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:

Why Some Dairy Products are More Closely Linked to Parkinson’s Disease

Parkinson’s is the second most common neurodegenerative disease after Alzheimer’s. Each year in the United States, approximately 60,000 new cases are diagnosed, bringing the total number of current cases up to about a million, with tens of thousands of people dying from the disease every year. The dietary component most often implicated is milk, as I discuss in my video Could Lactose Explain the Milk and Parkinson’s Disease Link?, and contamination of milk by neurotoxins has been considered the “only possible explanation.” High levels of organochlorine pesticide residues have been found in milk, as well as in the most affected areas in the brains of Parkinson’s victims on autopsy. Pesticides in milk have been found around the world, so perhaps the dairy industry should require toxin screenings of milk. In fact, inexpensive, sensitive, portable tests are now available with no false positives and no false negatives, providing rapid detection of highly toxic pesticides in milk. Now, we just have to convince the dairy industry to actually do it.

Others are not as convinced of the pesticide link. “Despite clear-cut associations between milk intake and PD [Parkinson’s disease] incidence, there is no rational explanation for milk being a risk factor for PD.” If it were the pesticides present in milk that could accumulate in the brain, we would assume that the pesticides would build up in the fat. However, the link between skimmed milk and Parkinson’s is just as strong. So, researchers have suggested reverse causation: The milk didn’t cause Parkinson’s; the Parkinson’s caused the milk. Parkinson’s makes some people depressed, they reasoned, and depressed people may drink more milk. As such, they suggested we shouldn’t limit dairy intake for people with Parkinson’s, especially because they are so susceptible to hip fractures. But we now know that milk doesn’t appear to protect against hip fractures after all and may actually increase the risk of both bone fractures and death. (For more on this, see my video Is Milk Good for Our Bones?.) Ironically, this may offer a clue as to what’s going on in Parkinson’s, but first, let’s look at this reverse causation argument: Did milk lead to Parkinson’s, or did Parkinson’s lead to milk?

What are needed are prospective cohort studies in which milk consumption is measured first and people are followed over time, and such studies still found a significant increase in risk associated with dairy intake. The risk increased by 17 percent for every small glass of milk a day and 13 percent for every daily half slice of cheese. Again, the standard explanation is that the risk is from all the pesticides and other neurotoxins in dairy, but that doesn’t explain why there’s more risk attached to some dairy products than others. Pesticide residues are found in all dairy products, so why should milk be associated with Parkinson’s more than cheese is? Besides the pesticides themselves, there are other neurotoxic contaminants in milk, like tetrahydroisoquinolines, found in the brains of people with Parkinson’s disease, but there are higher levels of these in cheese than in milk, though people may drink more milk than eat cheese.

The relationship between dairy and Huntington’s disease appears similar. Huntington’s is a horrible degenerative brain disease that runs in families and whose early onset may be doubled by dairy consumption, but again, this may be more milk consumption than cheese consumption, which brings us back to the clue in the more-milk-more-mortality study.

Anytime we hear disease risks associated with more milk than cheese—more oxidative stress and inflammation—we should think galactose, the milk sugar rather than the milk fat, protein, or pesticides. That’s why we think milk drinkers specifically appeared to have a higher risk of bone fractures and death, which may explain the neurodegeneration findings, too. Not only do rare individuals with an inability to detoxify the galactose found in milk suffer damage to their bones, but they also exhibit damage to their brains.

Other than avoiding dairy products, what can we do to reduce our risk of Parkinson’s? See Is Something in Tobacco Protective Against Parkinson’s Disease? and Peppers and Parkinson’s: The Benefits of Smoking Without the Risks?.

You may also be interested in my videos Treating Parkinson’s Disease with Diet and Parkinson’s Disease and the Uric Acid Sweet Spot.

For the effect of foods on another neurodegenerative disease that affects our ability to move normally, see ALS (Lou Gehrig’s Disease): Fishing for Answers and Diet and Amyotrophic Lateral Sclerosis (ALS).

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 Effects of the Hops Phytoestrogen in Beer on Breast Cancer Risk

Hops have been used for centuries as a flavoring agent in beer, but “[o]ver the years, a recurring suggestion has been that hops”—and therefore beer—may be estrogenic, thanks to a potent phytoestrogen in hops called 8-PN, also known as hopein. Might beer drinking affect our hormones? I discuss this in my video What Are the Effects of the Hops Phytoestrogen in Beer?.

Even just the alcohol in beer can reduce testosterone levels in men, so when beer was tested as a source of estrogens, the alcohol was first removed. Researchers tested the equivalent of one can of beer every day for a month on the hormone levels of postmenopausal women, so as to not confound the results with her own estrogens, and they found significant alterations of hormonal levels during the beer month and then a return to baseline a week afterwards. But does this have any clinical effects, whether good or bad?

A cross-sectional study of about 1,700 women found that beer drinkers appear to have better bone density, perhaps because of the pro-estrogenic effects. They don’t recommend women start drinking beer for bone health, but suggest it may have beneficial bone effects for women who already drink.

What about helping with hot flashes? About half of postmenopausal and premenopausal women in the United States suffer from hot flashes, whereas the prevalence in Japan may be ten times lower, presumed to be because of their soy consumption. What about hops? There have been a few studies showing potential benefit, leading to a 2013 review suggesting that “hop extract may be somewhat effective in treating menopausal discomforts especially against hot flushes,” but that was before a study reported extraordinary results with about a half teaspoon of dried hop flowers. In the placebo group, the women started out having 23 hot flashes a week and continued to have 23 hot flashes a week throughout the three-month study. In the hops group, the women started out even worse with about 29 hot flashes a week, but then got down to 19 at the end of the first month, then 9, and finally just 1 hot flash a week. And similar findings were reported for all the other menopausal symptoms measured.

Animal estrogens work, too. Millions of women used to be on horse hormones—Premarin, from pregnant mares’ urine. That drug also took care of hot flashes, as well as  curtailed osteoporosis, but caused a pesky little side effect called breast cancer. Thankfully, when this was realized and millions of women stopped taking it, breast cancer rates fell in countries around the world.

The question, then, is: Are the estrogens in hops more like the breast cancer-promoting horse estrogens or the breast cancer-preventing soy estrogens? The key to understanding the health-protective potential of soy phytoestrogens is understanding the difference between the two types of estrogen receptors, alpha receptors and beta receptors. Unlike animal estrogen, the soy phytoestrogens bind preferentially to the beta receptors, and in breast tissue, they’re like yin and yang with the alpha receptors signaling breast cell proliferation. This explains why horse hormones increase breast cancer risk, whereas the beta receptors, where the soy binds, oppose that proliferative impact. So, do the hops phytoestrogens prefer beta, too? No. 8-PN is a selective estrogen receptor alpha promoter. “Surprisingly and in clear contrast to genistein [the soy], 8-PN is a much weaker” binder of beta than of alpha. So, that explains why hops is such a common ingredient in so-called breast enhancing supplements—that is, because it acts more like estrogen estrogen. Given the breast cancer concerns, use of such products should be discouraged, but just drinking beer could provide the exposure to the hops estrogen, which could help explain why beer may be more carcinogenic to the breast than some other forms of alcohol.

A phytoestrogen in beer? For more on the background of this issue, see The Most Potent Phytoestrogen Is in Beer.

Other videos on phytoestrogen include:

To learn more about dietary effects on testosterone, see:

What about “natural” hormones for menopause? See my video Plant-Based Bioidentical Hormones.

For more on the risks of alcohol in terms of breast cancer risk, see Breast Cancer and Alcohol: How Much Is Safe? and Breast Cancer Risk: Red Wine vs. White Wine.

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: