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When Soy Meets Girl

by Tori Hudson, N.D.

Part I – A look at the health benefits of soy in women’s health

The use of soy in the diet dates back to the Chinese Emperor Shen Nung in 2838 BC. Tofu (a protein-rich curd made from a hot water extract of soybeans) was developed in China and was introduced by Buddhist missionaries to Japan and Korea between the 2nd and 7th centuries. Tofu was even a revered food of the Chinese Emperors in the Ming to Chin dynasties.

Soybeans have been a staple in the diet of Southeast Asians for several centuries. It is estimated that the protein from soy foods comprises 20%-60% of their daily protein. It appears as though soybeans did not make it into the western diet, via France and England until the 18th century.

In the late 1800′s there was an immigration of Chinese laborers into the United States and it is thought that this led to the introduction of soy foods into the U.S. diet. By 1890, soybeans were being grown all over the country. Since the turn of the 20th century, the United States has become the world’s largest producer of soybeans. We largely produce yellow soybeans whereas the Ancient Chinese favored the use of the black soybean.

Americans mostly use soy for the production of one of its least healthy products, vegetable oil. After the crushed soybeans are exposed to extraction with hexane, and the oil is now been removed, the defatted soybeans are pulverized to form soy flour. The soy flours have been exposed to various temperatures of heat. The least heat-treated grade is used in protein-enriched breads. The heat treatment inactivates the protease inhibitors contained in soy. 95% of soy flour is toasted and fed to livestock and other commercially bred animals.

Soy flour can be further treated to create isolated soy protein products with a high protein content. These dried products contain at least 90% protein versus the 50% protein found in soy flour.

Currently, there are a host of soy products found in most grocery stores and even some unusual ones found in natural foods stores. These include dried soybeans, soy oil, soymilk, soy flour, roasted soy nuts, tofu, tofu pate, tempeh, miso, soy sauce, natto, edamame, soy ice cream, soy cheese, soy candy bars, soy burgers and soy hot dogs, and probably a few I’ve forgotten or even hope not to run across. (example: soy marshmallows).

Soy Constituents

Soybeans are noteworthy for their high protein content, approximately 38%. They also contain 18% fat, primarily polyunsaturated fats and only a small amount of saturated fats. 13% of the soybean is made up of soluble carbohydrates (sucrose, stachyrose, raffinose, and others, 15% insoluble carbohydrates (dietary fiber), and 14% moisture, ash, and miscellaneous compounds.

Many common specific vitamin and mineral nutrients are also found in soy. Many soy foods are a good source of calcium. Not only does one half cup of cooked soybeans provide 88 mg of calcium, many brands of tofu are made using calcium sulfate as a coagulant and can contain between 120mg and 750 mg of calcium per ½ cup of tofu. Many soy milks are now also fortified with calcium; some contain 80 mg of calcium per cup but others as much as300 mg of calcium per serving. Soy foods also contain iron, zinc, copper, magnesium, niacin, pyridoxine and folic acid.

“The calcium content of tofu and soy milk per serving depends on how the tofu is processed and how much the soy milk has been fortified.

Perhaps the most recently well known compounds found in soy are the phytoestrogens. Soybeans contain a particular phytoestrogen called isoflavones. These isoflavones behave like weak estrogens, and are able to bind to estradiol receptors in the uterus, breast, brain, bone, arteries, etc. In some cases, they behave in a way that enables them to weakly mimic the effects of estrogen in some tissues, and in other situations, they are able to block the effect of estrogens.

Soybeans are the richest food source of isoflavones, containing 1-2 mg of isoflavones per gram of soy protein. The isoflavones of soy are genistein, daidzein, and glycitein. Not all soy protein products contain phytoestrogens. Some soy protein isolates have been processed with an alcohol extraction that removes the phytoestrogens. When eating soy foods, this is not really a concern, but when using a soy powder or soy capsule, be sure to look for the isoflavone content on the label. Soy protein that has not had the phytoestrogens removed usually contains about 1.2 mg/gram of protein as genistein, 0.5 mg/gram protein as daidzein, and small quantities of glycitein. All the different soy products contain different amount of isoflavones. It’s valuable to know the isoflavone content of the various soy foods and soy products in order to target your desired dose per day.

Fermented soy isoflavone pills Will contain lower amount of isoflavones but may be better absorbedGenestein has a 6-fold greater affinity for the beta estrogen receptor than for the alpha receptor. That is why it may act differently in different tissues depending on the nature of the estrogen receptors in that tissue. It may act as a pro estrogen in the bones but an anti-estrogen in the breast.

Some of the controversy about soy lies not only in it’s ability to selectively modulate estrogen receptors (see next section), but in its content of phytates, trypsin inhibitors, interference with thryoid function and difficult digestibility for some individuals. Soyfoods, especially cooked soybeans are difficult for some people to digest causing gas and stomach upset. Soy’s content of trypsin inhibitors can block the enzymes needed for protein digestion. When the protein is improperly digested, then the fermentation and gas production ensues. However, many researchers believe that so few trypsin inhibitors are left behind after processing the soy food, that for most people, their digestion is not affected.

The phytate content in soybeans has been suspicioned as another cause for concern with soy foods. Phytates block the uptake of minerals such as calcium, magnesium, iron and zinc. Although the phytate content of soybeans is higher than other grains or legumes, the mineral blocking effect of phytates is reduced when eaten with meat or fish. If you eat soy products in the context of a healthy varied diet, you should get adequate minerals. Phytates are also reduced in fermented products like tempeh and miso.

The genestein and daidzein in soy can also inhibit thryoid hormone synthesis. High soybean diets have been implicated in diet-induced goiter. This problem is not likely to occur in an average amount of soy in the diet and again in the context of a healthy varied diet. In some susceptible individuals, or in some who take very high doses of nutritional supplementation of soy isoflavones (above 200 mg per day), it is prudent to be aware of this potential interaction.

Mechanisms of Action of Isoflavones

The isoflavone genestein in particular appears to have a weak estrogenic effect. However, at higher concentrations and in different tissues, it selectively can have an anti-estrogenic effect. So, it can weakly bind to tissues that contain estrogen receptors. By doing so, it may be able to stimulate that estrogen receptor in a weak fashion compared to regular physiologic estrogen or estrogen replacement. It is estimated to be 1/400th to 1/1000th the potency of estradiol. It may also weakly bind to the estrogen receptor and have an ability to inhibit the binding of the body’s estrogen to that receptor, or even inhibit the binding of estrogens outside the body from binding (estrogen replacement, birth control pills, estrogen mimikers in the environment like PCB’s and DDT). Herein lies one of the most unique and little understood properties of genistein, as well as other isoflavones. It is selective as to where it is a pro estrogen and where it is an anti estrogen. It may also be pro and anti depending on the dose. In the total absence of physiological estrogens, genistein in low doses has weak estrogenic effects and can stimulate cell growth, including estrogen receptor positive breast cancer cells in a test tube. However, in that same test, when adding a higher dose of genistein, it inhibit the growth of breast cancer cells. ,

Genistein is also an inhibitor of tyrosine kinases. The tyrosine kinases appear to play a role in cell proliferation and transformation. The circulating levels of a constituent that inhibits tyrosine kinase may have beneficial effects in the treatment of cancer. ,

Isoflavones have been shown to inhibit aromatase. By doing so, they can block the conversion of androstenedione to estrogen thereby another mechanism in reducing the estradiol in the serum and less available estrogen to bind to estrogen receptors.

Isoflavones seem to stimulate sex hormone binding globulin synthesis in the liver and by doing so my reduce the biological effects of sex hormones such as estrogen and testosterone. An increase in sex hormone binding globulin decreases the relative amount of free testosterone and free estradiol. This reduces the clearance rate of these steroids and thus lowers their biological activity. Vegetarians have higher sex hormone binding globulin which may be due to the phytoestrogens in their diet. This mechanism may yet be another avenue for reducing the estrogen effect on tissues such as the breast.

Genistein is also able to have an antiangiogenic effect. The result is altered control and growth of blood vessel architecture. This may have implications in treating hereditary hemorrhagic talengiectesia, tumors and cancerous growths that are dependent on a blood supply.

A number of studies have shown that both daidzein and genistein inhibit free radicals and that genistein has been shown to increase the activity of antioxidant enzymes such as glutathione peroxide, glutathione reductase and superoxide dismutase.6 The antioxidant effects of isoflavones can also protect against the oxidation of LDL cholesterol thereby preventing atherosclerosis. More about this in the section on cardiovascular effects.

Part II – Clinical Effects

Perimenopausal and menopausal hot flashes

The effects of a 12 week diet high in phytoestrogens on menopausal symptoms were studied in 145 women with menopausal complaints. The phytoestrogen diet consisted of daily soybean foods and flaxseeds as approximately one-fourth of the caloric intake. The group of women who ate this diet had an overall greater (although not statistically significant) improvement in their symptoms than that of the non phytoestrogen diet group. However, when symptoms were evaluated separately rather than all together, the reductions in hot flashes and vaginal dryness were more significant.

Dietary soy supplementation was studied for its effect on hot flashes in fifty one postmenopausal women. The women were given 60 grams of isolated soy protein daily (76 mg of isoflavones), and 53 women took 60 grams of placebo (casein) daily for 12 weeks. The soy group was significantly superior to the placebo group in reducing the number of hot flashes: a 26 percent reduction by week 3, a 33 percent reduction by week 4, and a 45 percent reduction in daily hot flashes versus a 30 percent reduction with the placebo by week 12.

Other studies have included giving 160 mg of isoflavones daily for three months, which significantly reduced several menopausal symptoms, especially hot flashes, and the use of a soy bar containing only 40 mg isoflavones which showed a small decrease in menopausal symptoms over a 12 week period. A study comparing soy flour versus wheat flour in postmenopausal women showed a 20% to 40% reduction in hot flashes in the soy flour group over a period of 12 weeks.

Not all studies show that soy fares quite as well. In another study, women were given a high soy foods diet with a daily intake of 1 65 mg/day of isoflavones for four weeks. Investigators found no significant estrogen effect on blood measurements of LH, FSH, and sex-hormone-binding globulin (SHBG) such as were found when 0l.3 mg/day of Premarin was given. Once again, though, there was a small estrogenic effect on the vaginal tissue.

Vaginal epithelium

In a 1999 study, the effects of three soy powders containing different levels of isoflavones in 18 postmenopausal women were given to evaluate the effect on vaginal epithelium, as well as on various plasma hormone concentrations. Vaginal cytology results revealed no significant effects of soy or isoflavone consumption. This study suggests only modest effects of isoflavones on plasma hormones. These data are consistent with some other studies, but inconsistent with some who noted marginally but significantly increased maturation values, indicating an estrogen effect following a diet supplement with soy flour, red clover sprouts or flaxseed for a total of six weeks.

Bone

Soy appears to have a pro estrogen effect on bone in some experimental evaluations. The bone density of ovariectomized rats was evaluated in which soy replaced casein in the diet, compared to another group that received estrogen. The addition of soy inhibited bone loss, although not to the same extent as was achieved with the estrogen treatment. Another study of ovariectomized rats also reported a positive effect of the soy phytoestrogen genistein in maintaining bone. These authors also reported that genistein suppresses the bone losing cells ( osteoclasts), both in the test tube and in vivo.

Several human studies have provided further insight and comfort in the possible role of soy in our bone health. A study conducted at the University of Illinois found that menopausal women had an increase in mineral levels and density in their lumbar spines after taking 55-90 mg of isoflavones for six months. The placebo group showed the lowest bone density and the greatest bone loss, while the estrogen group showed the highest bone density and the slowest bone loss. What was surprising was that the soybean protein diet was effective in preventing bone loss in the fourth lumbar vertebra and, although less so, in the right hip as well. Soybean protein seems to have more of an effect on trabecular bone (more predominant in the spine) than on cortical bone (more predominant in the hip). The soybean protein did not show as great an ability in preventing bone loss as the estrogen group, but the positive effect it showed is encouraging. Further studies are needed to clarify whether this protective effect on bone is due to the protein itself or to the presence of the phytoestrogen isoflavones in soybean protein.

Another aspect of soy to keep in mind is as a source of calcium. A diet that includes greater amounts of soy products can account for a meaningful amount of calcium, and some soy foods can offer as much or more calcium than a serving of dairy products.

Brain

There is very little information to suggest that soy protein or isoflavones have either an estrogen agonist or antagonistic effect on the brain. Since there is increasing evidence that estrogen replacement therapy favorably influences both memory and cognitive function, the effects of soy phytoestrogens on the brain will become increasing
meaningful.

Heart disease

The potential mechanisms by which soy protein and/or isoflavones reduce blood cholesterol includes thyroid status, bile acid balance and the estrogenic effects of genistein and daidzein. Some studies have suggested that isoflavones exhibit antioxidant properties and therefore have a beneficial effect on arterial elasticity. It is also possible that individuals who eat more soy protein may then be foregoing the ingestion of foods relatively high in saturated fat and cholesterol, and thus having an indirect blood cholesterol-lowering effect.

Although we may not understand all the mechanisms yet, consuming more soy protein in the diet can be an effective method of improving one’s cholesterol. In fact, in October 1999, the U.S. Food and Drug Administration announcement that eating 25 grams of soy protein a day lowers the risk of coronary heart disease may have been one of the most significant moments in the history of the natural foods industry. The evidence that soy lowers cholesterol is substantial. Many studies have demonstrated this effect. Perhaps the best evidence comes from a review of 38 clinical trials. This meta-analysis concluded that consumption of soy protein rather than animal protein significantly decreased serum concentrations of total cholesterol, LDL cholesterol, and triglycerides. The soy intake averaged 47 grams per day. The average decreases were: in total cholesterol 9.3 percent, in LDL cholesterol 12.9 percent, and in triglycerides 10.5 percent. HDL cholesterol increased by 2.4 percent. In order to fully appreciate what this means, for every 1 percent reduction in total cholesterol there is a 2 percent reduction in heart disease.

An example of some of these studies includes one from the University of Illinois. The researchers fed 21 men with mildly elevated cholesterol a low fat diet containing muffins of 25 grams of protein and 20 grams of fiber. There were four groups studied depending on the kind of muffin combination: soy protein and soybean fiber; soy protein and cellulose; casein and soybean fiber; or casein and cellulose. After two weeks of eating just a low-fat diet, the individuals tested each muffin combination for four weeks each. Lipid blood tests were taken at the end of every dietary treatment. At the end of the study, they found that the two groups of muffins containing casein did not have a significant effect on cholesterol. The two muffins containing isolated soy protein significantly lowered total cholesterol.

Another important finding with soybean extracts is that they have been shown to reduce coronary artery atherosclerosis of male monkeys. It appears as though the soybean extract has estrogen-like effects on coronary arteries. In fact in one study of female monkeys, soybean extract was compared with giving estrogen or estrogen and progestins. The researchers found that the soybean extract was equivalent to the estrogen treatment in dilating the coronary arteries and better when compared to the estrogen plus the progestin.

Look for new studies in the year 2000 that further elucidate the benefits of soybean products in preventing and lowering the risk of heart disease and the risk of dying from premature heart disease.

Breast

One of the greatest fears for women contemplating menopause treatment options is the concern about estrogen replacement therapy and the increasing risk of breast cancer the longer it is used. Most of the research we have on soy is in relationship to lowering the risk of breast cancer in women who consume more soy in their diets from a young age (Japanese, Chinese women). In addition, we do have some laboratory research to glean theories from, regarding the safety of using soy products in women who have had or have breast cancer.

There is a great deal in the scientific literature that provides support for the conclusion that soy contributes to the prevention of breast cancer. Several studies have observed and concluded that Asian women who consume a traditional low fat, high soy diet have a four to six fold lower risk of developing breast cancer. The soy-derived isoflavones, i.e., genistein and daidzein, protease inhibitors, phytosterols, and saponins are remarkable in their activities against a variety of cancers. Biochemical mechanisms that explain the anticancer action of genistein are numerous, and include antiestrogenic effects, induction of cell differentiation (the more differentiated a cell, the less likely it is to become cancerous), inhibition of several enzymes that induce cancers, antioxidant effects, and antiangiogenesis (limiting the blood supply to cancer cell sites and tumors). Dietary phytoestrogens also inhibit cancer cell growth by competing with estradiol for the type II estrogen binding sites. Even more convincing evidence for the breast cancer protection benefit of soy comes from animal studies. Soy supplementation has reduced the number and size of tumors that were induced with a carcinogenic substance. A review paper of 26 animal studies of experimental carcinogenesis in which diets containing soy or soybean isoflavones were employed, 17 reported protective effects. No studies reported soy intake increased tumor development. The epidemiological data shows that consumption of nonfermented soy products, such as soymilk and tofu, tended to be either protective or not associated with cancer risk; however no consistent pattern was evident with the fermented soy products, such as miso. Protective effects were observed for both hormone and nonhormone related cancers. Another study that offers some insight evaluated the effects of soy consumption on steroid hormones in premenopausal women. Six healthy women in their 20′s ingested 12 oz of soy milk three times daily for one month. Daily isoflavone int akes were approximately 100 mg of daidzein and 100 mg of genistein. Serum estradiol levels decreased by 31% on cycle days 5-7, 12-14 and decreased by 31 % on days 20-22. Progesterone levels in the second half of the cycle decreased by 35%. Menstrual cycle length extended from 28.3 days to 31.8 days during the one month of soy. These results suggest that consumption of soy diets containing phytoestrogens may reduce circulating ovarian steroids, increase menstrual cycle length, two effects that may account in part for decreased risk of breast cancer. While a statement that soy reduces cancer risk cannot be made with certainty at this time, there is a sufficient amount of evidence to feel comforted in its use as a proactive measure one could take to help lower the risk of breast cancer.

There is a legitimate question to be raised regarding the safety of soy when it comes to women who have or have had breast cancer. Is it safe? And, is it different for premenopausal women than for postmenopausal women with a breast cancer history?

Premenopausal women normally have higher estrogen levels than postmenopausal women who are not on hormone replacement therapy. In premenopausal women who eat a diet or take supplements high in phytoestrogens, these weak plant compounds stimulate estrogen receptors and perform some of the same functions as our own body’s stronger estrogens. Our chemical messenger system then says, well, we already have enough total estrogen here, so I’ll tell my ovaries to produce less estrogen because I just don’t need that much more. By doing so, the rate of production of the body’s stronger estrogen declines, and the total estrogen effect on the body (lower internal estrogen production plus weak plant phytoestrogens) is now lower. This mechanism is in part what earns phytoestrogens the characteristic of being called both a “proestrogen” and an “antiestrogen”.

But with postmenopausal women, the result of these mechanisms may be different. Postmenopausal women produce less estrogen, and the total level is low. Eating a high phytoestrogen diet or soy supplement boosts the total estrogen levels, even though these estrogens are far weaker. Now, it would seem that because we have a higher total estrogen effect, it may affect the breast differently when the breast is prepared for less estrogen stimulation at this time in life. The problem is this: we have many facts about women who eat soy throughout their lifetimes starting at an early age, we have animal studies, we have laboratory studies about the mechanisms and some of the antitumor effects of soy. But, what we don’t have yet is a large body of information on women who begin to take large amounts of soy later in life starting after menopause, and we don’t have information on the effects of soy in women who have had breast cancer. Especially with breast cancer, there is some disagreement about the safety of eating soy.

