associated with a reduced incidence of vasomotor episodes; the average supplement of genistein is approximately 50 mg/day. After supplementing the diet with phytoestrogens, studies show a reduction in total cholesterol and LDL fraction. This is accompanied by an increase in bone mineral density after taking 90 mg of isoflavones for 6 months. Isoflavones may reduce the risk of developing breast cancer but it is not known whether phytoestrogen supplements will reduce breast cancer risk.
   Some of the well-known phytoestrogens include genistein, daidzen, coumestrol and zearalenone.

Phytoestrogens and heart disease
High intake of phytoestrogens in postmenopausal women appears to be associated with a favorable metabolic cardiovascular risk profile. A Western diet rich in tofu and other soy products may help protect older women from heart disease.

Phytoestrogen Isoflavones - Daidzen and Genistein, 1000 mg
 Source Naturals

Phytoestrogens derived from soybeans have been the focus of scientific research for several decades. Studies have shown that phytoestrogens can bind to the same receptor sites as estrogens. Soybeans are a significant dietary source of phytoestrogens; however, the amount of soy foods necessary to meet the body's needs can be difficult to incorporate into today's diet. In Asia, where soy is a staple, the daily intake can be up to 20 times that of a Western diet. Source Naturals phytoestrogens isoflavones is made from isoflavone-rich soybean powder that yields a consistent standardized isoflavone content. This unique chemical-free process requires approximately 400 pounds of soybeans to yield just one pound of finished product.

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Phytoestrogen Supplement Facts:
Serving Size 2 Tablets
Serving Per Container 60

Total Carbohydrates - 1 g
Protein - 1 g
Isoflavone-rich - 2 g*
Soybean Powder (Soylife™) Yielding:
   Daidzein - 34 mg
   Glycitein - 20 mg
   Genistein - 8 mg
   Total Isoflavones - 62 mg

Phytoestrogens and breast cancer
There is a lot of confusion and disagreement regarding the role of phytoestrogens and their influence on breast tissue and breast cancer. Japanese women eat a good amount of soy foods yet do not seem to have a higher rate of breast cancer. At this time my impression is that eating a small amount of soy, as part of a diet that has a wide range of foods, does not pose a risk or harm. Phtyoestrogens have weak estrogen and anti-estrogen effects and their overall influence depends upon the dose, frequency of use, individual metabolism, and the rest of the diet.

Distribution of soy-derived phytoestrogens in human breast tissue and biological fluids.
Obstet Gynecol. 2004 May. Laboratory of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences, Ghent University, Belgium.
Soy-derived phytoestrogens may exert several health-beneficial effects. Although plasma and urine levels of these compounds after ingestion have been thoroughly investigated, little is known about their tissue distribution, which is particularly important for tissues with high endogenous estrogen and estrogen receptor concentrations. We aimed to investigate the concentrations of genistein, daidzein, and equol in human breast tissue homogenate and to compare these with the corresponding values in serum and urine. A randomized, double-blind, placebo-controlled study was undertaken to evaluate the concentrations of soy-derived phytoestrogens achieved in breast tissue homogenate, serum, and urine after ingestion of either a soy-based food supplement (n = 9) or a placebo tablet (n = 19) for 5 consecutive evenings before aesthetic breast surgery. Urine concentrations of genistein, daidzein, and equol were significantly higher in the soy-supplemented subjects than in the subjects ingesting the placebo. Only genistein was found to be significantly higher in serum of the soy group than in the placebo group, and no significant differences were found in breast tissue homogenate concentrations of all analytes between the 2 groups. Intake of soy-based food supplements for 5 consecutive days did not result in significantly higher genistein, daidzein, and equol concentrations in breast tissue homogenate when compared with the placebo group. The concentrations were in the low nanomolar range, whereas in the corresponding serum samples, concentrations were a hundred-fold higher.

Soy isoflavones, estrogen therapy, and breast cancer risk: analysis and commentary.
Nutr J. 2008 June. Messina MJ, Wood CE. Nutrition Matters, Inc, 439 Calhoun Street, Port Townsend, WA 98368, USA.
In recent years the relationship between soyfoods and breast cancer has become controversial because of concerns--based mostly on in vitro and rodent data--that isoflavones may stimulate the growth of existing estrogen-sensitive breast tumors. This controversy carries considerable public health significance because of the increasing popularity of soyfoods and the commercial availability of isoflavone supplements. Overall, there is little clinical evidence to suggest that isoflavones will increase breast cancer risk in healthy women or worsen the prognosis of breast cancer patients. There is no evidence that isoflavone intake increases breast tissue density in pre- or postmenopausal women or increases breast cell proliferation in postmenopausal women with or without a history of breast cancer. The existing data should provide some degree of assurance that isoflavone exposure at levels consistent with historical Asian soyfood intake does not result in adverse stimulatory effects on breast tissue.

Types of phytoestrogens and their mechanism of action
More estrogen-like compounds in the plant kingdom are constantly being discovered. Phytoestrogens show a complex mode of action via interaction with the nuclear estrogen receptor isoforms ERalpha and ERbeta, exhibiting either estrogen-agonist or estrogen-antagonist effects. Their final biological activity depends on multiple factors such as the chemical structure of the phytoestrogen, the kind of tissue and cell type, the intrinsic estrogenic status, the route of administration, the metabolism as well as the time and the level of exposure.
   Plants contain several different families of natural substances among which are compounds with weak estrogenic or antiestrogenic activity in humans. These substances, termed phytoestrogens, include certain isoflavonoids, flavonoids, stilbenes, and lignans. The best-studied dietary phytoestrogens are the soy isoflavones and the flaxseed lignans. Their perceived health beneficial properties extend beyond hormone-dependent breast and prostate cancers and osteoporosis to include brain function, cardiovascular disease, immunity, inflammation, and reproduction.

What is the opinion of the medical establishment?
Long term replacement with Premarin (horse derived estrogens) and synthetic progesterone increases the risk for heart disease, cancer, blood clots and gallbladder disease. 
   The field of hormone or herbal therapy during or after menopause is very complicated and there is no consensus within the medical community regarding the best option for long term therapy. The medical community seems to be shifting its viewpoint on hormone replacement. It appears that most traditional doctors now prefer using low doses of hormones for a brief period of time to treat menopausal symptoms, but prefer not to continue hormone replacement therapy indefinitely as in the past.

Phytoestrogen Research Update
Psychological assessment of the effects of treatment with phytoestrogens on postmenopausal women: a randomized, double-blind, crossover, placebo-controlled study.
Fertil Steril. 2006 Apr;85(4):972-8. Department of Human Physiology and Pharmacology Vittorio Erspamer, University La Sapienza, Rome, Italy
Seventy-eight postmenopausal women were given 60 mg/day isoflavones or placebo for 6 months. After a washout period of 1 month, the patients who had been treated with phytoestrogens received placebo, and those who previously received placebo were administered phytoestrogens (for 6 months). Cognitive performance and mood were assessed by a battery of tests at the end of each treatment period. At the end of the study, the patients were also asked whether they preferred the first or second treatment. The 17 scores on cognitive performance test and the 6 for mood assessments 6 showed an advantage for the treatment with phytoestrogens. Similarly, of the 8 visual analogue scales used to indicate mood, 7 improved significantly after the treatment with phytoestrogens. Moreover, 49 patients preferred phytoestrogens, 9 placebo, and 18 had no preference. The preference was not related to the order of treatment. Conclusion: These results suggest that isoflavones may have positive effects on postmenopausal women improving cognitive performance and mood.

Phytoestrogens derived from red clover: An alternative to estrogen replacement therapy?
J Steroid Biochem Mol Biol. 2005 Apr;94(5):499-518.
The benefits of plant extracts from soy and red clover as alternatives to conventional hormone replacement therapy (HRT) have been debated in the past. Here, an attempt has been made to summarize the biochemical and pharmacological data in the light of clinical aspects. Red clover and soy extracts contain isoflavones, which have a high affinity to estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), progesterone receptor (PR) and androgen receptor (AR). The higher affinity to ERbeta compared to ERalpha has been used as an explanation why red clover extracts function as food additives to treat menopausal disorders and may reduce risk of breast cancer. Biochemical analysis shows that these representatives of phytoestrogens have multiple actions beside selective estrogen receptor modulator (SERM)-activity. They act as selective estrogen enzyme modulators (SEEMs), have antioxidant activity and interact with transcription factors such as NF-kappaB. Furthermore, it is indicated that they have protective effects on osteoporosis and the cardiovascular system. Currently 40-50mg of isoflavones (biochanin A, daidzein, formononetin and genistein) are recommended as daily dose. This recommendation is based on the daily intake of phytoestrogens in a traditional Japanese diet.

Evaluation of the estrogenic effects of legume extracts containing phytoestrogens.
J Agric Food Chem. 2003 Apr 9;51(8):2193-9.
Seven legume extracts containing phytoestrogens were analyzed for estrogenic activity. Methanol extracts were prepared from soybean (Glycine max L.), green bean (Phaseolus vulgaris L.), alfalfa sprout (Medicago sativa L.), mung bean sprout (Vigna radiata L.), kudzu root (Pueraria lobata L.), and red clover blossom and red clover sprout (Trifolium pratense L.). Extracts of kudzu root and red clover blossom showed significant competitive binding to estrogen receptor beta (ERbeta). Estrogenic activity was determined using an estrogen-dependent MCF-7 breast cancer cell proliferation assay. Kudzu root, red clover blossom and sprout, mung bean sprout, and alfalfa sprout extracts displayed increased cell proliferation above levels observed with estradiol. The pure estrogen antagonist, ICI 182,780, suppressed cell proliferation induced by the extracts, suggesting an ER-related signaling pathway was involved. The ER subtype-selective activities of legume extracts were examined using transiently transfected human embryonic kidney (HEK 293) cells. All seven of the extracts exhibited preferential agonist activity toward ERbeta. Using HPLC to collect fractions and MCF-7 cell proliferation, the active components in kudzu root extract were determined to be the isoflavones puerarin, daidzin, genistin, daidzein, and genistein. These results show that several legumes are a source of phytoestrogens with high levels of estrogenic activity.

The value of phytoestrogens as a possible therapeutic option in postmenopausal women with coronary heart disease.
J Obstet Gynaecol. 1999;19(5):455-9.
Large epidemiological studies have proved that the risk of coronary heart disease in postmenopausal women can be decreased by oestrogen replacement therapy. The effect is triggered by metabolic processes in the liver (decrease of LDL-cholesterol, increase of HDL-cholesterol) as well as by direct impact on the arterial wall (anti-oxidation, relaxation, anti-proliferation). The therapeutical usage of oestrogens is limited by an increased incidence of breast and endometrial cancer. Cyclic application of progestogens virtually eliminates the risk. Unfortunately, progestogens may antagonise the atheroprotective effect of oestrogens. Structurally modified oestrogens as well as selective oestrogen receptor modulators were investigated in clinical trials. They might provide the desired atheroprotective effects of oestrogen without negative side effects on the mammary gland or the endometrium. In this respect isoflavones also known as phytoestrogens, were analysed. Phytoestrogens are widespread and occur naturally in many plants, especially in soy products. Cell culture and animal experiments as well as clinical studies revealed that phytoestrogens such as genistein and daidzein protect arteries in the same way as oestrogen. Effects on the mammary gland or the endometrium could not be detected, but positive side effects on the bone metabolism and the decrease of certain types of cancer could be observed. In total, the therapeutic application of phytoestrogens in postmenopausal women seems to be of real and great benefit. We conclude that in women the risk of death from coronary heart disease increases after the onset of menopause. Recently discovered properties of phyto-oestrogens seem to be of great benefit as they do not seem to have any side effects on the mammary gland and the endometrium which are limiting factors for oestrogen replacement therapy.

Phytoestrogens in common herbs regulate prostate cancer cell growth in vitro.
Nutr Cancer. 2004;49(2):200-8. Shenouda NS, Zhou C
Department of Biochemistry and the Missouri University Center for Phytonutrient and Phytochemical Studies, University of Missouri, Columbia
Prostate cancer is an important public health problem in the United States. Seven phytoestrogens found in common herbal products were screened for estrogen receptor binding and growth inhibition of androgen-insensitive (PC-3) and androgen-sensitive (LNCaP) human prostate tumor cells. In a competitive 3H-estradiol ligand binding assay using mouse uterine cytosol, 2.5 M quercetin, baicalein, genistein, epigallocatechin gallate (EGCG), and curcumin displaced > 85% of estradiol binding, whereas apigenin and resveratrol displaced > 40%. From growth inhibition studies in LNCaP cells, apigenin and curcumin were the most potent inhibitors of cell growth, and EGCG and baicalein were the least potent. In PC-3 cells, curcumin was the most potent inhibitor of cell growth, and EGCG was the least potent. In both cell lines, significant arrest of the cell cycle in S phase was induced by resveratrol and EGCG and in G2M phase by quercetin, baicalein, apigenin, genistein, and curcumin. Induction of apoptosis was induced by all of the 7 compounds in the 2 cell lines as shown by TUNEL and DNA fragmentation assays. Androgen responsiveness of the cell lines did not correlate with cellular response to the phytoestrogens. In conclusion, these 7 phytoestrogens, through different mechanisms, are effective inhibitors of prostate tumor cell growth.

Phytoestrogens are potent inhibitors of estrogen sulfation: implications for breast cancer risk and treatment.
J Clin Endocrinol Metab. 2004 Apr;89(4):1779-87.
We investigated the ability of 37 flavonoids and flavonoid sulfoconjugates, including some abundant dietary constituents, to act as substrates and/or inhibitors of the sulfotransferase and sulfatase enzymes that interconvert active estrogens and inactive estrogen sulfates in human tissues. The enzymes studied include estrogen sulfotransferase, the thermostable phenolsulfotransferase that acts on a range of substrates including estrogens; steroid sulfatase; and two related enzymes, monoamine phenolsulfotransferase and arylsulfatase A. Several dietary flavonoids, including the soy isoflavones genistein and daidzein, were sulfated by these human sulfotransferases. Many flavonoids were potent inhibitors of thermostable phenolsulfotransferase. Genistein and equol were potent mixed inhibitors of hepatic estrogen sulfotransferase, with inhibitory constant values of 500 nM and 400 nM, respectively. Monoamine phenolsulfotransferase activity was relatively unaffected by flavonoids, but this enzyme was mainly responsible for the sulfation of flavonoids at concentrations greater than 1 micro M. Of the compounds tested, only daidzein 4,7-bisulfate, a trace metabolite in humans, significantly inhibited steroid sulfatase in the micromolar concentration range. Hence, dietary flavonoids may be able to influence the bioavailability of endogenous estrogens, and disrupt endocrine balance, by increasing the ratio of active estrogens to inactive estrogen sulfates in human tissues.

Reports: plasma and dietary phytoestrogens and risk of premalignant lesions of the cervix.
Nutr Cancer. 2004;49(2):109-24.
A number of epidemiological studies have observed an inverse association between phytoestrogens and risk of certain hormonally dependent cancers. We undertook an exploratory analysis of the relationship between specific phytoestrogens and premalignant cervical lesions. A case-control study of 122 women with histologically confirmed cervical squamous intraepithelial lesions (SILs) of the cervix and 183 cytologically normal controls was conducted from 1992 to 1996 in Honolulu, Hawaii. A cervical cell sample was obtained for human papillomavirus (HPV) testing. Dietary information was collected using a structured survey, and a fasting blood sample was taken for measurement of five isoflavonoids (genistein, glycitein, daidzein, O-desmethylangolensin, and equol), two flavonoids (hesperetin and naringenin), and two lignans (enterodiol and enterolactone). Plasma levels of equol and enterodiol were positively associated with cervical SIL risk. A nonsignificant positive association with cervical SIL risk was observed for plasma enterolactone. Consistent with the relationships observed for the plasma lignans, dietary sources of lignans, including garlic and taro leaves/ong choy/marunggay, were positively associated with cervical SIL risk. A positive association was also suggested for other lignan sources such as seaweed, onions, grapefruit, and seeds. This is the first study to observe a positive association between specific phytoestrogens and premalignancies of the cervix. The results of this investigation should be considered preliminary and need to be verified in larger, prospective studies.

Phytoestrogens
Zentralbl Gynakol. 2003 Jun;125(6):195-201.
The soy-isoflavones genistein and daidzein and the flaxseed-lignans secoisolariciresinol and matairesinol belong to the group of phytoestrogens. Epidemiological data suggest that phytoestrogens have a preventive effect against various estrogen-related diseases/symptoms such as breast cancer, menopausal symptoms, cardiovascular diseases, and osteoporosis. To prove these assumptions, available controlled clinical trials have been critically reviewed. Especially soy-isoflavones have been extensively studied. There is no scientific evidence for an effect of phytoestrogens on menopausal symptoms and risk factors of breast cancer. However, isoflavones-containing soy protein can lower total cholesterol, LDL cholesterol, and triglyceride serum levels. The strongest evidence exists for a preventive effect of soy isoflavones on postmenopausal bone loss of the lumbar spine. Distinct effects on estrogen-related diseases can be explained at least in part by the different affinity of isoflavones to estrogen receptors alpha and beta and the distinct tissue distribution of these receptors.

Phytoestrogens and prostatic growth.
All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India.
Natl Med J India. 2004 Jan-Feb;17(1):22-6.
The incidence of and mortality from prostate cancer in the West is higher than that in Asian countries. Migrants from Asia to western countries, who maintain their traditional diet, do not have an increased risk of prostate cancer. This has been attributed in part to 'phytoestrogens in vegetarian Asian diets. Prostate cancer is a hormone-dependent disease and estrogens retard the growth of prostatic tumors by interfering with the action of testosterone. Estrogen increases the level of sex hormone-binding globulin that binds testosterone, resulting in lower free testosterone levels, thereby decreasing androgenic stimulation of the prostate. Estrogens used to retard the growth of prostate cancer are associated with certain undesirable side-effects. Phytoestrogens have weak estrogenic potency and anticancer effects. Thus, these phytochemicals have a possible role in the prevention of hormone-dependent diseases such as prostate cancer. Although the relative potencies of various phytoestrogens compared with estradiol are low, the estrogen receptor (ER) complexes formed by estradiol and isoflavones have functional similarities. Also, phytoestrogens have a higher affinity to bind to ER-beta than ER-alpha. They are anti-proliferative and inhibit tyrosine and other protein kinases which play a key role in tumorigenesis, and also inhibit the production of the potent androgen 5alpha dihydrotestosterone in the prostate. Since prostate cancer cells usually multiply slowly and the development of this cancer can take many years before symptoms appear, the latent period provides a chemopreventive opportunity for natural therapy with phytoestrogens. Although phytoestrogens have not yet been used in long-term trials to evaluate their ability to reduce the risk of prostate cancer, the evidence thus far suggests that they have a protective effect against the growth of prostate tumors.

Adding to evidence of the potential benefits of so-called plant estrogens, a new study suggests that isoflavone supplements may help reduce menopausal bone loss. UK researchers found that, when taken for a year, the supplements appeared to curb spinal bone loss in women between the ages of 49 and 65. Isoflavones, compounds found in soybeans, chickpeas and other legumes, are similar to the female hormone estrogen. Because of this, researchers have been studying whether soy protein or supplements containing isoflavones might act as a sort of "natural" hormone replacement therapy. Studies have shown that Asian women, whose traditional diet is rich in soy, have a relatively low rate of hip fracture, as well as breast cancer and heart disease. In addition, animal research has suggested that isoflavones might lessen bone loss related to waning estrogen levels. Some studies of women, however, have found no evidence of bone benefits, and much of the research on isoflavones has involved only small groups of women followed for a relatively short time. The new study, which followed 177 women for a year, is one of the largest and longest investigations of an isoflavone supplement to date, according to the authors. They found that compared with women randomly assigned to take a placebo, those who took a daily isoflavone tablet showed less bone loss in the lower spine.

Phytoestrogens inhibit human 17beta-hydroxysteroid dehydrogenase type 5.
 Mol Cell Endocrinol 2001 Jan 22;171(1-2):151-62
The 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD 5) is involved in estrogen and androgen metabolism. In our study we tested the influence of environmental hormones, such as phytoestrogens (flavonoids, coumarins, coumestans), on reductive and oxidative 17beta-HSD activity of the human 17beta-hydroxysteroid dehydrogenase type 5 (17beta-HSD 5). These dietary substances were shown to be potent inhibitors of aromatase, different 17beta-HSDs and seem to play an important role in delay of development of hormone dependent cancers. Our studies show that reductive and oxidative activity of the enzyme are inhibited by many dietary compounds, especially zearalenone, coumestrol, quercetin and biochanin A. Among the group of flavones inhibitor potency is growing with increasing number of hydroxylations. We suggest that these substances are bound to the hydrophilic cofactor-binding pocket of the enzyme.

Soy Milk Lowers Blood Pressure
Soy milk drinkers have reason to raise their cup and cheer. A recent three month double blind study completed at the School of Medicine in Zaragoza, Spain tested the effect of 500 ml (about a pint) of soy milk compared with the same amount of cow’s milk in 40 men and women with mild-to-moderate hypertension. Before initiation of the study, urinary isoflavonoids (soy contains compounds called isoflavonoids, the best known being genistein) were undetectable in most cases, meaning that their diet contained little or no soy products. After three months of soy milk consumption, systolic blood pressure decreased by 18 mmHg compared with 2 mmHg in the cow’s milk group. Diastolic blood pressure decreased by 15 mmHg versus 4 mmHg in the cow’s milk group. The researchers conclude that chronic soy milk consumption lowers blood pressure in those with hypertension. This blood pressure-lowering action was correlated with the urinary excretion of the isoflavonoid genistein, meaning that the more genistein excreted in the urine (reflecting the higher amount in the body), the lower the blood pressure.
     Dr. Sahelian says: Those who drink large amounts of milk should consider reducing their milk consumption and partially or mostly substituting soy milk instead. Try soy milk brands that have a minimal amount of added sugar. Use stevia drops for additional sweetness.