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Soy and isoflavones

soy
Glycine max
Fabaceae
Soy
Isoflavones
Seed

Soy is an incredibly versatile plant and food. The bean is a great source of proteins, carbohydrates and fats and is a major food to millions of people across the world. Soy is also rich in isoflavones that have many health benefits.

Various soy products are available as food, supplements and medicinal products including whole soy beans, tofu (bean curd), fermented soy (tempeh), soy protein poweder, soy germ, soy extracts and soy isoflavones (such as genistein). 

Soya bean is native to East Asia and a significant source of protein and oil to an estimated 1.5 billion people across the world. Typical soy-derived foods are cooked beans, soy sprouts, soymilk, and tofu (bean curd). Soy contains isoflavones that have medical properties.

Traditional fermented soy foods include soy sauce, fermented bean paste called miso, natto and tempeh. Miso and natto are aglycone-rich fermented soy products, whereas tofu is a glucoside-rich nonfermented soy product. Recent study revealed that ingestion of aglycone-rich fermented soybeans had significantly higher bioavailability of isoflavones than glycoside-rich nonfermented soybeans.1.

Miso is a traditional Japanese fermented product using soybeans, rice, and/or barley with salt and molds. Different molds will help to make different flavors of miso.

Soy-based infant formula is used for infants who are allergic to pasteurized cow milk proteins. The US Food and Drug Administration (FDA) have accepted soy formula as safe for use as the sole source of nutrition.

The proteins, oils and carbohydrates can be removed to create simple extracts containing the medically active isoflavones. 

See also the free online book, Soybean and Health edited by Hany El-Shemy 

  1. Okabe Y, Shimazu T, Tanimoto H. Higher bioavailability of isoflavones after a single ingestion of aglycone-rich fermented soybeans compared with glucoside-rich non-fermented soybeans in Japanese postmenopausal women. Journal of the science of food and agriculture. 2011;91(4):658-663.

soyaSoy is a subtropical plant up to 1.3 m tall, which forms clusters of 3–5 pods, each containing 2–4 beans per pod. The botanical name is Glycine max. The genus name Glycine was first introduced by Carl Linnaeus in his first edition of General Plantarum of 1737. The word glycine derived from the Greek word “glykys” (sweet) refers to the sweetness of the pear-shaped edible tubers produced by a native American legume. The scientific name, G. max (L.) Merrill, proposed by Merrill in 1917 and has become the official name for this useful plant.

Soya bean is known as the large or yellow bean in Chinese and Japanese. Both the immature soybean and its dish are called edamame in Japan. The genus name, Glycine, takes its name from the amino acid of the same name. The English words "soy" and "soya" are derived from the Japanese pronunciation of shōyu, the Sino-Japanese word for soya sauce, through the German adaptation of the same word, soja.

American and European males have a ten-fold increase in the risk of prostate cancer compared to East Asian males due, in part, to difference in consumption of soy isoflavones. Consuming soy products as a teenager may help reduce breast cancer risk as an adult. Soybeans may also help reduce the risk of colon cancer and heart diseases.1

  1. Kurosu M. Biologically Active Molecules from Soybeans, Soybean and Health, (Ed.), ISBN: 978-953-307-535-8, InTech, DOI: 10.5772/18950. Available from: http://www.intechopen.com/books/soybean-and-health/biologically-active-molecules-from-soybeans. 2011.

Soybeans contains carbohydrates, proteins and fats but no cholesterol. The soy germ is also rich in vitamins, minerals, as well as phyto-nutrients including phytosterols and isoflavones. The most important isoflavones are genistein, glycitein, daidzein, and its breakdown product, equol. The isoflavones are responsible for the medicinal effects of soy extracts.

formula

Figure 1: Soy contains a number of isoflavones with a similar structure. The major isoflavones in soybean are genistein, daidzein, and glycitein, comprising about 50, 40, and 10% of total isoflavone profiles, respectively.1

The higher dietary intake of soy products such as bean curd or tofu in Asian compared to Western societies is thought to be associated with the lower incidence of menopausal hot flushes and hormone-sensitive cancers in Asian societies. These effects have been attributed to the protective effects of the isoflavones genistein, daidzein, glycitein and equol.

Isoflavones are mainly found in plants from the clover family, of which soy is a predominant species. Isoflavones are, however, not restricted to soy or red clover. They are also present in soy products and other legumes. They have been isolated from alfalfa, the Asia plant kudzu, but also from species unrelated to the beans family. Dry soybeans contain 1 to 5 μg/g isoflavones.2,3

Soy germ

Soy germ is derived from the soybean by a relatively simple process, in much the same way as wheat germ is obtained from wheat. The nutritional profile of soy germ is similar to whole soy; however, several nutrients are found in higher quantities than in whole soybeans, such as tocopherols, oligosaccharides, phytosterols and slightly more protein and isoflavones. The high level of oligosaccharides in soy germ act as a prebiotic (supports probiotic growth).

Soy germ supplements may prove a viable alternative for those women who have difficulty incorporating soy foods into their diet4,5 and are a better option for the incorporation into the regular diet than the more processed soy protein isolates.

Soy protein isolates

Isolated protein compounds can be derived from soy via a series of complex procedures that involve dehulling, flaking, then defatting soybeans by hexane extraction. The protein and carbohydrate portions are then separated and the flavour compounds and oligosaccharides removed. Finally, the protein is concentrated by alkali extraction and removal of the fibre. Part of this processing involves an acid wash in aluminium vats, which can lead to unacceptably high levels of aluminium in some soy products. The manufacture of soy protein isolates also involves high temperature processing that denatures the protein extensively, therefore lowering its nutritional value.

Soy protein isolates have been shown to reduce hot flushes and improve bone density.6,7 However, the effect of soy preparations on bone density and bone mineral turnover is still controversially debated.8-10

The benefits of soy protein isolates containing isoflavones for the cardiovascular system has been accepted in an official health claim and intake recommendation in the United States of America.11 Research on lipid profiles has been conflicting in the details.12,13 Possibly only minor effects on blood lipids may be expected when soy preparations are applied in menopause.

Soy extracts

Soy extracts are preparations where the protein or fat have been removed. Their content and relative composition of isoflavones is very close or identical with that of typical soy food such as tofu or soy milk.14 Since they are not enriched they cannot be considered “isolates” or “concentrates”.

Soy extract have been shown to be efficacious against menopausal hot flushes, among other conditions15, with long term safety demonstrated by lack of proliferation of oestrogen-dependent tissues.16

In general, positive effects on menopausal flushing, bone and cardiovascular health are modest, but menopausal women may benefit from soy preparations.

Not only menopausal women may profit from isoflavone supplementation. A positive outcome from a trial assessing the use of soy isoflavone supplement on menstrual migraine incidence suggests an oestrogen-like effect of the isoflavones can moderate the adverse impact of declining oestrogens during the menstrual phase of the cycle 17. In addition, research in prostate cancer prevention indicates potential benefits from the intake by men.18-20

Isolated isoflavones

Some synthetically derived or isolated isoflavones such as genistein or equol are promoted for the treatment of menopausal symptoms and associated problems. The effect against hot flushes and on bone mineral turnover has been demonstrated with preparations containing isolated genistein2,21,22 and equol.23 Safety has been shown in dedicated studies24-27, but also in long-term application with a duration of up to three years.2

Source and further information

Michio Kurosu (2011). Biologically Active Molecules from Soybeans, Soybean and Health, Prof. Hany El-Shemy (Ed.), ISBN: 978-953-307-535-8, InTech, DOI: 10.5772/18950. Biologically Active Molecules from Soybeans

References

1.         Kurosu M. Biologically Active Molecules from Soybeans, Soybean and Health, (Ed.), ISBN: 978-953-307-535-8, InTech, DOI: 10.5772/18950. Available from: http://www.intechopen.com/books/soybean-and-health/biologically-active-molecules-from-soybeans. 2011.

2.         Marini H, Bitto A, Altavilla D, et al. Breast safety and efficacy of genistein aglycone for postmenopausal bone loss: a follow-up study. The Journal of clinical endocrinology and metabolism. 2008;93(12):4787-4796.

3.         Chen KI, Erh MH, Su NW, Liu WH, Chou CC, Cheng KC. Soyfoods and soybean products: from traditional use to modern applications. Applied microbiology and biotechnology. 2012;96(1):9-22.

4.         Clerici C, Setchell KD, Battezzati PM, et al. Pasta naturally enriched with isoflavone aglycons from soy germ reduces serum lipids and improves markers of cardiovascular risk. The Journal of nutrition. 2007;137(10):2270-2278.

5.         Imhof M, Gocan A, Imhof M, Schmidt M. Improvement of menopausal symptoms by soy isoflavones: A randomized, double-blind study. Planta Med. 2008;74  (9):928.

6.         Arjmandi BH, Khalil DA, Smith BJ, et al. Soy protein has a greater effect on bone in postmenopausal women not on hormone replacement therapy, as evidenced by reducing bone resorption and urinary calcium excretion. The Journal of clinical endocrinology and metabolism. 2003;88(3):1048-1054.

7.         Albertazzi P, Pansini F, Bonaccorsi G, Zanotti L, Forini E, De Aloysio D. The effect of dietary soy supplementation on hot flushes. Obstetrics and gynecology. 1998;91(1):6-11.

8.         Ma DF, Qin LQ, Wang PY, Katoh R. Soy isoflavone intake increases bone mineral density in the spine of menopausal women: meta-analysis of randomized controlled trials. Clinical nutrition. 2008;27(1):57-64.

9.         Ma DF, Qin LQ, Wang PY, Katoh R. Soy isoflavone intake inhibits bone resorption and stimulates bone formation in menopausal women: meta-analysis of randomized controlled trials. European journal of clinical nutrition. 2008;62(2):155-161.

10.        Liu J, Ho SC, Su YX, Chen WQ, Zhang CX, Chen YM. Effect of long-term intervention of soy isoflavones on bone mineral density in women: a meta-analysis of randomized controlled trials. Bone. 2009;44(5):948-953.

11.        Rimbach G, Boesch-Saadatmandi C, Frank J, et al. Dietary isoflavones in the prevention of cardiovascular disease--a molecular perspective. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2008;46(4):1308-1319.

12.        Taku K, Umegaki K, Sato Y, Taki Y, Endoh K, Watanabe S. Soy isoflavones lower serum total and LDL cholesterol in humans: a meta-analysis of 11 randomized controlled trials. The American journal of clinical nutrition. 2007;85(4):1148-1156.

13.        Taku K, Umegaki K, Ishimi Y, Watanabe S. Effects of extracted soy isoflavones alone on blood total and LDL cholesterol: Meta-analysis of randomized controlled trials. Therapeutics and clinical risk management. 2008;4(5):1097-1103.

14.        Anonymous. USDA Database for the Isoflavone Content of Selected Foods. Release 2.0. Beltsville, MD: Agricultural Research Service, US Department of Agriculture; 2008.

15.        Amakura Y, Tsutsumi T, Sasaki K, Nakamura M, Yoshida T, Maitani T. Influence of food polyphenols on aryl hydrocarbon receptor-signaling pathway estimated by in vitro bioassay. Phytochemistry. 2008;69(18):3117-3130.

16.        Palacios S, Pornel B, Bergeron C, et al. Endometrial safety assessment of a specific and standardized soy extract according to international guidelines. Menopause. 2007;14(6):1006-1011.

17.        Burke BE, Olson RD, Cusack BJ. Randomized, controlled trial of phytoestrogen in the prophylactic treatment of menstrual migraine. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2002;56(6):283-288.

18.        Yan L, Spitznagel EL. Soy consumption and prostate cancer risk in men: a revisit of a meta-analysis. The American journal of clinical nutrition. 2009;89(4):1155-1163.

19.        Travis RC, Allen NE, Appleby PN, Spencer EA, Roddam AW, Key TJ. A prospective study of vegetarianism and isoflavone intake in relation to breast cancer risk in British women. International journal of cancer. Journal international du cancer. 2008;122(3):705-710.

20.        Hamilton-Reeves JM, Rebello SA, Thomas W, Kurzer MS, Slaton JW. Effects of soy protein isolate consumption on prostate cancer biomarkers in men with HGPIN, ASAP, and low-grade prostate cancer. Nutrition and cancer. 2008;60(1):7-13.

21.        Crisafulli A, Marini H, Bitto A, et al. Effects of genistein on hot flushes in early postmenopausal women: a randomized, double-blind EPT- and placebo-controlled study. Menopause. 2004;11(4):400-404.

22.        D'Anna R, Cannata ML, Atteritano M, et al. Effects of the phytoestrogen genistein on hot flushes, endometrium, and vaginal epithelium in postmenopausal women: a 1-year randomized, double-blind, placebo-controlled study. Menopause. 2007;14(4):648-655.

23.        Ishiwata N, Melby MK, Mizuno S, Watanabe S. New equol supplement for relieving menopausal symptoms: randomized, placebo-controlled trial of Japanese women. Menopause. 2009;16(1):141-148.

24.        McClain MR, Wolz E, Davidovich A, Bausch J. Genetic toxicity studies with genistein. Food Chem.Toxicol. 2006;44(1):42-55.

25.        McClain MR, Wolz E, Davidovich A, Pfannkuch F, Edwards JA, Bausch J. Acute, subchronic and chronic safety studies with genistein in rats. Food Chem.Toxicol. 2006;44(1):56-80.

26.        McClain RM, Wolz E, Davidovich A, Edwards J, Bausch J. Reproductive safety studies with genistein in rats. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2007;45(8):1319-1332.

27.        McClain RM, Wolz E, Davidovich A, Pfannkuch F, Bausch J. Subchronic and chronic safety studies with genistein in dogs. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. 2005;43(10):1461-1482.

soy productsSoybean (Glycine max) is a species of legume which originated from Asia and was introduced to the USA in 1765 by Samuel Bowen. The genus name ‘Glycine’ was first introduced by Carl Linnaeus in his first edition of General Plantarum of 1737. The word glycine derived from the Greek word “glykys” (sweet) refers to the sweetness of the pear-shaped edible tubers produced by native American legume. The scientific name, G. max (L.) Merrill, proposed by Merrill in 1917 has become the official name for this useful plant.

Typical soy-derived foods containing isoflavones are soy beans, soy sprouts, soy milk, tofu, miso, natto and tempeh, which all contain relatively large quantities of isoflavones. In the fermented food items the isoflavones are predominantly present in their aglycone form.

Soy-based infant formula (SBIF) is used for infants who are allergic to pasteurized cow milk proteins. The US Food and Drug Administration (FDA) has accepted SBIFs as safe for use as the sole source of nutrition.

Soy food such as miso, natto and tofu is the nutritional base for a large percentage of the world’s population. An estimated number of 1.5 billion people have a life-long daily exposure to soy food. When the safety of soy-based supplements and the isoflavones within is discussed, the experience from nutrition must not be forgotten. 

 

MenopauseOne of the key recommendations for soy consumption is to start early in life.

Life long intake of soy foods seems to be associated with the lower levels of many chronic diseases including menopausal hot flushes, osteoporosis, cardiovascular disease and cancer in Asian societies.

Soy may also be beneficial in skin disorders, inflammatory disorders, asthma, frailty, and cognition and to help maintain a healthy body weight.

Menopausal symptoms

Soy germ and isoflavones extracts are used in supplements to alleviate menopausal hot flushes, to maintain healthy bones and a healthy cardiovascular system.

Soy and breast cancer

The reduction in risk involves epigenetic changes that result in alterations in the expression of genes that regulate mammary epithelial cell fate including cell proliferation and differentiation.1

Soy intake may also influence the timing of menarche – a girl’s first menstruation. Early onset of puberty may confer adverse health consequences. Children with the highest intakes of vegetable protein has delayed onset while those who have the highest intake of animal protein experience pubertal onset up to 7 months earlier.

Furthermore, girls with high isoflavone intakes may experience the onset of breast development and peak height velocity approximately 7-8 months later.

Higher intakes of vegetable protein and isoflavones and lower intakes of animal protein may contribute to a lower risk of breast cancer or a lower total mortality.2

Another study found that early menarche was associated with low birth weight, having a teenage mother, being first born and having a mother who is smoking or or poor health (D'Aloisio et al., 2013).

A recent study found that soy did not seem to affect the age of onset of menarche in American girls.3  This is perhaps not surprising as it is the stimulation of alpha receptors by oestrogen which is responsible for the sexual development of girls. Soy stimulates the beta receptor which has minimal effect on sexual development.

References

1.         Hilakivi-Clarke L, Andrade JE, Helferich W. Is soy consumption good or bad for the breast? The Journal of nutrition. 2010;140(12):2326S-2334S.

2.         Cheng G, Buyken AE, Shi L, et al. Beyond overweight: Nutrition as an important lifestyle factor influencing timing of puberty. Nutrition Reviews. 2012;70(3):133-152.

3.         Segovia-Siapco G, Pribis P, Messina M, Oda K, Sabate J. Is soy intake related to age at onset of menarche? A cross-sectional study among adolescents with a wide range of soy food consumption. Nutrition journal. 2014;13:54.

capsulesThe typical daily dosage is soy extract containing 50 mg isoflavones, although higher dosages may be necessary in some situations.

54 mg genistein per day may be used in the prevention of menopausal bone loss and osteoporotic fractures.1,2

The lack of effect shown in some trials may also be related to dosage. 70 mg of soy isoflavones was shown to produce a modest but statistically significant reduction on the vasomotor symptoms after 12 weeks of treatment in menopausal women.  The lower dose of 35 mg did not improve vasomotor symptoms.3

Soy isoflavone in the dose of 90 mg/day has been shown to improve some menopausal syndromes and increasing limb bone density.4

References

  1. Marini H, Bitto A, Altavilla D, et al. Breast safety and efficacy of genistein aglycone for postmenopausal bone loss: a follow-up study. The Journal of clinical endocrinology and metabolism. 2008;93(12):4787-4796.
  2. Squadrito F, Altavilla D, Bitto A, Polito F, Minutoli L, Marini H. Genistein aglycone reduces FRAX rate in postmenopausal women. 9th International Symposium on the Role of Soy in Health Promotion and Chronic Disease Prevention and Treatment, Washington DC, 16-19 October. 2010.
  3. Jou HJ, Ling PY, Wu SC. Comparison of 70 mg and 35 mg isoflavone soya supplement for menopause symptoms. International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics. 2005;90(2):159-160.
  4. Chi XX, Zhang T. The effects of soy isoflavone on bone density in north region of climacteric Chinese women. Journal of clinical biochemistry and nutrition. 2013;53(2):102-107.

safety The safety of soy food has been thoroughly examined.

A very recent randomized controlled trial has verified that long-term intake of soy isoflavone tablets by postmenopausal women is safe. The study found no evidence of adverse effects on endometrial thickness, adverse events, or circulating hormone concentrations, or thyroid function, across a 3-year period.
 

The Japanese health ministry conducted a 50 year-survey with data from approximately 20,000 persons of all age classes.1

Typical soy consume is in the range of 65 g per day, with higher exposures in the elderly (91.7 g per day in the age group 60-69 years). Calculated as aglycones the average exposure to isoflavones is 26-54 mg per day. The exposure varies according to location: it is higher in Japan than in the more westernized Hong Kong or Singapore. Daily exposure reaches 76 mg/day in certain areas in China, which has been associated with a reduced risk of prostate cancer.1,2

A subpopulation of up to 10% of regular soy consuming people (150 million people) has an estimated daily intake of approximately 100 mg of isoflavones, calculated as aglycones.1

There are considerable differences between the types of soy products that are available for the management of menopausal and post-menopausal complaints. Some of these products are highly processed in order to obtain the isolated compound and in no way resemble the original soybean from which they were derived.

The health benefits and risks of such products are therefore assessed in a different light to those seen when soy is consumed as part of the diet.

Whole soy contains isoflavones, phytosterols, saponins, fibre, oligosaccharides, lecithin, tocopherols and other vitamins.

To attain all of the health benefits of soy, such as improvements in bone density, cardiovascular health and reduction in hot flushes, it may be necessary to consume supplements that are as close to this nutritional profile as possible.

Studies on clinical effects and on safety of application by now exist for soy food and soy extracts as well as isolated isoflavones – including long-term studies covering up to three years. So far none of the studies pointed to reasons of concern even with high doses of isoflavones exceeding the usual dietary intake.3

Soy and cancer

The safety of isoflavones in hormone-sensitive tissues such as breast, uterus and vaginal epithelium has been explicitly examined in clinical settings, in epidemiological and in case-control and cohort studies. The existing data by now supports beneficial effects of dietary isoflavones on women’s health, and the absence of safety issues on long-term use even in dose ranges which cannot be expected by the shift of dietary patterns to soy-rich food.

Many studies show a correlation between isoflavone intake and a reduction of cancer incidence, whereas other studies focused on opposite effect: the absence of cancer-inducing properties. None of the studies showed an increased incidence of cancer related to a higher intake of isoflavones: the majority of data points to a protective effect.

Conversely, it has also been shown that adopting a Western diet increases the risk of breast cancer in postmenopausal women. A study examined such women in the Shanghai Breast Cancer Study. The study found that the western diet increases breast cancer risk in postmenopausal Chinese women.4

Other studies have found soy and isoflavones to be protective against a range of other cancers including bladder cancer, gastrointestinal cancers, lung cancer, multiple myeloma, nasopharyngeal cancer, non-Hodgkin’s lymphoma and thyroid cancer.

Male fertility

Concerns has also been raised about soy intake and male fertility. This is unfounded. The results of a meta-analysis of clinical studies show that soy protein or isoflavones have no effect on reproductive hormones in men.

The ability of isoflavones to exert oestrogen-like effects in men by lowering bioavailable testosterone was evaluated via the effects of soy protein or isoflavone intake on testosterone, sex hormone-binding globulin (SHBG), free testosterone, and free androgen index (FAI) in men.

Peer-reviewed studies published in English were selected if [1] adult men consumed soy foods, isolated soy protein, or isoflavone extracts (from soy or red clover) and [2] circulating testosterone, SHBG, free testosterone, or calculated FAI was assessed. Data were extracted by two independent reviewers. Isoflavone exposure was abstracted directly from studies.

Fifteen placebo-controlled treatment groups with baseline and ending measures were analysed. In addition, 32 reports involving 36 treatment groups were assessed in simpler models to ascertain the results. 

No significant effects of soy protein or isoflavone intake on testosterone, SHBG, free testosterone, or FAI were detected regardless of statistical model. The results of this meta-analysis suggest that neither soy foods nor isoflavone supplements alter measures of bioavailable testosterone concentrations in men.5

Thyroidal safety

The is also a lot of anti-soy propaganda on the internet about the “dangerous effect” of soy on the thyroid. If soy had such a detrimental effect on the thyroid, there would have been many case reports published. However, there are only two clinical case reports suggesting a potential impact of soy food on the absorption of levothyroxine in new-borns.

Researchers reported the case of two patients with congenital hypothyroidism who continued to manifest clinical hypothyroidism while receiving recommended doses of hormone and ingesting soy products.6

The case of these two patients point to a potential interference of soy products with levothyroxine absorption in infants, which may become evident in infants with congenital hypothyroidism who are at risk for developmental and growth delay.

This situation in infants is not transferable to women in menopause or even to the general population, else thyroidal disorders would occur in any patient using levothyroxin and exposed to soy products.

