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:

Morning Sickness Can Be Beneficial

“Since the beginning of time, pregnant women have been reported to suffer from a syndrome variously known as morning sickness, pregnancy sickness, or nausea and vomiting during pregnancy.” The term “morning sickness” is actually misleading, as women can feel sick all day long. Sometimes, it can get so serious that women have to be hospitalized.

Researchers at Harvard’s Brigham and Women’s Hospital found that saturated fat seemed to be a primary dietary risk factor for severe sickness, with five times the odds for every 15 grams intake of saturated fat, “equivalent to one quarter-pound cheeseburger.” The reason saturated fat intake may be such a strong risk factor could be through its effects on estrogen, as “[s]aturated fat has been shown to increase circulating levels of estrogen.”

Why would we evolve to have such a negative reaction to saturated fat? Why would we evolve to get sick at all? As I discuss in my video Morning Sickness May Protect Mother and Child, “[p]regnancy sickness is a universal phenomenon, affecting 70% to 85% of all pregnant women.” If food aversions are included in the criteria, along with nausea and vomiting, the incidence is more like 100 percent. “Because pregnancy sickness is such a common phenomenon, one must question why is this so? Is there a purpose for such a potentially devastating condition?” In the past, pregnancy sickness was dismissed as just being in women’s heads, but recent “studies have reconsidered pregnancy sickness as an embryo-protective mechanism, an evolutionary adaptation to protect the embryo.”

Protect the baby from what? From meat. “Meat is the principal source of pathogens for humans. Meat is also the most common type of food avoided by pregnant women.” So, the development of an aversion to meat during pregnancy could be protective because “meat may have toxins that are mutagenic, carcinogenic, and teratogenic,” meaning causing birth defects, and tainted meat may also be contaminated by pathogens. “Pregnancy is a time of relative immunosuppression.” Normally, we can fend off most meat pathogens. “However, by biological design from evolutionary pressures, pregnant women are immunosuppressed to not reject the developing embryo”––as half the baby (from the father’s side) is foreign. So, morning sickness may have evolved as a way to get us to stay away from meat during this vulnerable time. This would be consistent with a “profound overrepresentation of meat taboos” in sample societies around the world.

If this theory is true, then we should be able to make five predictions. First, if nausea and vomiting in pregnancy are meant to be protective, women who experience them should have better pregnancy outcomes. Indeed, women who suffer from nausea and vomiting are significantly less likely to miscarry or have a stillbirth.

Second, the foods that trigger nausea and vomiting should contain things that can be particularly harmful to the baby, and, in fact, “[o]f all food types, animal protein (including meat, poultry, eggs, and seafood…) is the most dangerous. Meat is the source of a wide range of pathogens that pose a grave threat to pregnant women and developing organisms” that is, their developing embryos.

Third, nausea and vomiting in pregnancy should also coincide with the time when the embryo is most vulnerable, which is approximately weeks 5 through 15, when all the critical organ structures are being formed. And, indeed, that period is right when nausea and vomiting are in fact peaking.

Fourth, pregnant women should find meat and eggs most aversive during this time of heightened embryo sensitivity, and that, too, is the case. And finally, if this theory is true, one should expect a lower frequency of morning sickness among plant-based populations, and, yes, the few societies in which we don’t see such morning sickness problems are the ones that tend to have only plants as dietary staples, rather than meat.

What can you do if you suffer from morning sickness? See Natural Treatments for Morning Sickness.

What other effects can diet have on a healthy pregnancy? 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:

Vitamin D Supplements for Reducing Cancer Mortality

It all started with a famous study entitled “Do sunlight and vitamin D reduce the likelihood of colon cancer?” that was published in 1980. Johns Hopkins University researchers were trying to figure out why states like New Mexico and Arizona have only about half the colon cancer rates of states like New York, New Hampshire, and Vermont. Could it be because New Mexicans and Arizonans get so much more sun? The researchers proposed that perhaps vitamin D, known as the sunshine vitamin, is a protective factor against colon cancer. Since then, sun exposure has also been associated with lower rates of 14 other types of cancer.