Two reports have supported those people who think it may not be safe in women with breast cancer. One comes from a laboratory study that showed that low doses of genistein stimulated growth of a culture of estrogen sensitive breast cancer cells but higher doses of genistein inhibited growth of the breast cancer cells. Dr. Bob Arnot, in his book The Breast Cancer Prevention Diet interprets this study and recommends that you need to eat between 35 to 60 grams of soy protein per day. This translates to between 35mg to 120 mg of soy isoflavones per day. ( 1 gram of soy protein contains between 1-2 mg of soy isoflavones). The second report is from studying the nipple aspirate of 50 premenopausal women who are at high risk for breast cancer. The women had 3 months of a diet free of soy, with samples taken of their nipple fluid, blood, and urine. They then incorporated into their diet two servings a day of a soy based nutritional beverage powder for 12 months. The 38 grams of soy protein consumed each day contained 70 mg of genistein. Samples were taken at 3 month intervals. The report to date is that the soy increased the nipple aspirate fluid. This may be a marker for substances that might increase breast cancer risk , although certainly not clear.

Doubts as to the significance of the breast cancer protective effects of soy and the safety of soy in breast cancer patients will remain. Until there has been a prospective study on soy comparing women on a high soy diet with women on a no soy diet over the span of many years with identical risk factors in other areas will we be able to advise with absolute confidence. Perhaps more importantly, long term prospective studies with breast cancer patients comparing high and no soy diets, will be the final chapter in understanding the facts.

As a practitioner who advises women as to their health care decisions around menopause and around breast cancer, I had had to come to some decision about this now while waiting for more scientific information to unfold. Here’s what I tell my patients;

  1. We know that women who eat high soy diets during their lifetime have significantly less breast cancer.
  2. We know that soy phytoestrogens are significantly weaker, to the order of 10-3 times that of estradiol.
  3. Phytoestrogens compete with estradiol for the binding of estrogen receptor sites thereby blocking stronger estrogens from binding there.
  4. A review of the biological effects of soy, the mechanisms of action and metabolism of soy, and a review of the epidemiologic and animal studies most all of which provides evidence as to the cancer prevention effects of soy phytoestrogens.
  5. We also have seen soy inhibit tumor growth in animal studies.
  6. Three epidemiological trials in humans have reported a protective effect of soybean products against the development of breast cancer.
  7. Eat more than 35 mg of soy isoflavones daily; even more, if a breast cancer patient.
  8. Use soy isoflavone supplements in the range of 100mg-200 mg of isoflavones in addition to soy protein in the diet daily.
  9. Breast cancer patients who are suffering from menopausal symptoms are given hormone replacement therapy (HRT) – it is believed that the risk of a cancer recurrence is small and that the quality of life issues and benefits of HRT are greater than the risk of HRT. When comparing the strength of HRT to the strength of soy isoflavones, this decision to take hormone support for quality of life becomes even more poignant.

These studies and clinical observations give me great reassurance not only as to the benefit of soy for breast cancer survivors, but to the safety of soy as well. Looked at in another way, the benefits of soy in the areas of hot flashes, vaginal dryness, cholesterol lowering, and possibly bone density far outweigh any speculative insignificant potential risk. We must, however, continue to keep an open mind and extend our science and our scrutiny to the benefits as well as the potential risks.

Endometrium

Like breast cancer, scientific data supports the conclusion the soybeans are not an estrogen agonist ( pro estrogen effect ) for the endometrium (lining of the uterus). It is in fact probably an estrogen antagonist and is associated with low rates of endometrial cancer in countries where soy intake is high. Researchers at the Cancer Research Center at the university of Hawaii published a case-control multiethnic population study to examine the role of dietary soy, fiber, and related foods and nutrients on the risk of endometrial cancer. Over 300 women with endometrial cancer were compared with women in the general multiethnic population, and all women were interviewed with a dietary questionnaire. The researchers found a positive association between a higher level of fat intake and endometrial cancer as well as a higher level of fiber intake and a reduction in risk for endometrial cancer. They also found that a high consumption of soy products and other legumes was associated with a decreased risk of endometrial cancer. Similar reductions in risk were found for increased consumption of other sources of phytoestrogens such as whole grains, vegetables, fruits, and seaweeds. The authors of the study concluded that plant-based diets low in calories from fat, high in fiber, rich in legumes (especially soybeans), whole grain foods, vegetables, and fruits reduce the risk of endometrial cancer. These dietary associations may explain at least in part the reduced rates of uterine cancer in Asian countries compared with those in the United States.

Conclusion

As greater use of soy products and serious research continues, we will accumulate more information about the many uses and effects of soy. We will also develop a greater understanding of some of the limitations of soy, as well as some potential negative influences it may have on some individuals and in some circumstances. One of the more urgent changes needed in my opinion, is a greater source of organic and non genetically modified soy products. Consumers need to be able to make discriminating choices about their food source. As more individuals use soy, then the supply of these more natural sources of soy products will increase. From a wholistic point of view, it is probably optimal to increase the food source of soy phytoestrogens as a foundation for the use of soy products. The theory being that nature probably knows best and that the plant compounds found in their intended package so to speak, is probably what holds the most advantage for us. To augment, or to achieve higher levels of soy isoflavones for particular clinical conditions beyond what we can reasonably achieve in our diet, then soy protein, soy isoflavone powders and soy isoflavone encapsulated products can be added to the diet as supplementation. There are many excellent products on the market. In general, carefully read the label for the soy isoflavone content, particularly looking at the genistein and daidzein content when I’m seeking the clinical effects of the phytoestrogen compounds. If you want the benefits of the protein in soy, then look at the total protein content. Be careful to check for too much simple sugars in some of the protein powders. Look for non genetically modified products, and organic whenever possible.

The diversity in the soy options available, and the many clinical effects in women, have positioned soy foods and soy products as one of the leading natural medicines in women’s health today for both prevention and intervention.

References
  1. Gavaler J, Galvao-Teles A, Monteiro E, Van Thiel D, Rosenblum E. Clinical response to the administration of bourbon phytoestrogens to normal postmenopausal women. Hepatology 1991;14:87A.
  2. Setchell K, Borriello S, Hulme P, Axelson M. Nonsteroidal estrogens of dietary origin: possible roles in hormone-dependent disease. Am J Clin Nutr 1984;40:569-578.
  3. Zava D, Duwe G. Estrogenic and antiproliferative properties of genistein and other flavonoids in human breeast cancer cells in vitro. Nutr Cancer 1997;27:31-40.
  4. Peterson T, Barses S. Genistein inhibits both estrogen and growth factor stimulated proliferation of human breast cancer cells. Cell Growth Diff 1996;7:1345-1351.
  5. Hunter T, Cooper J. Role of tyrosine phosporylationi in malignant transformation by viruses and in cellular growth control. Prog Nucl Acid Res Mol Biol 1983;29:221-232.
  6. Powis G, Koxikowski A. Growth factor and oncogene signalling pathways as targets for rational anticancer drug development. Clin Biochem 1991;24:385-397.
  7. Adlercreutz H, Hockerstedt K, Bannwart C, et al. Effect of dietary components, including lignans and phytoestrogens, on enterohepatic circulation and liver metabolism of estrogens, and on sex hormone binding globulin. J Steroid Biochem 1987;27:1135-1144.
  8. Fotsis T, Pepper M, Adlercreutz H, Fleischmann G, Hase T, Montesano R, Schweigerer L. Genistein, a dietary-derived inhibitor of in vitro angiogenesis. Proc Natl Acad Sci USA 1993;90:2690-2694.
  9. Kurzer M, Xu X. Dietary phytoestrogens. Annu Rev Nutr 1997;17:353-381.
  10. Brzezinski A, Adlercreutz H, et al. Short-term effects of phytoestrogen-rich diet on postmenopausal women. Menopause: J North Amer Meno Soc 1997;1(2):89-94.
  11. Albertazzi P, Pansini F. The effect of dietary soy supplementation on hot flashes. Obstet Gynecol 1998;91(1):6-11.
  12. Eden J, Knight D, Mackey R, House F. Hormonal effects of isoflavones. First International Symposium on the Role of Soy in Preventing and Treting Chronic Disease: Proceedings from a symposium held in Mesa, Arizona, on February 20-23, 1994. Published in J Nutr 125 (Suppl 3S): 567S-909S, 1995.
  13. Woods M, Senie R, Kronenberg F. Effect of a dietary soy bar on menopausal symptoms (abstr). J Nutr 1995;125(Suppl 3S):41.
  14. Baird D, Umbach D, Lansdell L, et al. Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women. J Clin Endocrin Metab 1995. 80(5):1685-90.
  15. Duncan A, Underhill K, Xu X, et al. Modest hormonal effects of soy isoflavones in postmenopausal women. J Clinical Endocrinology and Metabolism 1999; 84(10):3479-3484.
  16. Wilcox G, Wahlqvist M, Burger H, Medley G. Oestrogenic effects of plant foods in postmenopausal women. 1990; Br Med J;301:905-906.
  17. Arjmandi B, Alekel L, Hollis B, Amin D, Stacwicz-Sapuntzakis M, Guo , Kukreja S. Dietary soybean protein prevents bone loss in an ovariectomized rat model of osteoporosis. J Nutr 1996;126:161-167.
  18. Blair H, Jordan S, Peterson T, Barnes S. Variable effects of tyrosine kinase inhibitors on avian osteoclastic activity and reduction of bone loss in ovariectomized rats. J cell Biochem. 1996;61:629-637.
  19. Erdman J, Stillman R, Lee K, Potter S. Short-term effects of soybean isoflavones on bone in postmenopausal women. Program and Abstract Book, Second International symposium on the Role of Soy in Preventing and Treating Chronic Disease. Brussels, Belgium, 1996.
  20. Anderson J, Johnstone B, Cook-Newell M. Meta-analysis of the effects of soy protein intake on serum lipids. N Engl J Med 1995;333(5):276-82.
  21. Bakhit R, et al. Intake of 25 grams of soybean protein with or without soybean fiber alters plasma lipids in men with elevated cholesterol concentrations. J Nutr 1994;124(2):213-222.
  22. Anthony M, Clarkson T, Hughes C. Plant and mammalian estrogen effects on plasma lipids of female monkeys. Circulation. 1994;90:I-235.
  23. Williams J, Honore E, Washburn S, Clarkson T. Effects of hormone replacement therapy on reactivity of atherosclerotic coronary arteries in cynomolgus monkeys. J Am Coll Cardiol. 1994;24:1757-1761.
  24. Messina M, Persky V, Setchell K, Barnes S. Soy intake and cancer risk: a review of the in vitgro and in vivo data. Nutr Cancer 1994;21:113-131.
  25. Adlercreutz H, et al. Dietary phytoestrogens and cancer: in vitro and in vivo studies. J Steroid Biochem Molec Biol 1992; 41(3-8):331-337.
  26. Barnes S, Peterson G, Grubbs C, Setchell K. Potential role of dietary isoflavones in the prevention of cancer. In Jacobs MM, ed. Diet and Cancer: Markers, Prevention, and Treatment. New York: Plenum Press, 1994:135-147.
  27. Lu L, Anderson K, Grady J, et al. Cancer Epidemiol Biomarkers Prev 1996;5:63-70. Effects of soya consumption for one month on steroid hormones in premenopausal women: implications for breast cancer risk reduction.
  28. Zava D, Duwe G. Estrogenic bioactivity of phytoestrogens in human breast cancer cells in monolayer culture. California Public Health Foundation, Cancer Research Division and Aeron Biotechnology, Inc.
  29. Petrakis N, Wiencke J, et al. A clinical trial of the chemopreventive effect of a soy beverage in women at high risk for breast cancer. Department of Epidemiology, University of California San Fancisco, SF, CA and Department of Pharmacology, University of Alabama at Birmingham, AL.
  30. Goodman M, Wilkens L, et al. Association of soy and fiber consumption with the risk of endometrial cancer. Am J epid 1997;146(4):294-306.