Published clinical data suggest that intake of isoflavones had either no or only modest effects on the levels of thyroidal hormones.7-10

Isoflavones do not increase the risk of a clinically relevant low thyroid function. Iodine deficiency is, however, a known risk factor for hypothyroidism. Especially in menopausal women a sufficient supply of iodine should be encouraged, independent of the ingestion of soy products.11

A recent review analysed the available clinical data and comes to the conclusion that even “hypothyroid adults need not avoid soy foods. In addition, there remains a theoretical concern based on in vitro and animal data that in individuals with compromised thyroid function and/or whose iodine intake is marginal soy foods may increase risk of developing clinical hypothyroidism. Therefore, it is important for soy food consumers to make sure their intake of iodine is adequate” 12. Additional clinical data not included in the review of Messina et al. (2006) is available 13-16. None of these studies points to a negative impact of isoflavones on thyroid turnover. The clinical trial of Imhof et al. (2008) also included measurements of thyroidal hormones (TSH, T3 and T4) in postmenopausal women. No impact of soy extract supplementation with 100 mg isoflavones per day (calculated as glycosides) was found after 12 and 24 weeks.17,18

Infant development

Long term feedings of a ready-to-eat soy based formula has been shown not to produce any differences in the growth, development, bone density or content of serum minerals compared to a cow-milk based formula in a study of 51 healthy full-term infants over three years.19

Another study demonstrated that in terms of development, it makes no difference whether an infant is fed milk or soy based formula.20

Oestrogen

The hormone, oestrogen, is a major regulator of growth and differentiation in a broad range of tissues, including the breast, and reproductive, central nervous and skeletal systems. Oestrogen is also known to be involved in breast and endometrial cancers.21

This has let to a concern that compounds with similar structures to oestrogen found in plants may have similar effects.

Phyto-oestrogens or “plant hormones”

It has long been known that plants can produce substances that can have hormonal effects in humans. A prominent example is that women gathering hops for brewing beer may experience anomalies in their menstrual cycle. Hop has also been used as an antidote to sexual desire in monks in the medieval ages. Even today, the growth of the male breast is a known consequence of excessive beer drinking, an effect, which can be, attributed to oestrogen-like constituents found in hops 22.

This has raised concerns about the potential hormone-like effect of soy isoflavones. As shown in figure 2, genistein has a similar structure to the various oestrogen subtypes. Concerns has been raised that so-called phyto-“estrogens” might also induce the growth of hormone-sensitive cancer in the same way as oestrogen.23,24

genistein

Figure 1: The isoflavone genistein has a very similar, but not identical, structure to oestrogen (estradiol, estriol and estrone).21

At first sight there are animal24-28 and laboratory29,30 studies that seem to confirm such concerns. Soy isoflavones have been shown to act on oestrogen receptors suggesting that isoflavones should trigger cell proliferation in hormone-sensitive tissues such as breast or uterus.

The significance of such studies should however be evaluated together with the overwhelming amount of other studies, including epidemiological and clinical studies in humans, which, not only confirm the safety of isoflavones, but also demonstrate the opposite effect: soy isoflavones protection against hormone-triggered cancer.

Human studies clearly show that the potential risk observed in animal and laboratory studies cannot be directly transferred to humans.

The dose of isoflavones applied in animal studies presumably demonstrating a risk was generally in a range far beyond what can be reached by consumption of soy food or supplements 31,32, and the way isoflavones are processed in rodents is highly different to the mechanisms of absorption, distribution and bioavailability in humans.33 The human hormonal system is also much more complex than the animal models.

Today, the dietary intake of isoflavones from soy is regarded as especially beneficial for many aspects of human health.34

The term ‘phytoestrogen’ – literally, a plant-derived compound able to behave like oestrogen and to activate the oestrogen receptor – was coined to describe this group of substances which are found in a large range of grains, seeds, legumes and medicinal plants, as well as some other commonly eaten foods.

The term was coined after the observation that sheep grazing on red clover developed infertility. It had originally been assumed that the phytoestrogens from red clover are powerful oestrogens, acting as a contraceptive due their hormonal effects.35 This has turned out not to be correct.

The riddle of the infertility of grazing sheep is still unsolved. It may be related to differences in the metabolism between sheep and other mammals, but it may as well be related to blaming the wrong herb.

Oestrogen receptors

It is not that long ago that researcher realised that we do not have just one oestrogen receptor but two: alpha and beta.36 These two receptors keep each other in check. For example, alpha receptors will elicit cell proliferation, while beta has anti-proliferative effects.

The oestrogen-receptor α (ER α) is found in the inner membrane of the uterus (endometrium) and breast cancer cells. On the other hand, ERβ is found in kidney, brain, bone, heart, lung, intestinal mucosa, prostate, and endothelial cells. 21

True oestrogen is a potent stimulator of the alpha receptor and will cause proliferation of those tissues, hence the problem of oestrogen in hormone sensitive cancers. Soy has negligent effect on the alpha receptor. 37,38 Activation of alpha receptor would require blood leves ten-fold higher than what can be reached by dietary intake of isoflavones.39,40

The terms phyto-oestrogen and plant hormone have created a lot of confusion.

The use of these terms should be dropped and be replaced by the much more accurate term SERM: Selective Estrogen Receptor Modulator. This is because soy isoflavones selectively stimulates the beta receptor and not the alpha receptor.  Soy isoflavones are SERMs with a preference for the beta-receptor.

It is stimulation of the alpha receptor which is responsible for secondary sexual development and breasts in maturing girls. Eating soy during this time improve the differentiation of breast tissue due to stimulation of the beta receptor, leading to a life long reduction in risk of breast cancer. 41

The stimulation of the alpha receptor by genistein is only 4 % of the effect of the most potent oestrogen, estradiol. In contrast, the affinity for the beta receptor is 87 %.42

receptor graph

Figure 2: Soy isoflavones are selective oestrogen receptor modulators (SERMs) with a very strong affinity for the oestrogen beta receptor and a very low affinity for the alpha receptor.

Isoflavones are particularly important for women and are known to influence the menstrual cycle 43, to reduce the incidence of oestrogen-responsive cancers,44,45 and to decrease the frequency and severity of menopausal symptoms.46,47

Women who eat a diet rich in phytoestrogens have a lower risk of breast cancer when compared to women with a low intake of soy and legumes 48. Soy products consumed regularly in Asian countries contain abundant amounts of isoflavones 49, and are said to be responsible for these positive effects 50, although other factors contained in soy products also have anti-cancer and other beneficial effects.

Unlike oestradiol (the true oestrogen hormone), none of the phytoestrogens can trigger the full range of oestrogenic actions due to the low ability to stimulate the alpha receptor. So, for example, physical maturation, ovulation and menstruation – which are typical alpha receptor-related effects – cannot occur in response to isoflavones.

A study on the long-term effects of soy formula fed to infants showed that at adulthood there were no significant developmental or reproductive differences between infants who were fed soy formula and those fed cow’s milk formula.51

Research is evolving on a daily basis on the many effects of phytoestrogens, including their non-hormonal actions. On the evidence to date, it seems realistic to suggest that women of all ages consume phytoestrogens regularly as part of a balanced diet. It is possible that the most benefit may be gained if exposure to phytoestrogens begins early in life, prior to puberty (Warri et al. 2008). However, the clinical data provides sufficient evidence that even post-menopausal women without noteworthy prior exposure to isoflavones will benefit from an increased intake though an improved bone health and less menopausal symptoms.46,52

Safety with cancer medications

Tamoxifen

There is no clinical evidence suggesting that that isoflavones promote breast cancer, or that exposure to isoflavones is associated with clinically demonstrated life-prolonging effects in breast cancer patients. Furthermore, benefits were demonstrated for the combination of tamoxifen and isoflavones.53

Breast cancer is one of the most frequent cancer types in Western industrialized nations. With the currently established therapy the five-year survival rate is relatively high, with 89 % 54. However, in 10-15 % of women there is a recurrence of cancer within three years. The anti-oestrogen drug, tamoxifen is used to reduce the risk of a recurrence, however, two thirds of women treated with tamoxifen suffer from typical menopausal symptoms such as hot flushes or night sweats, caused by ovarian failure within the first year of cancer treatment.55 Some writers have voiced concern about the safety of consuming phytoestrogens in the diet when a woman has breast cancer, especially in the context of tamoxifen therapy. Long-term studies with isoflavone exposure to healthy and cancer-bearing women do not support such concerns 11,56-58. In fact, soy food and isoflavone exposure to women with breast cancer including women treated with tamoxifen has been shown to improve the prognosis of the disease.59

Researchers observed the association of soy food intake after diagnosis of breast cancer with total mortality and cancer recurrence as well as with menopausal symptoms. Her findings were based on the Shanghai Breast Cancer Survival Study, a large population-cohort study of 5.042 breast cancer survivors 60. The study involved the assessment of the effects of soy exposure on recurrence, mortality, quality of life, bone loss, depression, cognitive decline, cardiovascular disease and histopathology of breast tissue. The researchers found that soy food intake, measured by soy protein and/or soy isoflavone intake, was inversely correlated with mortality and cancer recurrence 61. The hazard ratio associated with the highest quartile of soy protein intake was 0.67 (95 % CI 0.52-0.84) for recurrence compared with the lowest quartile. The multivariate adjusted mortality rates were 13.1 and 9.2 %, and the 5-year-recurrence rates were 13.0 and 8.9 %, respectively, for women in the lowest and highest quartiles of soy protein intake. Higher isoflavone exposure of breast cancer patients clearly improves the prognosis.

The improved prognosis was evident among women with oestrogen negative and positive breast cancer, and was also found in users and non-users of tamoxifen. Soy protein and isoflavones both correlated with the time of disease-free survival. Best effects were noted with approximately 11 g of soy protein daily, or with 30-70 mg of isoflavones. There was no difference with respect to pre- or postmenopausal women.

There was likewise no impairment of cancer therapy in large case control studies 60,62. In one cohort study in 1,954 breast cancer patients there was not only a reduced rate of cancer recurrence, but also no undesired interaction with tamoxifen 47. The study explicitly mentioned positive effects against oestrogen-receptor-positive breast cancer, and thus against a form of cancer which reacts very sensitively to oestrogens by growth stimulation 47.

Anastrozole

In postmenopausal women, the aromatase inhibitor, anastrozole is preferred above tamoxifen because it blocks the production of oestrogen in the fat tissue.  Research also suggests that soy is safe for women, or men, treated with anastrozole. In a recently published trial, the researchers observed an association between dietary soy isoflavone intake and breast cancer recurrence and survival among 524 post-operative breast cancer patients receiving adjuvant endocrine therapy.Isoflavone intake was clearly associated with a statistically significant reduction of the risk of breast cancer recurrence.63,64. The study results contradict the hypothesis of an increased breast cancer risk in menopausal women. They point to potential synergism of isoflavone effects with the efficacy of cancer drugs such as anastrozole.

Soy allergy

Since the 1910 soy-based formulas have saved the lives of many infants whose mothers could not breast feed and who were allergic to cow’s milk

Despite the prevalent view that soy allergy is a big problem, the documented level of soy allergy is actually very low in Europe and in Asia. The most commonly reported food allergens in the European and North American are cow's milk, egg, peanuts, tree nuts, wheat, crustacean shellfish, fish and soy. However, the true prevalence of fish and soy allergies are low in challenge-proven studies.

The prevalence of clinician diagnosed soya allergy, found that soy allergy was only present in two out of 1000 (0.2%) one year olds and in eight out of 1000 (0.8%) in 4 and 8 year olds in Sweden. Sensitisation based on a positive skin prick test was found to be 8.3% in a Hungarian study of 20-69 year olds,  but only 0.2% in seven year old children in the UK. When a convincing history was combined with sensitisation, prevalence of soya allergy ranged from 0% in 18 month olds in Sweden to 1.6% of 4 year olds, also in Sweden. Only one study performed a double-blind placebo-controlled food challenge, reporting 0% prevalence to soya in 0-22 year olds.65

Milk or dairy is the most common food allergy in Europe and worldwide. The self-reported dairy allergy was 21% in one study.  The highest rates of challenge-proven cow’s milk allergy was 2.3% (95% CI: 1.5-3.3%) in a Dutch study of infants.65

The overall prevalence of food allergy in Asia is somewhat comparable to the West. However, the types of food allergy differ in order of relevance. Shellfish is the most common food allergen from Asia, in part due to the abundance of seafood in this region. Peanut allergy in Asia is extremely low compared to the West for reasons not yet understood. Among young children and infants, egg and cow's milk allergy are the two most common food allergies, with prevalence data comparable to western populations. Soy allergy seems to be low in Asian countries.66

Phytic acid

Much is written on the internet about the “dangers” of phytic acid in soy products. Phytic acid (also known as inositol hexaphosphate (IP6) or phytate) is present in the brans and hulls of most grains, beans, nuts, and seeds. Rich sources of phytic acid are wheat bran and flaxseed. Phytic acid binds to minerals and metals. Phytic acid may therefore block the body's uptake of essential minerals such as magnesium, calcium, and iron. On the other hand, phytic acid is an antioxidant and has anti-cancer properties. Phytic acid also improves the removal of heavy metals including lead, and other toxic metals from the body.21

Phytic acid is highest in soaked soybeans and lowest in fermented products such as tempeh. The phytic acid content of soaked soybeans has been shown to be halved during tempeh fermentation and be further reduced when tempeh was stored for 72 hr at 5° and at 30°C. Deep fat frying of tempeh in peanut oil further halved the phytic acid content. Less than 10% of the phytic acid remained after tempeh fermentation, storage and frying (see figure below).67

phytate

Figure 3: Tempeh has the lowest level of phytic acid, soaked beans the highest.

Does phytic acid interfere with mineral absorption?

One study examined the effect of cooking on the content of phytate and the inhibitory effects of phytate on the bioavailability of minerals in eight Malaysian soy based dishes. The study found that cooking reduced the phytate content but it was not significantly different (P > 0.05). The study also found that phytate reduced the bioavailability of calcium and iron, but not zinc from the food.68

However, such studies does not tell us what happens in humans eating or drinking soy foods. Calcium is less available (75%) from soy milk compared to cow’s milk. However, tofu is a more concentrated food and the absorption of calcium is very good.

Using a cross-over design, two studies examined the calcium absorption from calcium-set tofu compared to milk in healthy, premenopausal women. In the first study, calcium absorption from tofu set with calcium carbonate was determined in Caucasian women by faecal recovery of the stable isotope, 44Ca. In the second study, calcium absorption was determined in Asian women from tofu set with calcium sulfate by appearance of 45Ca in the blood after 5 hour. Analysis of the studies, both separately and pooled, showed that calcium absorption was similar between calcium-set tofu and milk.69 In other words, calcium was just as well absorbed from the tofu as it was from cow’s milk.

Tofu reduces lead toxicity

Tofu has been shown to reduce lead levels in Chinese men and women exposed to lead. The higher the intake of tofu, the lower the lead blood levels. The study analysed 605 men and 550 women who completed baseline questionnaires and had blood lead measurements taken in 1996–1998 in a prospective cohort study on reproductive health. Mean blood lead levels were 13.2 µg/dl in men and 10.1 µg/dl in women. Blood lead levels were negatively associated with tofu intake in both genders. A linear trend test showed a 3.7% (0.5-µg/dl) decrease in blood lead level with each higher category of tofu intake (p = 0.003). The highest tofu intake group (≥750 g/week) had blood lead levels 11.3% lower (95% confidence interval: 4.1, 18.0) than those of the lowest tofu intake group.70

Taken together, these studies suggest that in a balanced diet of various soy foods, absorption of calcium and other minerals is significantly reduced and that substituting soy foods like soymilk, tofu and tempeh for dairy products is not going to produce mineral deficiencies.

Trypsin inhibitors

Another compound found in soy which are frequently cited as a problem is the presence of trypsin inhibitors. When active, these proteins inhibit trypsin, a digestive enzyme secreted by the pancreas, that allows us to digest proteins. Fortunately, trypsin inhibitors are almost completely deactivated by the typical cooking of soybeans to make soy foods. There is no scientific evidence that the small percentage remaining has any adverse effects on human healthy, digestibility or amino acid absorption. In addition, trypsin inhibitors have anti-cancer properties.71

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receptorEffects on oestrogen receptors and anticancer effects

The estrogenic or anti-estrogenic activity of a phytoestrogen can vary depending on the experimental conditions of in vitro and in vivo studies, and on the design of clinical and epidemiological trials. In addition, agonist or antagonist effects are dependent on the oestrogen status in the tissue and blood, and on the distribution of subtypes of oestrogen receptors in the organs. For example, while some in vitro studies on genistein assessed this phytoestrogen to be strongly estrogenic, clinical observation suggests a selective oestrogen-modulatory effect, which can, depending on the conditions, also be interpreted as an anti-estrogenic effect. In vitro genistein may increase the proliferation of oestrogen-dependent MCF-7 breast cancer cells in the absence of oestrogen, whereas in the presence of even small quantities of oestrogen genistein inhibits the activation of dormant breast cancer calls.1 Clinically a high intake of dietary genistein, e.g. by soy food, is correlated with a low incidence of breast cancer.2

Isoflavones should no longer be considered “phytoestrogens”, as they do not act as simple estrogen agonists. Today they are considered as “Selective Estrogen Receptor Modulators” (SERMs), which better reflects the complex interaction on the level of the estrogen receptors alpha and – most importantly – beta.

Studies continue to confirm the many antiproliferative activity of soy isoflavones:

  • Genistein was demonstrated to inhibit hormone sensitive cancer cell proliferation3, through mechanisms involving an arrest of the cell cycle. 4,5
  • Genistein reversed cancer-promoting estrogenic effects of bisphenol A through the induction of apoptosis.6
  • Genistein inhibits cancer cell proliferation by inhibition of topoisomerase II7
  • Genistein and daidzein downregulate genes enhancing cancer cell proliferation8

Quality in vivo studies consistently show that a soy- and isoflavone-rich diet has a protective effect against cancer development.9-17 The cited references are by no means exhaustive. The studies on tumour prevention clearly demonstrated a protective effect of soy isoflavones from various types of cancer. An increased risk cannot be extrapolated from the poorly designed or inappropriate animal models.

Antidiabetic effects

Genistein has been shown to improve diabetic wound healing in vivo. Genistein rescued the delayed wound healing and improved wound angiogenesis in chemiaclly-induced type 1 diabetes in mice.18

Cardiovascular effects

Research suggests that soy isoflavones have antiatherogenic effects by reducing the expression of adhesion molecules and acting as preventive agents as well as therapeutic agents.19

Genistein, at concentrations achievable by ingestion of phytoestrogen-rich soy, has been shown to cause dilatation ex vivo of small peripheral arteries from normal men and those with established coronary heart disease. The contribution of nitric oxide to dilatory responses by these compounds is pertinent to arteries from control males, whereas other nitric oxide-independent dilatory mechanism(s) are involved in arteries from coronary heart disease 20. Genistein has further been shown to activate cytoprotective antioxidant genes which may represent a novel strategy in the prevention and treatment of cardiovascular endothelial damage.21

Effect on bone

The effect of soy isoflavones on bone metabolism is varied. Some studies found that soy prevented bone loss after surgically induced “menopause” in rats by increase bone formation or by having a bone-sparing effect.22-25 Not all studies have shown positive effects. One study found that genistein administered as a once-daily oral supplement had no beneficial effect on the tibia in rat models for postmenopausal bone loss26 while another study found that equol but not genistein improved early metaphyseal fracture healing in osteoporotic rats.27

Effects on thyroid function

Soy foods appear to affect thyroid function in an inconsistent manner, as studies have shown both increases and decreases in the same parameters of thyroid activity. Soaking, fermentation, and heating may reduce problematic anti-nutrients contained in soy.28 A recent study found that dietary soy increases triiodothyronine in preovariectomized monkeys and prevents a decline in thyroxine after surgical menopause. The outcomes observed in this study suggest that soy protein and isoflavone consumption does not adversely affect, and may even preserve-thyroid function in postmenopausal women.28

Neuroprotective effects

Pretreatment with genistein resulted in an enhancement in the survival of human neuroblastoma SK-N-SH cells against 6-hydroxydopamine-induced neurotoxicity. The activation of the IGF-I receptor signaling pathway might be involved in actions of genistein.29

Renal protective activities

Consecutive treatment of soy protein isolate has been shown to protects against renal dysfunction, particularly tubulointerstitial nephritis, in deoxycorticosterone acetate-treated obese Zucker rats.30

Aromatase inhibition

Aromatase is the enzyme responsible for the conversion of androstenedione into estrone in fat cells. Lignans and isoflavones have been shown to inhibit aromatase in vitro.31 The levels of inhibition can vary, depending on which of the plant estrogens are tested. Hypothetically this could result in a reduction of the production and availability of endogenous estrogen. However, the quantities of isoflavones required for a noteworthy inhibition are unlikely to be achieved with dietary isoflavone exposure.

5-α-Reductase inhibition

Isoflavones and lignans reduce the conversion of testosterone to dihydrotestosterone (DHT) via inhibition of 5a-reductase enzyme activity. This can be expected to benefit those women with conditions related to androgen excess, and possibly men with prostate hyperplasia – another indication where isoflavones have been shown to exert beneficial effects.32-34 However, the concentrations of serum phytoestrogens required for a relevant inhibition of 5α-reductase may not be achieved with dietary sources.

Inhibition of 17β-hydroxysteroid dehydrogenase

Phytoestrogens may inhibit 17b-hydroxysteroid-dehydrogenase I (17b-HSOR I) the enzyme responsible for the metabolic transformation of estrone to oestradiol. Inhibition of 17b-HSOR I is related to an anti-estrogenic effect. Estrone is considered as being more cancerogenic to oestrogen-dependent tissues than oestradiol and reducing it may reduce cancer growth.35

Antioxidant effects

Isoflavones have been shown to possess strong anti-oxidant effects 36-38. This can be expected to potentiate other anti-cancer effects of the phytoestrogens.

Effects on adipogenesis

Dietary intake of soy foods is associated with lower mammary tumour risk and reduced body weight, adiposity and inflammation in rodent breast cancer models. The results of a study suggest a mechanistic pathway to support direct regulation of mammary adiposity by genistein for breast cancer prevention.39,40. Soy has also been shown to have hepatoprotective and positive metabolic effects in a study of non-alcoholic steatohepatitis in obese Zucker rats.41

Anticancer activities

Many of the health benefits provided by phytoestrogens are due to mechanisms other than their interaction with oestrogen receptors – for example, their influence on cell proliferation, protein synthesis, angiogenesis and lipid oxidation.42,43Cooking or processing soy beans seems only to enhance the anticancer properties. 44

Inhibition of angiogenesis

A highly complex cascade of receptors, enzymes and mediators is involved in the signalling cascade of angiogenesis. Each step in the chain of events leading to angiogenesis is a potential therapeutic target against tumour growth. The signalling cascade is complex and involves multitude of factors, which by themselves will activate enzymes or genes, lead to the formation of certain receptors, or facilitate the migration of cells (metastases as well as endothelial cells for microvessel formation). Isoflavones have effects on various levels of the signalling cascade of neoangiogenesis, as demonstrated in vitro and in animal experiments.45In animal experiments soy products inhibit cancer development, which is expressed by a reduced formation of microcapillaries in the tumour.46

Inhibition cancer proliferation

Isoflavones has been shown to reduce proliferation4,7,8,47-49, inhibit the growth promoter, IGF-150, and inhibit cancer pathways.51

Induction of apoptosis in cancer cells

Pathological processes lead to the activation of apoptosis, or programmed cell death. This mechanism does not work in cancer cells. The program of apoptosis is interrupted, and the cells become potentially immortal. One of the targets of tumour treatment is therefore the re-activation of apoptosis to the normal level. Genistein stimulates apoptosis leading to a reduction of tumour volume and reduced angiogenesis (development of new cancer blood vessels to support the tumour). Positive effects on re-establishing a normal pattern of apoptosis have been demonstrated with breast cancer cells 52, leukemic cells 53 and prostate cells54, amongst others.

Effects on matrix metalloproteinases, tyrosin kinase and NF-kB

Tumour growth is not an isolated event, but happens in tissue already occupied by healthy tissue. This healthy tissue is embedded in an extracellular matrix. In order to create space for an invasion of metastases and/or for tumour growth this extracellular matrix must first be degraded. The degradation requires proteases. Consequently, the matrixmetalloproteinases (MMPs) are an important therapeutic target for tumour prevention and treatment. The effect of MMPs on the extracellular matrix facilitates cell growth, cell division, migration and invasion of cancer cells, and angiogenesis 55. The activity of the MMPs is modulated by enzymes such as protein kinase or tyrosine kinase, and the master gene switch for inflammation, NF-kB. In tumours increased amounts of MMPs are liberated. E.g., in mice with breast cancer MMP-9 is elevated.56 Genistein inhibits tyrosine kinase, NF-kB56 and TGF-b1, another compound essential for tumour invasion.57

Chemopreventive effects

Soy isoflavone have been shown to significantly inhibit the development of chemically-induced mammary tumours.58-60

Radioprotection

Radiotherapy of locally advanced non-small cell lung cancer is limited by radiation-induced pneumonitis and fibrosis. In vitro and in vivo studies have demonstrated a differential effect of soy isoflavones on augmenting tumour destruction induced by radiation while protecting normal lung tissue. The results of the studies suggest that soy isoflavones given pre- and post-radiation protected the lungs against adverse effects of radiation including skin injury, hair loss, increased breathing rates, inflammation, pneumonitis and fibrosis, providing evidence for a radioprotective effect of soy.61

Epigenetic modification

Epigenetic modifications is mediated via a number of mechanisms. The most studied being methylation and acetylation of histones which affects the expression of genes. Soy isoflavones have been shown induce anticancer epigenetic changes associated with upregulation of anticancer genes (tumour suppressor genes) and downregulation of pro-cancer genes (oncogenes).62-65

Anti-metastatic effects

Cancer metastasis refers to the spread of cancer cells from the primary neoplasm to distant sites, where secondary tumours are formed, and is the major cause of death from cancer. Natural phytochemicals containing phenolic compounds have been widely demonstrated to have the capability to prevent cancer metastasis. Among phenolic compounds, flavonoids are a very large subclass, and they are abundant in food and nutraceuticals. The number of reports demonstrating that flavonoids are an effective natural inhibitor of cancer invasion and metastasis is increasing in the scientific literature. Catechin derivatives, genistein, silibinin, quercetin, and anthocyanin have been widely investigated for their inhibitory activities on invasion/metastasis.66

Inhibition of prostate cancer

Soy and its constituent isoflavone genistein inhibit the development and progression of prostate cancer through a variety of mechanisms.67

References

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  40. Montales MT, Rahal OM, Nakatani H, Matsuda T, Simmen RC. Repression of mammary adipogenesis by genistein limits mammosphere formation of human MCF-7 cells. The Journal of endocrinology. 2013;218(1):135-149.
  41. Davis J, Cain J, Butteiger D, Banz WJ. Antagonism of adipogenic programming by soy-based diet protects against non-alcoholic steatohepatitis (NASH) in obese Zucker rats. 9th International Symposium on the Role of Soy in Health Promotion and Chronic Disease Prevention and Treatment, Washington DC, 16-19 October. 2010.
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  43. Constantinou AI, Mehta RG, Vaughan A. Inhibition of N-methyl-N-nitrosourea-induced mammary tumors in rats by the soybean isoflavones. Anticancer research. 1996;16(6A):3293-3298.
  44. Dong X, Xu W, Sikes RA, Wu C. Apoptotic effects of cooked and in vitro digested soy on human prostate cancer cells. Food chemistry. 2012;135(3):1643-1652.
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  46. Guo Y, Wang S, Hoot DR, Clinton SK. Suppression of VEGF-mediated autocrine and paracrine interactions between prostate cancer cells and vascular endothelial cells by soy isoflavones. The Journal of nutritional biochemistry. 2007;18(6):408-417.
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  49. Diel P, Geis RB, Caldarelli A, et al. The differential ability of the phytoestrogen genistein and of estradiol to induce uterine weight and proliferation in the rat is associated with a substance specific modulation of uterine gene expression. Molecular and cellular endocrinology. 2004;221(1-2):21-32.
  50. Lee J, Ju J, Park S, Hong SJ, Yoon S. Inhibition of IGF-1 signaling by genistein: Modulation of E-cadherin expression and downregulation of (beta)-catenin signaling in hormone refractory PC-3 prostate cancer cells. Nutrition and cancer. 2012;64(1):153-162.
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soy foodsMenopausal hot flushes

The connection between an increased uptake of isoflavones and a reduced frequency of hot flushes was first been described in 1992. It was based on a lower incidence of hot flushes in countries with a high consumption of soy.1

Meta-analyses and reviews have confirmed a beneficial effect of isoflavones against menopausal complaints including hot flushes, profuse sweating, depression, poor sleep and headache.2-4

The prevalence of these complaints shows noticeable differences in different world regions. Whereas 74 % of European women complain about hot flushes, only 5 % of the Japanese women indicate the same problem 5.

Several factors including smoking, caffeine, being overweight and stress may increase hot flushes. As oestrogen supplementations may reduce hot flushes, it seems obvious that hot flushes are hormone related. The exact mechanism of hot flushes is, however, not known. Oestrogen deficiency alone is not sufficient to trigger the symptoms. Paradoxically, overweight women who have a higher oestrogen production through biosynthesis in the fat tissue, suffer from more instead of fewer hot flushes.6

Not all epidemiological studies confirm the inverse assotiaton between isoflavone intake and vasomotor symptoms. No consistent relations were found between any dietary phytoestrogen or fiber and incident of hot flushes in American women, although some individual quartiles were statistically significant.7 Because the intake in Western countries is generally very low compared to Asian intake, it is difficult to prove a significant effect of soy in Western populations. It is likely that a lifelong intake is better than starting late in life.

Diet with soy products

The International Menopause Society recommends isoflavones as “an efficacious alternative and addition to the treatment of symptoms of menopause and premenopause”. 8,9

A meta-analysis found that supplements containing soy isoflavone are significantly more effective than placebo in reducing the frequency and severity of hot flashes. The meta-analysis—which is the largest and most comprehensive conducted to date – found that that soy isoflavones for six weeks to 12 months significantly reduced the frequency of hot flushes by more than 20 per cent compared with placebo. Soy isoflavones also significantly reduced the severity of hot flushes by more than 26 per cent compared with placebo.

The review found that isoflavone supplements providing more than 18.8 mg of genistein (the median for all studies) were more than twice as potent at reducing the frequency of hot flushes than supplements with a lower level of genistein.10 The key finding in this study is that when you limit the analysis to isoflavone supplements derived from soy or those with profiles identical to soy, there is a very consistent effect on hot flush relief. Almost all studies in the meta-analysis show a consistent reduction in hot flush frequency and severity.

That dosage is important was confirmed in another study that found that a high dose (100 to 200 mg), and twice-daily to thrice-daily dosing frequency improved the benefit of isoflavones for hot flushes, particularly in equol producers and for night-time symptoms.11 The results may also explain the negative outcome in other studies based on lower levels of isoflavones and in Western women. 25% of the Western populations have a reduced capacity to produce the active compound equol from other soy isoflavones.

The most recent review also came to the conclusion that isoflavone supplements consistently alleviate menopausal hot flushes, as well as having positive effects in the cardiovascular system.12

Bone health

Soy isoflavone has a positive effect on bone health. However, lifelong intake of soy isoflavones is best. The results of a double-blind randomized trial found that soy protein supplement containing isoflavones did not improve bone mineral density, cognitive function or plasma lipids in healthy postmenopausal women when started at the age of 60 years or later.13

The measurement of bone mineral density is possibly not an ideal parameter for the assessment of protective isoflavone effects. Bone strength would appear to be a much more relevant factor when it comes to the prevention of bone fractures. A study found that soy food reduced the risk of fracture in postmenopausal women, particularly among those in the early years following menopause.14

The effects of isoflavones on bone health is likely to be dependent on menopausal status, isoflavone dose and type of supplement. Wei et al. (2012) examined the the effect of soy isoflavones on prevention of osteoporosis, and the effective dosage of soy isoflavones and its duration. Soy isoflavones are probably better at improving bone density rather than stimulating new growth. Prevention is better than a cure.

A meta-analysis found that soy isoflavone supplements significantly increased bone mineral density and decreased the bone resorption marker urinary DPD. However, it found no significant effect on the bone formation marker, alkaline phosphatase. The significant effect of soy isoflavones on bone mineral density and urinary DPD is relative to menopausal status, supplement type, isoflavone dose and intervention duration.15

Overall the results suggest that isoflavones may help prevent osteoporosis in both men and women, and reduce fracture risk, at least at the hip, in postmenopausal women while reducing menopausal complaints.16

Cardiovascular health

Meta-analyses confirm that soy lowers total and LDL cholesterol and triglyceride levels both in patients with hypercholesterolaemia and with type II diabetes. Dietary soy intake reduces plasma total cholesterol, LDL cholesterol and triglycerides.17,18

Japanese women have a low incidence of and mortality from breast cancer and cardiovascular disease, and experience fewer menopausal symptoms compared to Caucasians 19. The observation that this is related to soy products in the diet 20 is increasingly being supported by trials, especially when soy protein rather than isolates are used. A study of isoflavone rich soy protein on menopausal women showed improvement of bone density, hypertension and menopausal symptoms.21

In 1999, the US Food and Drug Administration approved a health-claim for soyfoods and coronary heart disease based on the hypocholesterolaemic effects of soy protein. The results of recently published meta-analyses indicate that soy protein directly lowers circulating LDL-cholesterol (“bad” cholesterol) levels by approximately 4 %. There is also intriguing evidence that soyfoods reduce coronary heart disease risk independent of their effects on lipid levels 22. Just 30 g soy protein daily for two months has been shown to have a favourable effects on serum lipids in 28 hyperlipidemic subjects.23

In keeping with these findings, the US Food and Drug Administration recommends 25 g per day of soy protein as part of a diet low in saturated fats for cholesterol reduction.24-26

Adding soy foods to a Mediterranean diet has been shown to improve levles of total cholesterol, triglycerides, VLDL, LDL, non-HDL cholesterol, apoB and ratio of triglycerides to HDL, cholesterol to HDL, apoB to apoA-1 as well as LDL particle number.27

Soy drink has been shown to be associated with less fat accumulation, decreased markers of inflammation and oxidative stress and enhanced plasma adiponectin in overweight men compared to conventional soy drink and bovine milk 28. Daily consumption of soymilk significantly decreased atherogenic plasma cholesterol concentration. This suggests that soy drink could be an important non-pharmacological cholesterol-reducing agent.29

The Mediteraanean diet is on of the most studied diet and research consistently provide evidence that the Mediterranean diet is associated with a long, healthy life. Soy isoflavones have been shown to improve the health benefits of a Mediterranean diet.30 The study found that daily intake of 40 mg of soy isoflavones together with a Mediterranean diet and exercise reduced insulin resistance in postmenopausal women who had insulin resistance in the first place. It was significantly better than lifestyle changes alone.

The results of another study suggest that soy protein combined with a low calorie diet for four weeks treatment may be a safe and effective alternative therapy to reduce the cardiovascular risk factors in hyperlipidaemic patients. Serum lipid abnormalities are an established risk factor for cardiovascular disease in hyperlipidaemic patients. Because of the side effect of long-term medications in these patients, soy protein, as a part of healthy diet, may improve their lipid profile.

Fifty two hyperlipidaemic patients of both sex and age range of 25-65 years received a low-calorie diet based on 1400 kcal energy (18 % protein, 24 % fat and 58 % carbohydrate) per day for four weeks. The treatment group received low-calorie diet including (30 g) of soy protein. The soy protein-low calorie diet was associated with a significant reduction in weight, body mass index, waist and hip circumferences (p < 0.05) after four weeks. Serum low-density lipoprotein was significantly (p < 0.05) decreased while an insignificant reduction was seen in total cholesterol.31

It is important to note that a beneficial effect on cardiovasuclar risk factors is also seen in nonproducers of equol. The study found that soy foods reduced serum LDL cholesterol equally in both equol producers and nonproducers. However, in equol producers (35 %),  soy consumption had the added cardiovascular benefit of maintaining higher HDL-cholesterol concentrations than those seen in equol nonproducers.32

Not all studies have shown a beneficial effect. One study found that soy protein and/or soy isoflavones had little effects on serum lipids and inflammatory markers33, and another study found that 300 mg daily of an isolated isoflavone compound  produced on change in blood lipids.34 The majority of studies have however been positive, especially when eating whole soy foods.

Endothelial dysfunction

Endothelial dysfunction has been identified as an independent coronary heart disease risk factor and a strong predictor of long-term cardiovascular morbidity and mortality. Most studies with soy isoflavones suggest a positive effect.35-39 although there is evidence to suggest that the benefits of soy isoflavones in preventing cardiovascular disease may be apparent primarily among equol excretors.40

Isoflavones have a protective effect on the risk of atherosclerosis and arterial degeneration through an effect on arterial walls, especially among older women.41-43

Metabolic syndrome, obesity and diabetes

Metabolic syndrome is a disorder involving obesity, diabetes and cardiovascular disease. Soy has also been found to improve lipid profiles of elderly women with metabolic syndrome.44 Soy has also been found to improve glycaemic control in metabolic syndrome. Soy milk has also been shown to play an important role in reducing waist circumference of overweight and obese patients.45Evidence from animal and observational studies support the beneficial effects of soy intake on glycaemic control.

Although a review of randomized controlled trials found no significant overall effect of soy intake on improvements of fasting glucose and insulin concentrations, a sub-group analysis found that whole soy foods improved fasting glucose concentrations.46, and a recent meta-analysis found that soy products was associated with a significant reduction in serum total, triglycerides) and low-density lipoprotein-cholesterol (“bad” cholesterol), and a significant increase in high-density lipoprotein-cholesterol (“good” cholesterol).

There were no significant effects on fasting glucose, insulin and glycated haemoglobin. The authors concluded that intake of soy and soy products has beneficial effects in type II diabetic patients in relation to serum lipids.47

Soy isoflavone supplementation has also been shown to be beneficial in the treatment of metabolic syndrome. A systematic review and meta-analysis concluded that soy isoflavone supplementation could be beneficial for body weight reduction, glucose, and insulin control in plasma 48. One year of treatment with 54 mg genistein daily has also been shown to improve surrogate endpoints associated with risk for diabetes and cardiovascular disease in postmenopausal women with metabolic syndrome.49

Hypertension

Epidemiologic studies suggest that consuming soy reduces the incidence of cardiovascular disease and several small-scale clinical trials have suggested a potential beneficial effect of short-term soy consumption on blood pressure.50-52 A meta-analysis concluded that soy isoflavones had an effect of lowering blood pressure in hypertensive subjects, but not in normotensive subjects.53

Stroke

Higher intake of isoflavone in stroke patients has been shown to be associated with prolonged recurrence-free survival, and reduced risk of stroke recurrence and major adverse cardiovascular events independent of baseline vascular function.54

Inflammation and immunity

The immune system may be compromised after menopause because of the effects of aging and diminishing concentrations of oestrogen, an immune-modulating hormone. A randomised, controlled study found that isoflavones have beneficial effects on CRP levels in postmenopausal women. CRP is a biomarker of inflammation and high levels are associated with inflammation and heart disease. 55 Another study of inflammation found that isoflavone supplementation reduced an oxidative marker of DNA damage and improved markers of immunity in postmenopausal women.56 Young women with a higher than average intake of dietary isoflavone intakes in the U.S. has been shown to be associated with decreased serum CRP concentrations, a factor associated with beneficial effects on inflammation, and subsequently may have the potential to improve health status among young women and reduce their risk of cardiovascular disease later in life.57

Another study found that moderate endurance training in combination with a soy-based protein supplement improves aerobic energy supply and metabolic function in healthy sports students, even without changes in body composition and without changes in the exercise-induced stress and inflammatory reaction.58

Soy isoflavones are potent antioxidants and protect against oxidative damage. The results of study found a positive effect of isoflavone supplementation on oxidative stress in women, thus suggesting that the healthful action ascribed to soy consumption may be partially related to the antioxidant potential of its isoflavones. The study found a significant inverse correlation between DNA damage and plasma isoflavone concentrations (p < 0.01).59

Soy food has also been shown to lower circulating levels of biomarkers of inflammation including IL-6, TNFa, and soluble TNF receptors 1 and 2 in Chinese women.60

Asthma and chronic obstructive airways disease

Even asthma has been shown to improve with soy consumption in Japan. Increasing soy consumption was associated with a decreased risk of COPD and breathlessness61 and the results of a post-hoc analysis study suggest that, in patients with asthma, consumption of a diet with moderate to high amounts of soy genistein is associated with better lung function and better asthma control.62

Gout

Eating seafood and red meat often aggravates gout. Soy may be a good alternative. A large study found a direct association between seafood consumption and hyperuricemia and an inverse association between consumption of soy food and hyperuricemia among middle-aged, Chinese men.63

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