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Isoflavones: a Botanical Approach to Disease Prevention
Elizabeth Srejic -
September 13, 2004

Photo courtesy of The Solae Co.
Although the Western world has been somewhat tardy in realizing the many benefits of soybeans, health-conscious consumers are beginning to explore the numerous health applications of isoflavones, plant compounds useful against a bevy of ailments.

Isoflavones are a category of polyphenols, part of the ubiquitous class of phytochemicals—naturally occurring, nonnutritive plant chemicals. Within the body, intestinal microflora convert isoflavones into isoflavonoids, a subgroup of flavonoids, another wide-ranging group of plant chemicals. Isoflavonoids act as phytoestrogens, which reportedly produce a range of beneficial outcomes within the body, including a significant inhibitory role during the initiation and promotional phases of cancer development.

Although several plants contain isoflavones, soybeans are one of the richest natural sources of these compounds. The key isoflavones present in soybeans include genistein and daidzein and their respective beta-glycosides, genistin and daidzin.1

Soy isoflavones have received considerable attention in recent years due to their potential role in the prevention and treatment of chronic diseases including certain cancers and osteoporosis, as well as their ability to lower deleterious low-density lipoprotein (LDL) cholesterol levels and relieve menopausal symptoms.2 Fairly new published data and research suggest the consumption of even 10 g/d (the typical Asian intake) of isoflavone-rich soy protein per day may be associated with health benefits, and if this amount were incorporated into the American diet, it would represent only approximately 15 percent of total U.S. protein intake.3

One need only consider Southeast Asian cultures—where soy has been a cornerstone of the diet for several millennia—for compelling evidence backing the purported health benefits of soy. Heavy consumption of soy in Southeast Asian populations is associated with reduced rates of certain cancers and cardiovascular disease, whereas sparse soy intake among Western civilizations is linked to higher rates of these chronic illnesses.4 The incidence of breast cancer varies worldwide, but its prevalence among Japanese and other Asian women is only a third to a half of that for Caucasian women. 5

“Growing scientific evidence for the potential benefits of isoflavones should motivate more consumers to increase their isoflavone intake and seek out products that provide a significant source of it,” said Pam Stauffer, marketing manager with Minneapolis-based Cargill, manufacturers of the isoflavone ingredient AdvantaSoy®.

Soy isoflavones have shown tremendous potential to fight disease on several fronts.

Within the body, they are biotransformed by intestinal microflora and absorbed, undergo enterohepatic recycling, and can reach circulating concentrations in appreciable excess of endogenous estrogen levels.6

By acting as weak estrogens or anti-estrogens, these plant-derived phytoestrogens have been shown to exert positive effects on both preand postmenopausal women. In premenopausal women, whose hormone levels are elevated, phytoestrogens block the effects of estrogen to some extent and thus protect against breast cancer, an illness now thought to be promoted by prolonged exposure to high levels of estrogen. In postmenopausal women, phytoestrogens may help mitigate hot flashes and other symptoms of menopause by acting as exogenous estrogens and thus replenishing declining estrogen levels.

For these reasons, the use of isoflavones as a natural alternative to prescription estrogens is increasing among postmenopausal women undergoing estrogen replacement therapy.7

On the cardiac front, human clinical intervention trials have indicated isoflavones guard against heart disease by lowering levels of harmful LDL and total cholesterol. Excess plasma levels of LDL cholesterol contribute to atherosclerosis, or buildup of plaque—a thick, hard deposit on the inner walls of arteries that are crucial to the nourishment of both heart and brain. If a blood clot forms and blocks a narrowed artery, it wields potential to cause a heart attack or stroke. Probable mechanisms by which soy isoflavones might prevent atherosclerosis include exertion of beneficial effects on plasma lipid concentrations, antioxidant effects, antiproliferative and antimigratory effects on smooth muscle cells, certain effects on thrombus formation, and maintenance of normal vascular reactivity.8

A study conducted at St. Michael’s Hospital, Toronto, tested the effects of high- and low-isoflavone soy-protein foods on both lipid and nonlipid risk factors for coronary artery disease (CAD) by administering either a low-fat dairy food control diet, a high-isoflavone soyfood diet (50g soy protein and 73 mg isoflavones daily) or a low-isoflavone soyfood diet (52 g soy protein and 10 mg isoflavones daily) among 41 hyperlipidemic men and postmenopausal women for one month.9 No significant differences were seen between the high- and low-isoflavone diets; however, both soy diets resulted in significantly lower total cholesterol, estimated CAD risk, and ratios of total to HDL cholesterol, LDL to HDL cholesterol, and apolipoprotein B to A-I than the control diet.

On the basis of blood lipid and blood pressure changes, the calculated CAD risk was significantly (10.1 +/- 2.7 percent) lower with the soy diets.

One study conducted at the Center for Clinical and Basic Research, Ballerup, Denmark, tested the impact of phytoestrogens alone or combined with oral estrogen on experimental atherosclerosis in ovariectomized, cholesterol-fed female rabbits.10 In Study A, 45 rabbits were randomized to either a soy-free diet with or without 4 mg/d oral 17 beta-estradiol (E2), or a soy-rich diet without any hormone for 14 weeks.

In Study B, 100 rabbits were randomized into five groups (0.5, 1, 2 or 4 mg/day of E2, or no hormone) based on a soy-rich diet for 30 weeks.

The results of Study A showed aortic cholesterol content was twice the amount in the group treated with the soy-free diet compared with the soy-rich group and with the soy-free plus E2 group. In Study B, aortic cholesterol content showed no significant difference between the groups, but a tendency towards a lower aortic cholesterol content compared with placebo was observed in E2-treated animals. The researchers concluded phytoestrogens significantly reduced aortic cholesterol content with a potency comparable to that of ERT, and seemed to mildly enhance the antiatherogenic effect of E2 in this model.

The outcomes of these and similar trials led the U.S. Food and Drug Administration (FDA) to approve a health claim for the relationship between consumption of soy protein and reduced risk of CAD.11

“Isoflavones may also benefit heart health by helping to maintain arterial elasticity, although this hypothetical cardiovascular benefit is not yet confirmed by any means,” added Ram Chaudhari, Ph.D., senior executive vice president, chief scientific officer with Schenectady, N.Y.- based Fortitech, which supplies isolated highly purified soy isoflavones and specializes in putting together stable, complete nutrient systems.

Numerous studies indicate the presence of an inverse association between isoflavone intake and risk of breast cancer, a leading cause of death in women 40 to 55 years of age; the risk of developing breast cancer is one in eight women in North America and one in 12 in Western Europe, according to a May 2002 review published in Obstetrical & Gynecological Survey.12 Research performed at the University of Florida found increased isoflavone intake affects estrogen metabolism by altering steroid hormone concentrations and menstrual cycle length, thereby demonstrating a potential to reduce the risk for breast carcinoma.13 In the study, premenopausal women between the ages of 25 and 55 years were randomized to an experimental group supplemented with 40 mg/d genistein or to a control group administered a placebo over a 12-week period. Changes in subjects’ biomarkers were analyzed at baseline and post-intervention. In the experimental group, serum-free estradiol and estrone levels decreased moderately, serum hormone-binding globulin levels increased, free estradiol decreased and estrone decreased. Women consuming soy also experienced a 3.52- day decrease in mean menstrual cycle length and a 1.46-day decrease in mean follicular phase.

Another study on isoflavones and breast cancer—a populationbased case-control study of the disease by age 50 in southern Germany—evaluated the association between dietary intake of different phytoestrogens and premenopausal breast cancer risk among 278 premenopausal cases and 666 age-matched controls and found daidzein and genistein reduced premenopausal breast cancer risk in the study population.14 The researchers also noted only “low levels” of daidzein and genistein were required to produce these effects.

A Chinese study conducted at Shanghai Medical University, China, also confirmed the benefits of isoflavones in breast cancer both in vitro and in vivo by showing genistein inhibited in vitro invasion of MCF-7 and MDA-MB-231 (breast cells), down-regulated matrix metalloproteinase 9 (a cancer gene), upregulated tissue inhibitor of metalloproteinases 1 and inhibited growth of these breast cancer cells transplanted in nude mice by increasing tumor cell apoptosis; further, genistein was shown to inhibit angiogenesis by decreasing vessel density and production and release of vascular endothelial growth factor and transforming growth factor beta 1.15 The scientists concluded genistein exerts multiple suppressive effects on breast carcinoma and may help halt its progression.

Isoflavones may also guard against development of colon cancer. This premise is backed by numerous clinical trials. In a study conducted at the University of Missouri, two varieties of ovariectomized female mice were fed diets containing casein, soy protein without isoflavones (Soy-IF), soy protein + genistein, soy protein + a commercial soy isoflavones concentrate (as Decatur, Ill.-based Archer Daniels Midland’s (ADM’s) Novasoy ®), or soy protein + estrone (a weak estrogenic hormone secreted by the mammalian ovary) from weaning.16 Colon tumors were induced in the animals. According to the results of the study, the scientists concluded soy protein and soy isoflavones (as Novasoy) protect mice from colon cancer.

Similarly, researchers at the University of Vienna Medical School showed either a single large oral dose of genistein or administration of soy protein for four months elevated CYP27B1 (cytochrome P450, an enzyme) and decreased CYP24 expression (cells overexpressing CYP24 often develop carcinogenesis) in the mouse colon.17 The researchers concluded soy product consumption is inversely correlated with colon tumor incidence possibly due to enhanced colonic synthesis of the antimitotic hormone 1,25-dihydroxyvitamin D3.

Epidemiologic and experimental data suggest isoflavones may help prevent and treat cancer of the prostate gland, a hormonedependent disease. Estrogens have been shown to retard the growth of prostatic tumors by interfering with the action of testosterone,18 while phytoestrogens may arrest growth and cause apoptosis in prostate cancer cells in vivo and in vitro.19 For example, a study published in the May 2004 issue of The Prostate supplemented a group of early-stage prostate cancer patients with 60 mg/d of soy isoflavones or placebo for 12 weeks to evaluate whether the treatment would cause any change in hormonal and proliferative risk parameters implicated in prostate cancer development.20 Serum free testosterone was reduced or showed no change in 61 percent of subjects in the isoflavone group compared to 33 percent in the placebo group. Serum total PSA decreased or was unchanged in 69 percent of the subjects in the isoflavone treated group compared to 55 percent in the placebo group. The researchers concluded supplementing early-stage prostate cancer patients with soy isoflavones, even in a study of short duration, altered surrogate markers of proliferation such as serum PSA and free testosterone in a larger number of subjects in the isoflavone-supplemented group than the group receiving placebo.

A study conducted at the University of Alabama at Birmingham arrived at a similar conclusion regarding the relationship between isoflavone supplementation and prostate cancer risk.21 The researchers explored the possible chemopreventive effects of genistin or daidzin on prostate carcinogenesis in a rat study. The animals were exposed to a 0, 25 or 250 mg genistein/kg AIN-76A diet from conception until necropsy at 11 months. The rats were then injected with substances designed to cause prostate carcinomas.

Genistein in the diet inhibited the development of induced prostate invasive adenocarcinomas, in a dose-dependent manner, without altering body, prostate or testes weights. The scientists concluded lifetime dietary genistein protects against chemically induced prostate cancer development in rats.

According to a review published in Orthopaedic Nursing/National Association of Orthopaedic Nurses, interest in the use of phytoestrogens from dietary soy products to attenuate postmenopausal bone loss [without associated side effects] has increased during the past 10 years as health care consumers, practitioners and scientists have searched for alternative treatments to the use of hormone replacement therapy.22 Dietary phytoestrogens, primarily isoflavones found in soy foods, may alter bone turnover in postmenopausal women by decreasing bone resabsorption and increasing bone formation, the review stated.

A controlled Chinese study on ovariectomized female Wistar rats treated with phytoestrogen showed phytoestrogen caused increased bone mineral density (BMD) levels, whereas rats not treated with phytoestrogen showed thinned bone cortex and bone trabecula thinned with poor integrity, distortion, breaks and reduced size.23

Two human studies conducted on postmenopausal women have also demonstrated preventive effects of phytoestrogens against osteoporosis. In the first study, a randomized, placebo-controlled trial conducted at Helsinki University Central Hospital, Helsinki, Finland, bone resorption was reduced during phytoestrogen use among 55 postmenopausal women with a history of breast cancer administered phytoestrogens (114 mg of isoflavonoids) or placebo tablets daily for three months.24 The results of the trial indicated isoflavonoid-induced inhibition of bone resorption may contribute to lowered risk of osteoporosis. In the second study, a double blind, placebo-controlled, randomized trial held at the Chinese University of Hong Kong, China, 203 eligible subjects were randomly assigned to three treatment groups and administered daily doses of either placebo, approximately 40 mg isoflavones (mid dose) or approximately 80 mg isoflavones (high dose).25 All were given 12.5 mmol (500 mg) calcium and 125 IU vitamin D3. BMD and bone mineral content (BMC) of the whole body, spine, and hip were measured using dual energy x-ray absorptiometry at baseline and one year post treatment. Both univariate and multivariate analyses showed women in the high dose group experienced mild, but statistically significant, improvement in BMC at the total hip and trochanter compared with the placebo and mid-dose groups, even after further adjustments for potential confounding factors. It concluded soy isoflavones have a mild, but significant, independent effect on the maintenance of hip BMC in postmenopausal women with low initial bone mass. The soy isoflavones used in the study were SoyLife®, a soygerm ingredient with standardized levels of isoflavones, produced by Minneapolis-based Acatris.

SoyLife is currently part of a $4.5 million United States Department of Agriculture (USDA) study examining the effects of soy isoflavones on bone health, according to the company.

“We are seeing an increased interest in soy isoflavones for maintaining bone health after menopause,” said Jocelyn Mathern, R.D., technical specialist for Acatris.

Many women are looking for alternatives to hormone replacement therapy (HRT) and research on soy isoflavones for bone health is looking really positive.”

Although the benefits of soy and soy isoflavones have become a major focus for many food and beverage manufacturers, the applications have been limited due to fact that most isoflavone ingredients in the marketplace are highly insoluble, according to Troy Figgins, vice president, Soy Foods Division, with Carpinteria, Calif.-based New Sun Nutrition. “Most commercial isoflavone food additives contain a high percentage of insoluble components—including fat, protein, and ash—which diminish the clarity and solubility of soy isoflavone additives and create a bitter taste,” Figgins said. “In addition, traditional isoflavone extracts are also difficult to distribute evenly in foods and beverages, and require flavor masking and expensive additives that introduce strange colors and unpleasant mouthfeel. Current soy additive manufacturers are striving to achieve products of isoflavone concentrations as high as 40 to 50 percent, yet have not been able to make these products soluble enough for use in foods and beverages.” Intellisoy™—a completely clear, highly soluble soy isoflavone ingredient with GRAS (generally recognized as safe) status and no taste—is derived from soy via a patented water-based extraction method in which isoflavones are extracted in a soluble and natural form, separated from the unwanted parts such as proteins and lipids, and concentrated into a clear isoflavone liquid. The ingredient, which uses pure water instead of chemical solvents to maintain solubility, dissolves without residue and contains over 70 percent soluble soy fiber, according to Figgins.

“Most of the health benefits of soy are associated with its protein matrix, which contains the healthful bioactive components (including isoflavones),” said Geri Berdak, director of public affairs with Minneapolisbased The Solae Co. “During production of Solae soy protein, the protein matrix and bioactives are carefully preserved, regardless of whether manufacturers will take advantage of the benefit of the protein or the isoflavones.”

One way The Solae Co. has tackled the issue of taste—which Berdak calls “the number one barrier to eating more healthfully”—is by conducting extensive consumer research to determine what consumers think tastes good or bad, and creating ingredients and formulations to meet consumer definition of “great tasting.”

Chaudhari, who also called taste the greatest delivery challenge, noted microencapsulation is a solution used to isolate certain ingredients in isoflavonecontaining formulations to prevent unwanted reaction of different ingredients. Such reaction can lead to unwanted flavors and other unwanted effects.

“The most common delivery systems for our soy products are in beverages, both dry and ready to drink, bakery products such as breads, frozen soy desserts and soy yogurts,” said William Fenske, vice president, technical services for Minneapolis-based Sunrich. “We find that the best way to get soy along with its isoflavones is to give the consumer a form that is familiar and convenient.” According to Fenske, Sunrich does not concentrate the isoflavone content in any of its soy products, due to the belief that natural levels of unmodified isoflavones are the healthiest and safest levels for people to consume.

Numerous animal and human studies have evaluated the health effects of isoflavones on menopause-related symptoms and chronic diseases. The outcomes of the majority of these studies suggest foods or supplements containing isoflavones cause beneficial physiological effects and supplementation with isoflavones is a strategy to prevent disease.

Even though consumers have been slow to catch on to the benefits of isoflavones, awareness and the market for these products is gradually increasing, Chaudhari said. “As we move forward, the future for isoflavones is very bright. It’s only a matter of time, now, before isoflavones gain more attention as new scientific evidence and new finished product applications develop, and issues like taste, texture, mouthfeel and adulteration due to interaction with other ingredients are resolved.”

Beyond Soy: Red Clover Isoflavones

Another botanical source of isoflavones is red clover, or Trifolium pretense, a wild plant used as feed for cattle and other livestock as well as a dietary supplement to treat a wide array of illnesses. Like soy isoflavones, red clover isoflavones have shown promise in the treatment of a number of health conditions including cardiovascular disease, menopause, bone loss associated with osteoporosis, and various forms of cancer. Several studies have demonstrated these and other possible benefits in human health. Some of these studies include:

* A study conducted at the Minneapolis VA Medical Center, in which red clover isoflavones were shown to decrease levels of triglycerides in symptomatic menopausal women;1
* A mouse study conducted at the The University of Sydney, Australia, in which red clover isoflavones were shown to represent a non-toxic dietary treatment for prostatic hyperplasia and a reduction in the potential for neoplastic transformation;2
* A randomized, placebo-controlled, double blind trial held at Monash University, Melbourne, Australia, in which isolated isoflavones from red clover enriched in biochanin (genistein precursor) lowered low-density lipoprotein (LDL) “bad” cholesterol in men;3
* An English study on women aged 49 to 65 years that showed isoflavones have a potentially protective effect on the lumbar spine in women through attenuation of bone loss;4
* An in vivo study performed at University College London Medical School, London, in which one-month supplementation with red clover isoflavones had a positive effect on high-density lipoprotein (HDL) “good” cholesterol, and a small effect on insulin-like growth factor (IGF) status in premenopausal women;5
* An Australian study that found isoflavone supplementation from red clover may favorably influence blood pressure and endothelial function in postmenopausal Type II diabetic women;6
* A mouse study conducted at Monash University, Clayton, Australia, in which isoflavones derived from red clover had a significant effect on prostatic growth, and were capable of reducing the enlarged non-malignant prostate phenotype in adult mice by acting as anti-androgenic agents;7
* A Dutch study performed at Vrije Universiteit Medical Centre, Amsterdam, The Netherlands, in which treatment with 80 mg/d isoflavones resulted in a significant reduction in hot flushes from baseline and a significant decrease in hot flushes of 44 percent between the active and placebo group at the end of the study, demonstrating the effectiveness of red clover isoflavones in the management of menopause-related hot flushes;8
* A study out of the University of Sydney, Australia, in which isoflavonoid compounds from red clover were shown to protect from inflammation and immune suppression induced by ultraviolet (UV) radiation;9 and
* A Viennese study in which scientists stated the estrogenic activity of two red clover extracts make these extracts interesting candidates for hormone replacement therapy (in postmenopausal women).10




A Sensible Part of Your Diet: The anti-soy argument
Messina, M., PhD. (2003, April).
A sensible part of your diet: the anti-soy argument. Alive, 78.
April 22, 2003

Soy food consumption has increased markedly over the past 10 years, largely because of media coverage of research indicating soy may decrease risk of several chronic diseases including heart disease, osteoporosis, and breast and prostate cancer.

In addition, because it is a rich source of isoflavones (phytoestrogens), soy almost certainly alleviates menopausal symptoms. This is why soy is viewed as an alternative to conventional hormone replacement therapy.

Although a few less reputable manufacturers may make exaggerated claims, overall, the soy industry has been responsible in its promotional efforts, many of which are supported by recommendations from independent health agencies. The American Cancer Society includes soy consumption as one of seven steps to reduce prostate cancer risk. The National Cancer Institute classifies genistein (the main soybean isoflavone) as a key anti-cancer agent, and the United States Food and Drug Administration (FDA) and the American Heart Association both endorse soy protein for cholesterol reduction.

Perhaps though, the best way to appreciate the amount of scientific interest in soy and isoflavones is to cite the number of scientific papers published each year on these subjects. Currently, about 600 papers are published annually. Despite this volume, the Internet is filled with sites devoted to the alleged dangers of soy consumption. In my view, this information is inaccurate and represents selective use of scientific literature.

Soy foods have been consumed for centuries by some Asian populations. In awarding the health claim for cholesterol-lowering effects of soy protein, the FDA reviewed all safety issues related to soy consumption. Although there are more than 100 studies suggesting possible harm from eating soy, most of these are in vitro (cell studies) and animal studies, and this research actually represents only about one to two percent of all soy research published.

When any food is the subject of intense research, some small percentage of research will suggest potential harm. One has to look at the total evidence and place most emphasis on the results from human studies published in the peer-reviewed literature when making conclusions about safety and efficacy. Following is a brief discussion of some of the specific safety issues.

Thyroid: Seven well-designed clinical trials, including one that looked at the effects of isoflavone supplements, have found soy to have little or no impact on thyroid function in healthy adults.

Cognition: Three human trials have found that soy foods and isoflavone supplements improve certain aspects of cognition. It is too early to conclude that soy will reduce risk of dementia, but the evidence at this point is encouraging.

Testosterone and sperm count: Seven clinical trials have looked at the effects of soy foods or isoflavones on serum testosterone, and one of these looked at sperm count. None of the studies found any negative effects.

Estrogen and breast cancer: Most human studies show soy has either little effect or slightly decreases serum estrogen levels. Soy may modestly increase the length of the menstrual cycle, however. Both effects are seen as possibly reducing breast cancer risk, although most evidence suggests soy protects against breast cancer only if consumed when young. One 14-day study on soy caused changes that represent an increased breast cancer risk; however, the final results (published one year later) from this trial did not show this to be the case. Furthermore, a two-week study is too short to support clinical conclusions, as acknowledged by the authors of this study.

Soy is not a miracle food, but, in my view, it warrants a larger role in western diets. I recommend consuming about two servings per day, which in total provide about 15 grams of soy protein and 50 milligrams of isoflavones. At this intake, soy protein would still represent less than 20 percent of the total protein intake of western adults.

Mark Messina has a PhD in nutrition science, was formerly employed by the National Cancer Institute, and is currently an adjunct associate professor of nutrition at Loma Linda University and president of his own consulting company, Nutrition Matters, Inc. He has organized five international symposia on the health effects of soy foods, has given more than 300 presentations on soy to health professionals and consumers in 25 countries, and is the co-author of three books on soy and plant-based diets.

Messina, M., PhD. (2003, April). A sensible part of your diet: the anti-soy argument. Alive, 78.

Article: A Sensible Part of Your Diet: The anti-soy argument
Author: mark Messina, PhD
Pages: 78
Date: April 2003
Source: Alive magazine
Publisher: Alive Publishing Group, INC

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