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:

Plant vs. Animal Food Purines for Preventing Gout

More than 2,000 years ago, “Hippocrates described gout as a disease of kings primarily because it was the wealthy who could afford the ‘rich’ foods, which seemed to precipitate gouty attacks.” Today, however, we can all eat like kings and acquire some diseases of royalty ourselves. That’s why I produced my video Preventing Gout Attacks with Diet.

Gout is caused by needle-sharp crystals of uric acid in our joints. Uric acid comes from the breakdown of purines, which are the breakdown product of genetic material—DNA, the foundation of all life. So, “there is no such thing as a purine-free diet, but foods do vary in their purine content.” It was long thought that people with gout just needed to stay away from all high-purine foods, whether from animals, like organ meats, or plants, like beans, but this strategy proved ineffective. Yes, all uric acid comes from the breakdown of purines, so limiting meat makes sense, but plant sources “have largely been exonerated.”

“The association of gout with alcohol intake and increased dietary purine consumption had been known since ancient times, but there were no prospective trial data” to back it up until fairly recently. The Harvard Health Professionals Follow-Up Study, which followed about 50,000 men for a dozen years, found that alcohol intake was “strongly associated with an increased risk of gout.” In terms of food, they found “an increased risk of gout with higher meat consumption or seafood consumption,” but not with higher consumption of purine-rich plant foods. Perhaps this is because the purines in plants are less bioavailable? So, though it had been suggested that gout sufferers should moderate purine-rich animal and plant foods, their “results suggest that this type of dietary restriction may be applicable to purines of animal origin but not to purine-rich vegetables.”

Although it was not surprising that meat, including seafood, had significant associations with the incidence of gout, this lack of effect of purine-rich plant foods was new. There don’t appear to be any long-term studies showing purine-rich plant foods increase risk, though there are still some guidelines continuing to disseminate those outdated recommendations.

Not only has the intake of purine-rich plants not been associated with high uric acid levels, but the vegetables gout sufferers are specifically told to stay away from—mushrooms, peas, beans, lentils, and cauliflower—were actually found to be protective. This may be because foods rich in fiber, folate, and vitamin C appear to protect against uric acid buildup and gout. “Fiber,” for example, “has been recognized as having a potential role in binding uric acid in the gut for excretion.”

Lack of association between purine-rich vegetables and urate could be due to the co-packaging of these “beneficial plant components (such as vitamin C, dietary fiber or some phytochemicals), which may have masked an effect of purine on [uric acid]. Vegetable intake, regardless of purine content, may also be protective as it may increase [uric acid] excretion.”

By changing the pH of our urine, we can change uric acid clearance. Eating an alkaline diet, which was a vegetarian diet in the case of the study I profile in my video, was found “effective for removing uric acid from the body.” Those eating the alkaline diet excreted significantly more uric acid than those eating the acidic diet. As such, uric acid levels in the blood of those eating the acid-forming diet rose within days.

So, one would assume uric acid levels are lower in vegetarians, and, indeed, those eating vegetarian diets long-term were found to have significantly lower levels in their blood. To prove cause and effect, though, you need to do an interventional trial, where you take people, change their diets, and see what happens. Researchers took ten guys to study the build-up of uric acid in their kidneys, kept them on a standard Western diet for five days, and measured their relative supersaturation for uric acid. Then, they tried a vegetarian diet for five days. The result? Within days, the intake of the vegetarian diet led to a 93 percent decline in the risk of uric acid crystallization.

You can do it the other way, too: Take a bunch of people with gout, feed them a big meal of meat, and see if you can trigger an attack. Seven patients were put in a hospital, “stabilized on a low-purine diet and then challenged with a meat-laden dinner.” In response, their uric acid levels shot up, and they started getting gout attacks. Then they added alcohol, and their uric acid levels shot up even further. In all, the researchers were able to trigger gout attacks in six out of the seven patients with just single meals.

Now, some meats have less purines than others. For those who aren’t squeamish, inches-long superworms, for example, have particularly low purine levels.

Not all animal foods increase gout risk, though. Low-fat dairy products were found to be protective. Given that, we would predict vegans to be at a disadvantage, which is indeed what was found, though all groups tested—meat eaters, fish eaters, vegetarians, and vegans—were within the normal range of around 3.5 to 7.

Should gout patients add milk to their diets? Well, although drinking the equivalent of ten cups of skim milk at a time appears to have an acute lowering effect on uric acid levels, in the long term over months, at the equivalent of two cups a day, there was not a statistically significant lowering effect. Gout patients were given skim milk powder for three months, and it did not appear to help. Though soymilk has also been associated with a lower risk of uric acid buildup, there are no interventional trials to back that up.

The bottom line is that we now have good research on how to reduce risk of gout “without the use of drug treatments through modification of diet.” That’s important, because allopurinol is the “drug of choice.” It’s considered generally safe, but what does it mean when doctors talk about a relatively safe drug? Well, about “2% of patients develop hypersensitivity reactions, which can sometimes be severe and fatal with a mortality rate of ~20%”—and that’s the safe drug. The other leading drug, colchicine, has “no clear-cut distinction between nontoxic, toxic, and lethal doses.”


A better choice is through diet, and these videos show you how sweet that diet choice can be:

And, for alkalinizing your urine, see How to Treat Kidney Stones with Diet and Testing Your Diet with Pee and Purple Cabbage.

Uric acid is double-edged sword, as both high and low levels are associated with increased mortality. If our uric acid levels are too high, we can get gout; if they’re too low, it may increase our risk of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. This is presumed to be because uric acid acts as a powerful brain antioxidant. See my videos Miocene Meteorites and Uric Acid and Parkinson’s Disease and the Uric Acid Sweet Spot for more on this.

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: