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Isoflavones are water-soluble chemicals found in many plants. In this article, we will discuss a group of isoflavones that are phytoestrogens, meaning that they cause effects in the body somewhat similar to those of estrogen. The most investigated phytoestrogen isoflavones, genistein and daidzein, are found both in soy products and the herb red clover . Soy additionally contains glycitein, an isoflavone that is more estrogenic than genistein and daidzein, but is usually present in relatively low amounts. Red clover also contains two other isoflavones: biochanin (which can be turned into genistein) and formonenetin (which can be turned into daidzein).
Certain cells in the body have estrogen receptors, special sites that allow estrogen to attach. When estrogen attaches to a cell’s estrogen receptor, estrogenic effects occur in the cell. Isoflavones latch onto estrogen receptors too, but produce weaker estrogenic effects. This leads to an interesting two-part action. When there is not enough estrogen in the body, isoflavones can stimulate cells with estrogen receptors and partly make up for the deficit. However, when there is plenty of estrogen, isoflavones may tend to block real estrogen from attaching to estrogen receptors, thereby reducing the net estrogenic effect. This may reduce some of the risks of excess estrogen (for example, breast and uterine cancer) while still providing some of estrogen's benefits (such as, preventing osteoporosis).
Isoflavones also appear directly to reduce estrogen levels in the body, perhaps by fooling the body into thinking that it has plenty of estrogen.
Isoflavones are widely thought to be the active ingredients in soy products . However, growing evidence suggests that there are other active ingredients as well, such as proteins, fiber, and phospholipids.
There are three major isoflavones found in soy: genistein, daidzein, and glycitein. Each of these isoflavones can occur in two types or states. The first type, predominant in raw soy products, is called an “isoflavone glycoside.” In an isoflavone glycoside, the isoflavone is attached to a sugar-like substance known as a “glycone.” The second type, predominant in fermented soy products, is called an “isoflavone aglycone.” These consist of isoflavones without a glycone attached, and are also called “free isoflavones.” Since isoflavone aglycones are the most pure form of isoflavones, it has been hypothesized (but not proven) that they are more effective than other forms. 1
Although isoflavones are not essential nutrients, they may help reduce the incidence of several diseases. Thus, isoflavones may be useful for optimum health, even if they are not necessary for life like a classic vitamin.
Roasted soybeans have the highest isoflavone content: about 167 mg for a 3.5-ounce serving. Tempeh (a cake of fermented soybeans) is next, with 60 mg, followed by soy flour with 44 mg. Processed soy products such as soy protein and soy milk contain about 20 mg per serving. The same isoflavones found in soy are also contained in certain red clover products.
What Is the Scientific Evidence for Isoflavones?
Numerous studies have found that soy can reduce blood cholesterol levels and improve the ratio of LDL ("bad") versus HDL ("good") cholesterol. 4 Although it was once thought that isoflavones are the ingredients in soy responsible for improving cholesterol profile, on balance, current evidence suggests otherwise. 5 Non-isoflavone constituents of soy, such as proteins, fiber, and phospholipids, may be equally or perhaps even more important than the isoflavones in soy. 6 It is also possible that the exact types of isoflavones in a particular product made a difference. One study of red clover isoflavones found evidence that biochanin but not formononetin can reduce LDL cholesterol. 7 Another study found that soy products may at times have an unusual isoflavone profile, containing high levels of the isoflavone glycitein rather than the more usual genistein and daidzein. 8 Glycitein could be inactive regarding cholesterol reduction.
Finally, some evidence hints that soy isoflavones may be only effective for reducing cholesterol when it is converted by intestinal bacteria into a substance called equol. 9 It appears that only about one-third of people have the right intestinal bacteria to make equol.
Although study results are not entirely consistent, the balance of the evidence suggests that isoflavones from soy may be helpful for symptoms of menopause , especially "hot flashes."
Improvements in hot flashes, as well as other symptoms, such as vaginal dryness, have been seen in many studies of soy, mixed soy isoflavones, isoflavone aglycones, or genistein alone. 10 However, the effects have been slight or non-existent in other studies. 11 At least two studies found that people who are equol producers (see previous section) may experience greater benefits. 12 The herb Pueraria mirifica, which also contains a number of isoflavones, has also shown some benefit for menopausal symptoms. 13 However, several other studies have failed to find benefit with whole soy or concentrated soy isoflavones. 14 Another study failed to find benefit with a mixture of soy isoflavones and black cohosh . 15 Isoflavones from red clover have also shown inconsistent benefit 16 with the largest and most recent trial failing to find any reduction in hot flash symptoms. 17 Furthermore, in double-blind, placebo-controlled trials, soy or purified isoflavones failed to reduce hot flashes among survivors of breast cancer. 18 What can one make of this mixed evidence? The problem here is that placebo treatment has a strong effect on menopausal symptoms. In such circumstances, statistical noise can easily drown out the real benefits of a treatment under study. Estrogen is so powerful for hot flashes and other menopausal symptoms that its benefits are almost always clear in studies; most likely, soy or concentrated isoflavones have a more modest effect, not always seen above the background.
Estrogen has a powerfully protective effect on bone. Study results on whether isoflavones have the same effect have produced inconsistent results. 19 On balance, it is probably fair to summarize current evidence as indicating that isoflavones (either as soy, genistein, mixed isoflavones, or tofu extract) have at least a modestly beneficial effect on bone density.
The best evidence is for genistein taken alone. In a 24-month, double-blind study of 389 postmenopausal women with mild bone loss, use of genistein at a dose of 54 mg daily significantly improved bone density as compared to placebo. (All participants were additionally given calcium and vitamin D.) 20 However, it is not clear that isoflavones consumed in the diet, even at high concentrations, is beneficial. For example, in a placebo-controlled study involving 237 healthy women in the early stages of menopause, the consumption of isoflavone-enriched foods (providing an average of 110 mg isoflavone aglycones daily) for 1 year had no affect on bone density or metabolism. 21 Interestingly, one small, but long-term study suggests that progesterone cream (another treatment proposed for use in preventing or treating osteoporosis) may decrease the bone-sparing effect of soy isoflavones. 22 Bone is always subject to two influences: bone building and bone breakdown. Estrogen primarily works by reducing the bone breakdown part of the equation, thereby leading to a net result of increased bone growth. Growing evidence suggests that isoflavones act on both sides of this equation, directly stimulating new bone creation while at the same time slowing bone breakdown. 23 There is mixed evidence that isoflavones are more effective for osteoporosis in people who have the intestinal bacteria to produce equol. 24
In a 24-week, double-blind study, 49 women with menstrual migraines ( migraine headaches associated with the menstrual cycle) received either placebo or a combination supplement containing soy isoflavones and extracts of dong quai and black cohosh . 25 Beginning at the 20th week, use of the herbal supplement resulted in decreased severity and frequency of headaches as compared to placebo. However, it is not clear which of the ingredients in the combination was helpful. The authors of the study apparently considered black cohosh and dong quai as phytoestrogens, but the current consensus is that they do not belong in that category.
- Clerici C, Setchell KD, Battezzati PM, Pirro M, Giuliano V, Asciutti S, Castellani D, Nardi E, Sabatino G, Orlandi S, Baldoni M, Morelli O, Mannarino E, Morelli A. Pasta naturally enriched with isoflavone aglycons from soy germ reduces serum lipids and improves markers of cardiovascular risk. J Nutr. 137(10):2270-8.
- Nakamura Y, Tsuji S, Tonogai Y. Determination of the levels of isoflavonoids in soybeans and soy-derived foods and estimation of isoflavonoids in the Japanese daily intake. J AOAC Int. 83(3):635-50.
- Somekawa Y, Chiguchi M, Ishibashi T, Aso T. Soy intake related to menopausal symptoms, serum lipids, and bone mineral density in postmenopausal Japanese women. Obstet Gynecol. 97(1):109-15.
- Anderson JW, Johnstone BM, Cooke-Newell ME. Meta-analysis of the effects of soy protein intake on serum lipids. N Eng J Med. 1995;333:276-281.
- Blakesmith SJ, Lyons-Wall PM, George C, et al. Effects of supplementation with purified red clover ( Trifolium pratense ) isoflavones on plasma lipids and insulin resistance in healthy premenopausal women. Br J Nutr. 2003;89:467-475.
- Messina M, Gardner C, Barnes S. Gaining insight into the health effects of soy but a long way still to go: commentary on the fourth International Symposium on the Role of Soy in Preventing and Treating Chronic Disease. J Nutr. 132(3):547S-551S.
- Nestel P, Cehun M, Chronopoulos A, DaSilva L, Teede H, McGrath B. A biochanin-enriched isoflavone from red clover lowers LDL cholesterol in men. Eur J Clin Nutr. 58(3):403-8.
- Sirtori CR, Bosisio R, Pazzucconi F, et al. Soy milk with a high glycitein content does not reduce low-density lipoprotein cholesterolemia in type II hypercholesterolemic patients. Ann Nutr Metab. 2002;46:88-92
- Meyer BJ, Larkin TA, Owen AJ, Astheimer LB, Tapsell LC, Howe PR. Limited lipid-lowering effects of regular consumption of whole soybean foods. Ann Nutr Metab. 48(2):67-78.
- Murkies AL, Lombard C, Strauss BJ, et al. Dietary flour supplementation decreases post-menopausal hot flushes: effect of soy and wheat. Maturitas. 1995;21:189-195.
- Khaodhiar L, Ricciotti HA, Li L, Pan W, Schickel M, Zhou J, Blackburn GL. Daidzein-rich isoflavone aglycones are potentially effective in reducing hot flashes in menopausal women. Menopause. 15(1):125-32.
- Uesugi S, Watanabe S, Ishiwata N, Uehara M, Ouchi K. Effects of isoflavone supplements on bone metabolic markers and climacteric symptoms in Japanese women. Biofactors. 22(1-4):221-8.
- Manonai J, Chittacharoen A, Theppisai U, et al. Effect of Pueraria mirifica on vaginal health. Menopause. 2007 Mar 30.
- Penotti M, Fabio E, Modena AB, Rinaldi M, Omodei U, Viganó P. Effect of soy-derived isoflavones on hot flushes, endometrial thickness, and the pulsatility index of the uterine and cerebral arteries. Fertil Steril. 79(5):1112-7.
- Verhoeven MO, van der Mooren MJ, van de Weijer PH, Verdegem PJ, van der Burgt LM, Kenemans P, CuraTrial Research Group. Effect of a combination of isoflavones and Actaea racemosa Linnaeus on climacteric symptoms in healthy symptomatic perimenopausal women: a 12-week randomized, placebo-controlled, double-blind study. Menopause. 12(4):412-20.
- van de Weijer P, Barentsen R. Isoflavones from red clover (Promensil®) significantly reduce menopausal hot flush symptoms compared with placebo. Maturitas. 2002;42:187.
- Tice JA, Ettinger B, Ensrud K, Wallace R, Blackwell T, Cummings SR. Phytoestrogen supplements for the treatment of hot flashes: the Isoflavone Clover Extract (ICE) Study: a randomized controlled trial. JAMA. 290(2):207-14.
- Van Patten CL, Olivotto IA, Chambers GK, Gelmon KA, Hislop TG, Templeton E, Wattie A, Prior JC. Effect of soy phytoestrogens on hot flashes in postmenopausal women with breast cancer: a randomized, controlled clinical trial. J Clin Oncol. 20(6):1449-55.
- Nikander E, Kilkkinen A, Metsä-Heikkilä M, Adlercreutz H, Pietinen P, Tiitinen A, Ylikorkala O. A randomized placebo-controlled crossover trial with phytoestrogens in treatment of menopause in breast cancer patients. Obstet Gynecol. 101(6):1213-20.
- Marini H, Minutoli L, Polito F, Bitto A, Altavilla D, Atteritano M, Gaudio A, Mazzaferro S, Frisina A, Frisina N, Lubrano C, Bonaiuto M, D'Anna R, Cannata ML, Corrado F, Adamo EB, Wilson S, Squadrito F. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med. 146(12):839-47.
- Brink E, Coxam V, Robins S, Wahala K, Cassidy A, Branca F, PHYTOS Investigators. Long-term consumption of isoflavone-enriched foods does not affect bone mineral density, bone metabolism, or hormonal status in early postmenopausal women: a randomized, double-blind, placebo controlled study. Am J Clin Nutr. 87(3):761-70.
- Lydeking-Olsen E, Beck-Jensen JE, Setchell KD, Holm-Jensen T. Soymilk or progesterone for prevention of bone loss--a 2 year randomized, placebo-controlled trial. Eur J Nutr. 43(4):246-57.
- Fanti O, Faugere MC, Gang Z, et al. Systematic administration of genistein partially prevents bone loss in ovariectomized rats in a nonestrogen-like mechanism [abstract]. Am J Clin Nutr. 1998;68(suppl):1517S-1518S.
- Wu J, Oka J, Higuchi M, Tabata I, Toda T, Fujioka M, Fuku N, Teramoto T, Okuhira T, Ueno T, Uchiyama S, Urata K, Yamada K, Ishimi Y. Cooperative effects of isoflavones and exercise on bone and lipid metabolism in postmenopausal Japanese women: a randomized placebo-controlled trial. Metabolism. 55(4):423-33.
- Burke BE, Olson RD, Cusack BJ. Randomized, controlled trial of phytoestrogen in the prophylactic treatment of menstrual migraine. Biomed Pharmacother. 56(6):283-8.