Menopause and Isoflavones

Both soy and red clover contain phytoestrogens (naturally occurring substances with estrogen-like actions) called isoflavones. It is thought that the isoflavones in these foods may offer some benefits of estrogen with less risk.

Soy, a major source of isoflavones.

Improvements in hot flashes as well as other symptoms, such as vaginal dryness and mood, have been seen in many studies of soy, mixed soy isoflavones, aglycone isoflavones, and the isoflavone genistein alone.

For example, a double-blind study of 247 women suffering from menopausal hot flashes compared the effects of placebo and genistein over a period of one year. Genistein was taken at a dose of 54 mg per day. The results indicated that use of genistein significantly reduced hot flashes as compared to placebo.

Certain women may benefit from soy isoflavones more than others. In about one-third of people, isoflavones are converted by intestinal bacteria into a substance called equol. At least two studies suggest that these equol producers may experience greater reduction in their menopausal symptoms than non-equol producers.

Safety Issues

Studies in animals have found soy isoflavones essentially nontoxic. ¹ The long history of the use of soy as food in Asia would tend to suggest they are safe as well. Even though absolute safety cannot be assumed from 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 84 consecutive days. ² In Japan, the maximum safe intake level of soy isoflavones has been set at a total of 70 to 75 mg daily (food plus supplement sources).

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 appear to be fairly minimal. ³ Nonetheless, it is not zero. According to most but not all studies, use of soy has enough of an estrogen-like effect to slightly alter the menstrual cycle and change levels of sex hormones in young women. ⁴ Thus, some of the risks of estrogen could, in theory, 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 anti-estrogenic effect by blocking real estrogen, some studies in animals have found evidence that, under certain circumstances, soy isoflavones might stimulate breast cancer cells. ^{5 6} Studies directly examining the effects of isoflavones on human breast tissue have produced contradictory results. ⁷ . However, on balance, there is no convincing evidence that consuming moderate amounts of soy isoflavones (at levels typical of an Asian diet) increases the risk of breast cancer in healthy women or worsens the prognosis of women with breast cancer. ⁸ 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. ⁹ Estrogen also stimulates uterine cells, leading to an increased risk of uterine cancer. Most studies have found that isoflavones do not stimulate uterine cells. ¹⁰ However, one fairly large (365 participants) and long-term (5 years) study did find uterine stimulation in 3.37% of women on isoflavones and 0% of those on placebo. ¹¹ 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 unborn fetuses. ¹² 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 benefit of tamoxifen treatment. ¹³ One double-blind study of post-menopausal women found the use of red clover isoflavones at a dose of 80 mg daily for 90 days resulted in increased levels of testosterone. ¹⁴ The potential significance of this is unclear. In men, isoflavones might decrease testosterone levels, but the effect appears to be slight at most. ¹⁵ Other concerns relate to soy’s potential effects involving the thyroid gland. When given to individuals with impaired thyroid function , soy products have been observed to reduce absorption of thyroid medication. ¹⁶ In addition, some evidence hints that soy isoflavones may directly inhibit the function of the thyroid gland (though perhaps only in people who are iodine deficient). ¹⁷ To make matters more confusing, studies of healthy humans and animals given soy isoflavones or other soy products have generally found that soy either had no effect on thyroid hormone levels or actually increasedlevels. ¹⁸ The bottom line: In view of soy’s complex effects regarding the thyroid, individuals with impaired thyroid function should not take large amounts of soy products except under the supervision of a physician.

While fears have been expressed by some experts that soy isoflavones might interfere with the action of oral contraceptives, one study of 36 women found reassuring results. ¹⁹ 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 (an organ that is important for immunity) and also causes changes in the prevalence of various white blood cells consistent with impaired immunity. ²⁰ Although the genistein was injected rather than administered orally, the blood levels of genistein that these injections produced were not excessively high; they were comparable to (or even lower than) what occurs in children fed soy milk formula. In addition, there are several reports of impaired immune responses in infants fed soy formula. ^{21 22 23} 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. ²⁴ However, observational studies are far less reliable than clinical trials. Direct studies designed to test the potential effects of isoflavones on brain function, and lasting up to 12 months, have found either no effect or a slightly positive effect on brain function. ^{25 26} 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. ²⁷ Similarly, while soy products are sometimes recommend for reducing blood pressure, there is also a well-documented case report in which use of high dose soy isoflavones caused extreme elevation in blood pressure in a woman participating in a scientific study (of soy isoflavones). ²⁸ Some researchers have raised concern 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. ²⁹