As I discuss in my video Do Vitamin D Supplements Reduce the Risk of Dying from Cancer?, vitamin D may also affect cancer survival. Higher blood levels of vitamin D were associated with lower mortality of patients with colorectal cancer. How much lower? Nearly half the mortality. And, the higher the vitamin D levels, the lower the death rate appeared to fall. This may explain why the survival rate from colon cancer may depend in part “on the season of diagnosis.” The risk of rapid death is lowest if you’re diagnosed in the fall after you’ve spent the summer building up your vitamin D stores. Other risk factors could be seasonal, too. For example, perhaps people are taking advantage of the fall harvest and eating healthier, which might explain lower risk in the autumn. Additionally, “[a]lcohol intake is a risk factor and may be highest in the winter season…” What about physical activity? In the summer, we may be more likely to be outside running around, not only getting more sun, but also getting more exercise, which may itself be protective.

These kinds of studies just provide circumstantial evidence. Establishing a cause-and-effect relationship between colon cancer and vitamin D deficiency using observational studies is challenging because of confounding factors, such as exercise habits—so-called lurking variables. For example, there may be a tight correlation between ice cream sales and drowning deaths, but that doesn’t mean ice cream causes drowning. A more likely explanation is that there is a lurking third variable, like hot weather in summertime, that explains why drowning deaths are highest when ice cream consumption is also at its highest.

This actually happened with hormone replacement therapy. Women taking drugs like Premarin appeared to have 50 percent less risk of heart disease, so doctors prescribed it to women by the millions. But, if we dig a little deeper into the data, we find that, indeed, women taking estrogen had 50 percent lower risk of dying from heart disease, but they also had a 50 percent lower risk of dying from accidents and homicide, so it probably wasn’t the drug. The only way to know for sure is to put it to the test in a randomized, clinical trial, where half the women are given the drug and we see what happens. A decade later, such a study was done. Instead of having a 50 percent drop in risk, within a year of being given the hormone pills, heart attack and death rates shot up 50 percent. In retrospect, the lurking variable was likely socioeconomic class. Poor women are less likely to be prescribed hormone replacement therapy and more likely to be murdered and die of heart disease. Because of the lurking variable, a drug we now know to be dangerous had initially appeared to be protective.

Besides lurking variables, there’s also the possibility of reverse causation. Perhaps low vitamin D levels didn’t worsen the cancer. Instead, maybe the cancer worsened the vitamin D levels. This may be unlikely, since tumors don’t appear to directly affect vitamin D levels, but cancer treatment might. Even simple knee surgery can cause vitamin D levels to drop dramatically within hours, thought to be due simply to the inflammatory insult of cutting into someone. So, maybe that could help explain the link between lower vitamin D and lower survival. And, cancer patients may be spending less time running around the beach. So, yes: Higher vitamin D levels are associated with improved survival in colorectal cancer, and the same has been found for breast cancer. In fact, there is about double the risk of breast cancer recurrence and death in women with the lowest vitamin D levels. What’s more, higher vitamin D levels are associated with longer survival with ovarian cancer, as well as having better outcomes for other cancers like lymphoma. But, the bottom-line, as we learned with hormone replacement, is that we have to put it to the test. There weren’t a lot of randomized controlled trials on vitamin D supplements and cancer, however…until now.

We now have a few randomized controlled trials, and vitamin D supplements do indeed appear to reduce the risk of dying from cancer! What dose? Researchers suggest getting blood levels up to at least about 75 nanomoles per liter. These levels are not reached by as many as three-quarters of women with breast cancer nor achieved by a striking 97 percent of colon cancer patients .

Getting up to these kinds of levels—75 or, perhaps even better, 100 nanomoles—might require about 2000 to 4000 IU of vitamin D a day, levels of intake for which there appear to be no credible evidence of harm. Regardless of what the exact level is, the findings of these kinds of studies may have a profound influence on future cancer treatment.

What about just getting sun instead? Be sure to check out my six-part video series:

It’s better, of course, to prevent colon cancer in the first place. See, for example:

For more on that extraordinary story about Premarin and hormone replacement therapy, see How Did Doctors Not Know About the Risks of Hormone Therapy?

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: