Isoflavones' therapeutic uses

• PRINCIPAL PROPOSED USES: High cholesterol, menopausal symptoms

• OTHER PROPOSED USES: Aging skin, blood sugar control (prediabetes), cancer prevention, cyclic mastalgia, enhancing mental function, female infertility, osteoporosis, premenstrual syndrome, weight loss

DEFINITION: Natural plant product used to treat specific health conditions

Overview

Isoflavones are water-soluble chemicals found in many plants. This article focuses on a group of isoflavones that are phytoestrogens, meaning they cause effects in the body somewhat similar to those of estrogen. The most investigated phytoestrogen isoflavones, genistein, and daidzein, which are found in soy products and the herb red clover. Soy also contains glycitein, an isoflavone that is more estrogenic than genistein and daidzein but is usually in relatively low amounts. Red clover also has two other isoflavones in te form of biochanin and formonenetin.

Specific cells in the body have estrogen receptors, unique sites that allow estrogen to attach. When estrogen binds to a cell’s estrogen receptor, estrogenic effects occur in the cell. Isoflavones also latch onto estrogen receptors, but they produce weaker estrogenic effects. This leads to an interesting two-part action. When there is insufficient estrogen in the body, isoflavones can stimulate cells with estrogen receptors and partly compensate for the deficit. However, when there is plenty of estrogen, isoflavones may 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 benefitssuch as preventing osteoporosis.

Isoflavones also appear directly to reduce estrogen levels, perhaps by fooling the body into thinking that it has plenty of estrogen. Isoflavones are widely thought to be the active ingredient in soy products. However, growing evidence suggests that there are other active ingredients, such as proteins, fiber, and phospholipids.

Requirements and Sources

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.

Mature and green soybeans are rich in isoflavones, with about 167 milligrams (mg) for a 3.5-ounce serving. Products made from soybeans are also good sources of isoflavones, including soymilk, miso, natto, and tofu, each with around twenty milligrams per serving. Tempeh, a type of fermented soybean cake, offers sixty milligrams per serving, and soy flour contains forty-four milligrams per serving. The types of isoflavone vary between food and supplement sources. Soy sources of isoflavones include genistein, daidzein, and glycetein, while red clover isoflavones include formononetin, biochanin A, daidzein, and genistein. Supplements may contain a variety of isoflavones, but their benefits and side effects differ from those consumed in food sources.

The same isoflavones found in soy are also contained in certain red clover (Trifolium pratense) and alfalfa (Medicago sativa) products. Other sources of isoflavones include lentils, split peas, chickpeas, pistachios, peanuts, and several beans, including fava, pinto, and lima.

Therapeutic Dosages

When purified isoflavones from red clover or soy are used, the dose generally ranges from forty to eighty milligrams daily. This is considerably higher than the average isoflavone intake in Japan, which is about twenty-five milligrams daily. However, postmenopausal Japanese women may consume closer to fifty milligrams daily. To prevent osteoporosis, 80 mg of soy isoflavones are recommended per day. Six weeks of forty milligram daily intake may improve symptoms of irritable bowel syndrome (IBS).

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 called 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. Because isoflavone aglycones are the purest form of isoflavones, it has been hypothesized, but not proven, that they are more effective than other forms.

Therapeutic Uses

Soy products are known to improve cholesterol profile, but isoflavones may not be the active cholesterol-lowering ingredient in soy. Isoflavones may, however, improve other measures linked to cardiovascular risk, such as levels of blood sugar, insulin, and fibrinogen.

According to some but not all studies, soy protein or concentrated isoflavones from soy or red clover may slightly reduce menopausal symptoms, such as hot flashes and vaginal dryness. However, isoflavones have failed to prove effective for the hot flashes that often occur in breast cancer survivors. There is conflicting evidence regarding whether soy or isoflavones may help prevent osteoporosis, but on balance, the evidence suggests a modest benefit.

One study tested a purified soy isoflavone producttechnically, isoflavone aglyconesfor treating aging skin. In this double-blind trial, twenty-six Japanese women in their late thirties and early forties were given either a placebo or forty milligrams daily of soy isoflavone aglycones for twelve weeks. Researchers monitored two types of wrinkles near the eye: fine and linear. The results indicated that using the soy product significantly reduced fine wrinkles compared with the placeboffects on linear wrinkles were not significant. As a secondary measure, researchers also analyzed skin elasticity and found an improvement in the women given the isoflavones compared with those given the placebo. This was much too small of a study for its results to be considered reliable.

A small and poorly reported double-blind, placebo-controlled study provides weak evidence that red clover isoflavones might be helpful for cyclic mastalgia. A combination product containing soy isoflavones, black cohosh, and dong quai has shown some promise for menstrual migraines.

One study found that soy isoflavones improved the effectiveness rate of in vitro fertilizationused for female infertility. A double-blind study performed in China found that the use of a soy isoflavone supplement improved blood sugar control in healthy postmenopausal women. A later review of research found soy products may be beneficial for women trying to get pregnant, but the body of research in this area continues to be underexplored.

In a small double-blind trial, soy isoflavones appeared to reduce some symptoms of premenstrual syndrome (PMS). A very small study found hints that soy isoflavones might help reduce abdominal fat buildup.

Observational studies hint that soy may help prevent breast and uterine cancer in women. If this connection is real and not a statistical accident—observational studies are notorious for falling prey to statistical accidents—the explanation may lie in the estrogen-like action of soy isoflavones. As noted above, isoflavones decrease the action of regular estrogen by blocking estrogen receptor sites and may also reduce levels of circulating estrogen. Since estrogen promotes breast and uterine cancer, these effects could help prevent breast cancer. Soy also appears to lengthen the menstrual cycle by a few days, which would also be expected to reduce breast cancer risk. However, only a large, long-term intervention trial could show that soy or isoflavones reduce breast and uterine cancer risk. While research remains mixed, soy products are generally believed to be safe for consumption by women at risk for, or those who have breast cancer, but the safety of soy isoflavone supplements is less certain.

Observational studies also hint that soy might help prevent prostate cancer in men. Men have very low levels of circulating estrogen, so the net effect of increased soy consumption might be to increase estrogen-like activity in the body. Since real estrogen is used as a treatment to suppress prostate cancer, perhaps the mild estrogen-like activity of isoflavones has a similar effect. Isoflavones might also decrease testosterone levels and alter the ratios of certain forms of estrogen, both of which would be expected to provide benefits. In one double-blind study, men with early prostate cancer were given either isoflavones or a placebo, and their PSA levels were monitored. PSA is a marker for prostate cancer, with higher values generally showing an increased number of cancer cells. The results showed that using isoflavones dailyslightly reduces PSA levels. Whether this meant that soy slowed the progression of cancer or simply lowered PSA directly is not clear from this study alone. However, in another study of healthy men not known to have prostate cancer, soy isoflavones at a dose of eighty-three milligrams per day did not alter PSA levels. These two studies provide some direct evidence that soy isoflavones may help treat or prevent prostate cancer.

According to most studies, soy isoflavones do not improve mental function. One study failed to find that soy protein with isoflavones improved the general quality of lifehealth status, depression, and life satisfactionin postmenopausal women. Soy isoflavones have also failed to prove effective in reducing homocysteine levels.

Some research indicates that soy isoflavones taken with vitamin D supplements may help the symptoms of IBS. In one study, women who took forty milligram supplements each day for six weeks saw significant improvements in inflammation and intestinal permeability. However, further research is needed to confirm these findings.

Scientific Evidence

High cholesterol. Numerous studies have found that soy can reduce blood cholesterol levels and improve the ratio of low-density lipoproteinLDL, or bad cholesterolto high-density lipoproteinHDL, or good cholesterol. Although it was once thought that isoflavones are the ingredients in soy responsible for improving cholesterol profile, on balance, evidence suggests otherwise. Nonisoflavone constituents of soy, such as proteins, fiber, and phospholipids, may be as important as, or perhaps even more important than, the isoflavones in soy.

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.

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. Glycitein could be inactive regarding cholesterol reduction.

Finally, some evidence hints that soy isoflavones may effectively reduce cholesterol only when intestinal bacteria convert it into a substance called equol. Only about one-third of people have the right intestinal bacteria to make equol.

Menopausal Symptoms. 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. However, the effects have been slight or nonexistent in other studies. At least two studies found that people who are equol producers may experience greater benefits. The herb Pueraria mirifica, which also contains several isoflavones, has also shown some benefits for menopausal symptoms.

However, several other studies have failed to find benefits with whole soy or concentrated soy isoflavones. Another study failed to find benefits with a mixture of soy isoflavones and black cohosh. Isoflavones from red clover have also shown inconsistent benefits. In double-blind, placebo-controlled trials, soy or purified isoflavones failed to reduce hot flashes among breast cancer survivors.

What can one make of this mixed evidence? The problem here is that a 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. Soy or concentrated isoflavones likely have a more modest effect, which is not always seen above the background.

Osteoporosis. Estrogen has a powerfully protective effect on bone. Studies exploring whether isoflavones have the same effect have produced inconsistent results. On balance, it is probably fair to summarize the evidence as indicating that isoflavones such 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 twenty-four-month, double-blind study of 389 postmenopausal women with mild bone loss, the use of genistein at a dose of fifty-four milligrams daily significantly improved bone density compared with the placebo. Participants were also given calcium and vitamin D.

However, it is not clear that isoflavones consumed in the diet, even at high concentrations, are beneficial. For example, in a placebo-controlled study involving 237 healthy women in the early stages of menopause, the consumption of isoflavone-enriched foodsproviding an average of 110 mg isoflavone aglycones dailyfor one year did not impact bone density or metabolism. 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.

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 slowing bone breakdown. There is mixed evidence that isoflavones are more effective for osteoporosis in people with intestinal bacteria that produce equol.

Menstrual migraines. In a twenty-four-week, double-blind study, forty-nine women with menstrual migraines received either a placebo or a combination supplement containing soy isoflavones and extracts of dong quai and black cohosh. Beginning at the twentieth week, using the herbal supplement resulted in decreased severity and frequency of headaches compared with the placebo. However, it is unclear which of the ingredients in the combination was helpful. The study's authors considered black cohosh and dong quai as phytoestrogens, but the current consensus is that they do not belong in that category.

Safety Issues

Studies in animals have found soy isoflavones essentially nontoxic. The long history of using soy as food in Asia would also tend to suggest that they are safe. Even though absolute safety cannot be assumed from the historical consumption of soy as food, it is reassuring to note that researchers found no evidence of ill effects when they gave healthy postmenopausal women 900 mg of soy isoflavones a day for eighty-four consecutive days. In Japan, soy isoflavones' maximum safe intake level is seventy to seventy-five milligrams daily taken through food sources and supplements.

Still, concerns have been raised about estrogenic and other potential side effects of excessive soy isoflavone intake. Overall, the estrogenic effect of soy isoflavones in women appears fairly minimal. Nonetheless, it is not zero. According to most studies, soy has enough estrogen-like effect to slightly alter the menstrual cycle and change levels of sex hormones in young women. Thus, some of the risks of estrogen could apply to isoflavones as well.

For example, because estrogen can stimulate breast cancer cells, there are theoretical concerns that isoflavones may not be safe for women who have already had breast cancer. While isoflavones, in general, should have an antiestrogenic effect by blocking real estrogen, some studies in animals have found evidence that, under certain circumstances, soy isoflavones might stimulate breast cancer cells. Studies directly examining the effects of isoflavones on human breast tissue have produced contradictory results. However, on balance, there is no convincing evidence that consuming moderate amounts of soy isoflavonesat levels typical of an Asian dietincreases the risk of breast cancer in healthy women or worsens the prognosis of women with breast cancer. Nevertheless, given the theoretical risk and the absence of large, randomized trials investigating the safety of isoflavone supplements, prudence suggests that women who have had breast cancer or are at high risk for it should consult a physician before taking any isoflavone product.

Estrogen also stimulates uterine cells, leading to an increased risk of uterine cancer. Most studies have found that isoflavones do not stimulate uterine cells. However, one fairly large study with 365 participants over five years did find uterine stimulation in 3.37 percent of women on isoflavones and 0 percent of those on the placebo. This could indicate a slightly increased risk of uterine cancer with high-dose isoflavone use.

Similarly, preliminary studies and reports have raised concerns that intensive use of soy products or isoflavones by pregnant women could exert a hormonal effect that impacts fetuses. The use of soy formula by infants is also of concern along these lines, as an infant subsisting on soy formula has a relatively enormous isoflavone intake; on a per-weight basis, it may exceed the average Asian adult isoflavone intake by a factor of ten.

The drug tamoxifen blocks estrogen and is used to help prevent breast cancer recurrence in women who have had breast cancer. One animal study found that soy isoflavones might remove the benefits of tamoxifen treatment.

One double-blind study of postmenopausal women found the use of red clover isoflavones at a dose of eighty milligrams daily for ninety days resulted in increased levels of testosterone. The potential significance of this is unclear. In men, isoflavones might decrease testosterone levels, but the effect appears to be slight at most.

Other concerns relate to soy’s potential effects on the thyroid gland. When given to individuals with impaired thyroid function, soy products have been observed to reduce the absorption of thyroid medication. In addition, some evidence hints that soy isoflavones may directly inhibit the function of the thyroid gland, though perhaps only in iodine-deficient people. To make matters more confusing, studies of healthy humans and animals given soy isoflavones or other soy products have generally found that soy either did not affect thyroid hormone levels or increased levels. Given soy’s complex effects on the thyroid, individuals with impaired thyroid function should not take large amounts of soy products except under the supervision of a physician.

Although some experts have expressed fears that soy isoflavones might interfere with the action of oral contraceptives, one study of thirty-six women found reassuring results. Some evidence suggests that the isoflavone genistein might impair immunity. One study in mice found that injected genistein has negative effects on the thymus gland and causes changes in the prevalence of various white blood cells consistent with impaired immunity. Although the genistein was injected rather than administered orally, the blood levels of genistein that these injections produced were not excessively high. In fact, they were comparable to, or even lower than, the amount given to children fed soy milk formula. In addition, there are several reports of impaired immune responses in infants fed soy formula. While it is too early to conclude that genistein impairs immunity, these findings are a potential cause for concern.

One observational study raised concerns that soy might impair mental function in adults. However, observational studies are far less reliable than clinical trials. Direct studies designed to test the potential effects of isoflavones on brain function, lasting up to twelve months, have found either no effect or a slightly positive effect on brain function. While this does not rule out a harmful long-term effect on cognition, it is reassuring.

There exists one case report in which soy isoflavone supplements caused migraine headaches in a man who had never experienced migraines before; presumably, this was a highly individual reaction, such as an allergy. Similarly, while soy products are sometimes recommended for reducing blood pressure, there is also a well-documented case report in which the use of high-dose soy isoflavones caused extreme elevation in blood pressure in a woman participating in a scientific study of soy isoflavones.

Some researchers have raised concerns that genistein may influence the ability of blood to clot properly. A placebo-controlled study involving 104 healthy women, however, found no evidence that the isoflavone genistein had any significant adverse effect on blood clotting. Conversely, a 2019 study found isoflavone genistein aided in bone density, hot flashes, blood pressure, and control of the glycemic index.

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