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:

Is Milk Lowering Uric Acid a Good Thing or a Bad Thing?

Parkinson’s disease, the second most common neurodegenerative disorder after Alzheimer’s, is characterized by a slowness of movement, rigidity, tremor, and stooping posture, all of which worsen over time. Non-movement symptoms such as cognitive impairment and sleep, smell, and mood disturbances occur as the disease spreads to other areas of the brain. The cause of Parkinson’s is perhaps “one of the important questions posed by the neurobiology [science] of aging.” For example, why is the consumption of dairy products associated with increased risk of Parkinson’s? Perhaps because they contribute to our exposure to pesticides and other neurotoxins like dieldrin, which continues to be found in the autopsied brains of Parkinson’s victims. Even though dieldrin was banned decades ago, it lingers in the environment and we “continue to be exposed to the pesticide through contaminated dairy and meats…”

The cause of Parkinson’s “is unlikely to be due to milk compounds such as calcium, vitamin D, total fat, or total protein as these compounds are not associated with [the disease] when derived from other sources.” However, it could be lactose, the milk sugar, perhaps accounting for the increased associated risk of death and bone fractures, as well as Parkinson’s. Earlier onset of Huntington’s disease has also been identified. There is, however, a third possibility.

As I discuss in my video Parkinson’s Disease and the Uric Acid Sweet Spot, milk lowers uric acid levels, and uric acid may be protective against Huntington’s and also slow the decline caused by Parkinson’s. More importantly, it may lower the risk of getting Parkinson’s in the first place. Why? Perhaps because uric acid is an important antioxidant in the brain, something we’ve known for more than 30 years. We can demonstrate uric acid’s importance directly on human nerve cells in a petri dish. When the pesticide rotenone is added, oxidative stress goes up. Add the pro-oxidant homocysteine, and it goes up even more. But, when uric acid is added, it completely suppresses the oxidative stress caused by the pesticide.

Drinking milk, however, has a uric acid-lowering effect. In the paper making this assertion, a study they cited was “A cute effect of milk on serum urate concentrations,” but that was just a cute typothey meant Acute effect. Indeed, drink cow’s milk, and, within hours, uric acid levels drop 10 percent. Drink soymilk, and, within hours, they go up 10 percent. Now, for gout, a painful arthritic disease caused by too much uric acid, the uric acid-lowering effect of dairy is a good thing—but uric acid is “a double-edged sword.”

If our uric acid levels are too high, we can get gout, but, if they’re too low, it may increase our risk of neurodegenerative diseases, such as Alzheimer’s, Huntington’s, Parkinson’s, and multiple sclerosis.

Incidence rates of gouty arthritis over five years indicate that if our uric acid is over 10.0 mg/dl, we have a 30 percent chance of suffering an attack of gout within the next 5 years. However, at levels under 7.0 mg/dl, our risk is less than 1 percent, so it might make sense to have levels as high as possible without going over 7.0 to protect the brain without risking our joints. But having excessive uric acid in the blood puts more than just our joints in jeopardy. Yes, having levels that are too low may increase our risk of MS, Parkinson’s, Alzheimer’s, and even cancer, but having levels that are too high may increase our risk of gout, kidney disease, and heart disease.

In fact, having a uric acid level over 7.0 mg/dl isn’t only associated with an increased risk of gout, but also an increased risk of dying from all causes. However, having a low uric acid level may also shorten our lifespan by increasing mortality. High uric acid levels are associated with increased risk of death from heart disease, but low uric acid levels are associated with increased risk of fatal stroke. So, keeping uric acid at optimum levels, the sweet spot between 5.0 and 7.0 mg/dl, may protect the brain in more ways than one.

If we measure the uric acid levels in patients with Parkinson’s, they come in around 4.6 mg/dl, which may help explain why dairy consumption may increase risk for Parkinson’s since milk pushes down uric acid levels. Dairy intake may also explain the differences in uric acid levels among meat-eaters, vegetarians, and vegans. In the graph in my video, you can see that vegan men have significantly higher uric acid levels at 5.7 mg/dl than vegetarians, presumably because vegans don’t drink milk, and those who both eat meat and consume milk fall between the vegans and vegetarians.


For more on Parkinson’s see:

Uric acid as an antioxidant? I’ve touched on that before in Miocene Meteorites and Uric Acid.

If uric acid levels are too high consider cutting down on Flesh and Fructose and eating cherries. (See Gout Treatment with a Cherry on Top and Treating Gout with Cherry Juice for more information.) Also, check out Preventing Gout Attacks with Diet.

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:

How to Achieve Food Synergy

There are thousands of phytochemicals that will never make it onto the side of a cereal box but may play a role in reducing the risk of chronic diseases—and those are just the ones we know about. Whole plant foods have consistently been found to be protective, so it’s reasonable for scientists to try to find the “magic bullet” active ingredient that can be sold in a pill, but “[p]ills or tablets simply cannot mimic this balanced natural combination of phytochemicals present in fruits and vegetables.” When isolated out, the compound may lose its activity or behave differently. The antioxidant and anticancer activities of plant foods are thought to derive from the “additive and synergistic effects of phytochemicals in fruits and vegetables,” meaning the whole may be greater than the sum of its parts. This helps explain why a pill can’t replace the complex combination of phytochemicals present in whole plant foods.

As T. Colin Campbell has pointed out, more than a hundred trials “overwhelmingly show no long-term benefit for vitamin supplements, along with worrisome findings that certain vitamins may even increase disease occurrence for diabetes, heart disease, and cancer.” Supplementation with fish oil, for example, appears useless or, even worse, “posing increased risk for diabetes,” yet the science doesn’t seem to matter. People continue to buy them. “The public desire for quick fixes through pills…is overwhelming, especially when money can be made.”

Each plant has thousands of different phytochemicals, as well as entirely different phytonutrient profiles. So, there may be synergistic effects when eating different foods together, too. Eating beta-carotene in carrot form is more beneficial than in pill form. because of all the other compounds in the carrot that may synergize with the beta-carotene. Well, when we dip that carrot in hummus, we suddenly have the thousands of carrot compounds mixing with the thousands of chickpea compounds. So what happens if we mix different fruits with different vegetables or different beans?

As you can see in my video Food Synergy, combining foods across different categories increased the likelihood of synergy. For example, a study showed the antioxidant powers of raspberries and adzuki beans. If there were a strictly additive effect, the expected combined antioxidant power would simply be that of the raspberries plus that of the adzuki beans. However, the observed combined antioxidant power was actually greater than the sum of one plus the other.

What about cancer-fighting effects? The study was repeated, but, this time, different combinations of food were dripped on breast cancer cells growing in a petri dish. For some foods, the same synergistic effects were found. Grapes, for example, can suppress the growth of breast cancer cells about 30 percent, but onions worked even better, cutting breast cancer cell growth in half. One would assume that if we added half the grapes with half the onion, we’d get a result somewhere in the middle between the two. Instead, the researchers found that cancer cell growth was suppressed by up to 70 percent with that combination. The whole plus the whole was greater than the sum of the whole parts. Given these findings, did the researchers recommend people eat a variety of foods? Perhaps adding some raisins along with chopped red onions to our next salad? Where’s the money in that? No, the reason the researchers were investigating the different types of interactions was “to identify mixtures that hold synergistic interactions that can ultimately lead to the development of functional foods”—maybe something like grape-flavored Funyuns.


Why should we care about the antioxidant power of foods? See

If you’re not familiar with this concept of reductionism, be sure to check out some of these other videos: Industry Response to Plants Not Pills, Why Is Nutrition So Commercialized?, and Reductionism and the Deficiency Mentality.

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: