Phytoestrogen supplements health benefit and side effects, influence on cancer and heart disease
March 12 2017 by
Ray Sahelian, M.D.

Phytoestrogens are a group of plant-derived compounds which include mainly isoflavones (found in soy products), lignans, coumestanes, stilbenes and the flavonoids quercetin and kaempherol. They 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 (blood vessel dilation or contraction) 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.
   Some of the well-known phytoestrogens include genistein, daidzen, coumestrol and zearalenone.

Phytoestrogens derived from soybeans have been the focus of scientific research for several decades. Studies have shown that they 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.

Phytoestrogens and breast cancer
There is a lot of confusion and disagreement regarding their influence on breast tissue and breast cancer (article by Ray Sahelian, M.D.
). Japanese women eat a good amount of soy foods yet do not seem to have a higher rate of breast cancer. Eating a small amount of soy, as part of a diet that has a wide range of foods, does not appear to pose a risk or harm. Phytoestrogens 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.

Cancer, 2017. Dietary isoflavone intake and all-cause mortality in breast cancer survivors: The Breast Cancer Family Registry. Soy foods, isoflavones, and breast cancer. In this large, ethnically diverse cohort of women with breast cancer living in North America, a higher dietary intake of isoflavone was associated with reduced all-cause mortality.

Nutr Cancer, 2015. Anticarcinogenic Effects of Dietary Phytoestrogens and Their Chemopreventive Mechanisms. Besides well-known mechanisms such as antioxidant property and apoptosis, newly elucidated anticarcinogenic modes of action including epigenetic modifications and topoisomerase inhibition have been provided to examine the possibility of phytoestrogens as promising reagents for cancer chemoprevention and/or treatment and to suggest the importance of plant-based diet of phytoestrogens.

Distribution of soy-derived phytoestrogens in human breast tissue and biological fluids.
Obstet Gynecol. 2004.
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 or a placebo tablet 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.
Nutrition J. 2008.
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.

Toxicol Appl Pharmacol. 2013. Phytoestrogens in menopausal supplements induce ER-dependent cell proliferation and overcome breast cancer treatment in an in vitro breast cancer model. Based on our in vitro data we suggest that menopausal supplement intake during breast cancer treatment should better be avoided, at least until more certainty regarding the safety of supplemental use in breast cancer patients can be provided.
   My comments: This in vitro study argues against their use but sometimes in vitro studies do not have as much relevance as finding out what dietary intake actually does in an actual human body. I prefer taking into account evidence from epidemiological studies.

Phytoestrogens and heart disease
High intake 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.

Curr Pharm Des. 2015. Phytoestrogen-Rich Dietary Supplements in Anti-Atherosclerotic Therapy in Postmenopausal Women. Clinical and epidemiologic data indicate that phytoestrogens possess anti-atherosclerotic effects and may be used to prevent and treat cardiovascular diseases, and that adding phytoestrogens to the diet can contribute to the health of postmenopausal women.

Soy Milk lowers blood pressure
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.

Psychological assessment of the effects of treatment with phytoestrogens on postmenopausal women: a randomized, double-blind, crossover, placebo-controlled study.
Fertil Steril. 2006.
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. 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.
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.

Osteoporosis and bone loss
J Clin Densitom. Oct-Dec 2013. Phytoestrogens in the prevention of postmenopausal bone loss. Postmenopausal osteoporosis is a condition associated with low bone mass resulting from the increased bone resorption that occurs following a decline in estrogen levels. Phytoestrogens are plant-derived compounds that have affinity to the estrogen receptor and are able to act as either estrogen agonists or antagonists. Because of their structural similarity to 17-beta-estradiol, they have been studied extensively for their role in the prevention of postmenopausal bone loss. An extensive number of studies employing different types of isoflavone preparations (including soy foods, soy-enriched foods, and soy isoflavone tablets) have been conducted in a wide range of populations, including Western and Asian women. Although there is considerable variability in study design and duration, study population, type of soy isoflavone employed in the intervention, and study outcomes, the evidence points to a lack of a protective role of soy isoflavones in the prevention of postmenopausal bone loss.

Prostatic growth
All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.
Natl Med J India. 2004.
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.

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.

Evaluation of the estrogenic effects of legume extracts containing phytoestrogens.
J Agric Food Chem. 2003.
Seven legume extracts containing phytoestrogens were analyzed for estrogenic activity. Methanol extracts were prepared from soybean (Glycine max), green bean (Phaseolus vulgaris), alfalfa sprout (Medicago sativa), mung bean sprout (Vigna radiata), kudzu root (Pueraria lobata), and red clover blossom and red clover sprout (Trifolium pratense). 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. Several legumes are a source of phytoestrogens with high levels of estrogenic activity.

Phytoestrogens inhibit human 17beta-hydroxysteroid dehydrogenase type 5.
Mol Cell Endocrinol 2001.
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.

So what are transgenders doing that could potentially be dangerous? We are taking supplements which claim to be anti-androgens, in an attempt to reduce the production of testosterone. Along with those supplements we also take more supplements in an attempt to also increase estrogen production. Many transgenders desire to actually shrink away their male genitalia, and they desperately try to grow breasts. One widely used, typical regimen suggested around the net to transgenders is to take the following: Fenugreek at least 3 times per day, to help grow breasts. Saw Palmetto at least 3 times per day as an anti-androgen, to suppress testosterone production. Black cohosh as a estrogenic booster and anti-androgen. Large amount of SOY intake including soy isoflavons because they contain the desired phytoestrogens to try to replace the testosterone are recommended. And flax to do the same, thought to be a good estrogen booster, where transgender males are encouraged to rub flax oil into their breasts in an attempt to grow those breasts. This is only one recommended supplemental regimen, others even include DHEA, and breast creams, and other hormonal type creams. Is it even safe for men to try to stifle their testosterone production and add to their bodies supplements containing huge amounts of phytoestogrens? I think an article on your site would be extremely beneficial to so many people out there who are struggling along in their daily lives, desperately trying to feminize their bodies.
   A. This is a topic I have not studied in enough depth to know how to advise, but I will keep my eyes open for any new information.

Buy Phytoestrogen supplement isoflavones
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.

A product made by Source Naturals has:
Total Carbohydrates 1 g
Protein - 1 g
Isoflavone-rich - 2 grams
Soybean Powder (Soylife) Yielding:
   Daidzein - 34 mg
   Glycitein - 20 mg
   Genistein - 8 mg
   Total Isoflavones - 62 mg

Supplement Facts
Serving Size: 1 Tablet
  Amount Per Serving %DV
Total Carbohydrate 1 g <1%*
Dietary Fiber <1 g 3%*
Total Soy Isoflavones (from soy isoflavone extract)(seed) 38 mg **
* Percent Daily Values (DV) are based on a 2000 calorie diet.
** Daily Value (DV) not established.

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