How Phytoestrogens Can have Anti-Estrogenic Effects

When the Women’s Health Initiative study found that menopausal women taking hormone replacement therapy suffered “higher rates of breast cancer, cardiovascular disease, and overall harm,” a call was made for safer alternatives. Yes, the Women’s Health Initiative found that estrogen does have positive effects, such as reducing menopausal symptoms, improving bone health, and reducing hip fracture risk, but negative effects were also found, such as increasing the blood clots in the heart, brain, and lungs, as well as breast cancer.

Ideally, to get the best of both worlds, we’d need what’s called a selective estrogen receptor modulator—something with pro-estrogenic effects in some tissues like bone but at the same time anti-estrogenic effects in other tissues like the breast. Drug companies are trying to make these, but phytoestrogens, which are natural compounds in plants, appear to function as natural selective estrogen receptor modulators. An example is genistein, which is found in soybeans, which happen to be structurally similar to estrogen. How could something that looks like estrogen act as an anti-estrogen?

The original theory for how soy phytoestrogens control breast cancer growth is that they compete with our own estrogens for binding to the estrogen receptor. As more and more soy compounds are dripped onto breast cancer cells in a petri dish, less and less actual estrogen is able to bind to them. So, the estrogen-blocking ability of phytoestrogens can help explain their anti-estrogenic effects. How do we then explain their pro-estrogenic effects on other tissues like bone? How can soy have it both ways?

The mystery was solved when it was discovered there are two different types of estrogen receptors in the body and the way in which a target cell responds depends on which type of estrogen receptor they have. The existence of this newly discovered estrogen receptor, named “estrogen receptor beta…to distinguish it from the ‘classical’ estrogen receptor alpha,” may be the “key to understanding the health-protective potential of soy” phytoestrogens. And, unlike our body’s own estrogen, soy phytoestrogens preferentially bind to the beta receptors.

For instance, within eight hours or so of eating about a cup of cooked whole soybeans, genistein levels in the blood reach about 20 to 50 nanomoles. That’s how much is circulating throughout our body, bathing our cells. About half is bound up to proteins in the blood, so the effective concentration is about half the 20 to 50 nanomoles. What does that mean for estrogen receptor activation?

In my video Who Shouldn’t Eat Soy?, I feature a graph explaining the mysterious health benefits of soy foods. Around the effective levels we would get from eating a cup of soybeans, there is very little alpha activation, but lots of beta activation. What do we find when we look at where each of these receptors are located in the human body? The way estrogen pills increase the risk of fatal blood clots is by causing the liver to dump out extra clotting factors. But guess what? The human liver contains only alpha estrogen receptors, not beta receptors. So, perhaps eating 30 cups or so of soybeans a day could be a problem, but, at the kinds of concentrations we would get with just normal soy consumption, it’s no wonder this is a problem with drug estrogens but not soy phytoestrogens.

The effects on the uterus also appear to be mediated solely by alpha receptors, which is presumably why no negative impact has been seen with soy. So, while estrogen-containing drugs may increase the risk of endometrial cancer up to ten-fold, phytoestrogen-containing foods are associated with significantly less endometrial cancer. In fact, protective effects are found for these types of gynecological cancers in general: Women who ate the most soy had 30 percent less endometrial cancer and appeared to cut their ovarian cancer risk nearly in half. 

Soy phytoestrogens don’t appear to have any effect on the lining of the uterus and can still dramatically improve some of the 11 most common menopausal symptoms (as compiled by the Kupperman Index).

In terms of bone health, human bone cells carry beta estrogen receptors, so we might expect soy phytoestrogens to be protective. And, indeed, they do seem to “significantly increase bone mineral density,” which is consistent with population data suggesting that “[h]igh consumption of soy products is associated with increased bone mass…” But can soy phytoestrogens prevent bone loss over time?

In a two-year study, soymilk was compared to a transdermal progesterone cream. The control group lost significant bone mineral density in their spine over the two years, but the progesterone group lost significantly less than that. The group drinking two glasses of soymilk a day, however, actually ended up even better than when they started.

In what is probably the most robust study to date, researchers compared the soy phytoestrogen genistein to a more traditional hormone replacement therapy (HRT) regimen. Over one year, in the spine and hip bones, the placebo group lost bone density, while it was gained in both the soy phytoestrogen and HRT estrogen groups. The “study clearly shows that genistein prevents bone loss…and enhances new bone formation…in turn producing a net gain of bone mass.”

The main reason we care about bone mass is that we want to prevent fractures. Is soy food consumption associated with lower fracture risk? Yes. In fact, a significantly lower risk of bone fracture is associated with just a single serving of soy a day, the equivalent of 5 to 7 grams of soy protein or 20 to 30 milligrams of phytoestrogens, which is about a cup of soymilk or, even better, a serving of a whole soy food like tempeh, edamame, or the beans themselves. We don’t have fracture data on soy supplements, though. “If we seek to derive the types of health benefits we presume Asian populations get from eating whole and traditional soy foods,” maybe we should look to eating those rather than taking unproven protein powders or pills.

Is there anyone who should avoid soy? Yes, if you have a soy allergy. That isn’t very common, though. A national survey found that only about 1 in 2,000 people report a soy allergy, which is 40 times less than the most common allergen, dairy milk, and about 10 times less than all the other common allergens, such as fish, eggs, shellfish, nuts, wheat, or peanuts.


What if you’re at high risk for breast cancer? See BRCA Breast Cancer Genes and Soy

What if you already have breast cancer? See:

What if you have fibroids? See Should Women with Fibroids Avoid Soy?.

What about hot flashes? See Soy Phytoestrogens for Menopause Hot Flashes.

What about genetically modified soy? See GMO Soy and Breast Cancer.

Not all phytoestrogens are beneficial, though. See What Are the Effects of the Hops Phytoestrogen in Beer? and The Most Potent Phytoestrogen Is in Beer.

How deleterious is hormone replacement therapy? See How Did Doctors Not Know About the Risks of Hormone Therapy?.

Synthetic estrogens used in animal agriculture are also a concern. For more on this, see Zeranol Use in Meat and Breast Cancer.

In health,
Michael Greger, M.D.

PS: If you haven’t yet, you can subscribe to my free videos here and watch my live, year-in-review presentations:

Resveratrol Supplements Are Finally Put to the Test

“If one searches the Internet for anti-aging interventions, a vast array of techniques are offered, from starvation regimes to dietary supplements and growth hormones. All are for sale, but none so far have been proven as the magic bullet, despite exorbitant claims on many of the websites.” Resveratrol is one supplement you’ll likely come across, a component of red wine that gained notoriety as a possible explanation for the so-called French Paradox, which turned out to be not so paradoxical after all (see What Explains the French Paradox?).

As I discuss in my video Resveratrol Impairs Exercise Benefits, it turns out that “[c]ountries with high wine consumption are those in which saturated fat consumption used to be low but increased in recent years.” So, the low mortality from ischemic heart disease may just reflect the earlier, lower levels of saturated fat consumption, and the wine may just be a confounding factor. It did, however, help spark interest in resveratrol, the purported active ingredient of red wine about which scientific papers are now published every day.

More than a hundred of those papers on resveratrol have been called into question, though, as one of the leading researchers in the field was found guilty of taking millions in taxpayer money only to fabricate and falsify his data.

Hundreds of studies still remain, though. Does this mean pills can now replace a healthy diet? Even a group of resveratrol scientists don’t think resveratrol is worth supplementing: “In contrast to the lacking data on resveratrol in humans, the animal data are promising and indicate the need for further human clinical trials.” In rodents, resveratrol supplementation decreased cardiovascular risk factors, improved cardiovascular function and physical capacity, and decreased inflammation, leading to improved vascular function. But, when it was put to the test in people, almost the exact opposite was found.

Specifically, combining resveratrol with athletic training abolished the reduction in blood pressure, cholesterol, and triglycerides normally associated with training; had a more arterial-constricting effect than a dilating effect; “and led to a significantly lower increase in the training-induced increase in maximal oxygen uptake.”

Rodents on resveratrol get enhanced exercise performance, but, in people, the resveratrol induced a 45 percent lower increase in maximum aerobic capacity compared with those taking a sugar pill. The human subjects were working out like crazy, and the resveratrol undercut their efforts.

This raises a larger issue. Mouse models are a cornerstone of modern biomedical research, and yet systematic studies as to their usefulness are rarely done. Consider this: nearly 150 human clinical trials testing anti-inflammatory drugs have failed—without exception—after those same drugs had shown promise in trials on mice. In analyzing the carry-over from the mouse trials to the human trials, researchers determined that “[t]he result was surprising, almost shocking: the correlation was not only poor, it was virtually absent for the main study areas: burns, trauma, endotoxemia.” It turns out, for example, that mice may be up to a million times less sensitive to inflammatory endotoxins than humans.

The takeaway is that the negative effects they found add to the growing body of evidence questioning the positive effects of resveratrol supplementation in humans. Maybe the problem, though, was resveratrol supplementation—that is, giving people capsules containing 50 times the resveratrol they would normally get from eating grapes, berries, peanuts, or chocolate. Was it just too much of a good thing? To see if the amount one gets from drinking red wine would be beneficial, we can look to the Chianti region of Tuscany to determine whether resveratrol levels achieved with diet help protect against inflammation, cancer, cardiovascular disease, and death. The answer? None of the above. Despite the fact that U.S. annual sales of resveratrol supplements have reached $30 million, there are limited and conflicting human clinical data demonstrating any human benefits, and there are no data concerning its long-term safety.

The exercise study was supported in part by a manufacturer of resveratrol supplements. To their credit, however, the researchers responded to an angry letter by a supplement company consultant that “it is our opinion that we, as scientists, have a responsibility to report what we find, and not to twist our findings to fit the commercial interests.”


The benefits of red wine over white do not appear to be due to the resveratrol, but to the estrogen synthase blockers. See Breast Cancer Risk: Red Wine vs. White Wine.

What about the role of red wine in the Mediterranean diet? I have a whole series of videos, including:

I just published a whole new series on alcohol. Check it out:

Sadly, the epic failure of resveratrol supplements is par for the course when it comes to trying to get your nutrition in pill form. See, for example:

In health,
Michael Greger, M.D.

PS: If you haven’t yet, you can subscribe to my free videos here and watch my live, year-in-review presentations:

The post Resveratrol Supplements Are Finally Put to the Test appeared first on NutritionFacts.org.

Best Food for the Common Cold

It is well known that deficiencies in certain vitamins and minerals can lead to significant impairment of immune function and an increased susceptibility to infection that can be reversed by supplementation in deficient individuals. “However, it is unclear to what extent supplementation may aid in maintaining an optimal balance within the immune system in adequately nourished individuals.” As I discuss in my video, Kiwifruit for the Common Cold, researchers in New Zealand tried supplementing with whole kiwifruit. In a petri dish, gold kiwifruit puree appeared to boost natural killer cell activity in human blood and also boost the response to the tetanus vaccine. But, does the same thing that happens in a petri dish happen in people? In another study, researchers found that two immune-related sets of genes were upregulated by eating three kiwifruit a day. But, does that translate into actually helping us fight off infection? We didn’t know the answer until recently.

Researchers in New Zealand found that the consumption of gold kiwifruit reduces the severity and duration of certain upper respiratory tract infection symptoms. Why study gold kiwifruits? The study was funded by the company that owns the patent to gold kiwifruits.

In the study, a few dozen elderly individuals were randomized into one or two groups, eating either two bananas a day or four kiwifruit a day for a month, and then switching. The next month, the banana group ate kiwis, and the kiwi group ate bananas. The rationale for providing banana as the “placebo” was to provide an alternative fruit that had relatively similar calories, but lower nutritional value.

The study’s purpose was to determine whether regular consumption of gold kiwifruit reduces the incidence, duration, and severity of symptoms of upper respiratory tract infections, like the common cold, in comparison to bananas. They found no reduction in overall incidence, but those who did get sick during the kiwifruit phase had significantly reduced severity and duration of head congestion, as well as a reduced duration of sore throat. And not just by a little. The sick banana eaters suffered for five days with a sore throat and congestion, compared to the kiwifruit eaters, who felt better after just a day or two. That’s significant.

The reason the researchers studied older individuals is that they tend to be more susceptible to respiratory infections. Small children are another at-risk group, averaging twice as many upper respiratory tract infections as adults, four to six per year. So, in another study, 66 preschoolers were randomized into the same two groups, kiwifruit versus bananas. In the kiwi group, not only were there again significant improvements in the symptoms of those who got sick, fewer got sick in the first place—45% lower odds of a cold or flu-like illness, which means that the children eating kiwis had almost a 50% reduction in the chance of having a cold or flu.

This suggests that kiwifruit consumption may be a “daily prescription for health”; though about 1 in 150 children report being allergic to kiwifruit, which ranks them number three after milk and eggs, and above peanuts, in a survey of 3,500 kids, of the most common food allergies. So, kiwis are not for everybody.


The upside of the financial conflict of interest is that it offers a rare source of funding for fruit and vegetable research. For more on kiwis, see Kiwifruit for Irritable Bowel Syndrome, Kiwifruit and DNA Repair, and Kiwifruit for Insomnia.

What else can we do to lower our risk of pesky respiratory infections? Check out Can Gargling Prevent the Common Cold?, Preventing the Common Cold with Probiotics?, Nutritional Yeast to Prevent the Common Cold, and Using the Produce Aisle to Boost Immune Function.

In health,

Michael Greger, M.D.

PS: If you haven’t yet, you can subscribe to my free videos here and watch my live, year-in-review presentations: