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:

The Best Dried Fruit for Osteoporosis

“We are in an epidemic of osteoporosis. There can be no doubt about that.” Ten million Americans have it, and one in three older women will get it. “We urgently need public health strategies to maintain bone health throughout the life cycle and to prevent osteoporosis in later life.” Might fruits and vegetables be the unexpected natural answer to the question of osteoporosis prevention? My video Prunes for Osteoporosis sought to find out.

Evidence from a variety of studies “strongly points to a positive link between fruit and vegetable consumption and indexes of bone health,” such as bone mineral density, and the “size of the effect in the older women [is] impressive: doubling the fruit intake” is associated with a 5 percent higher spine mineralization. The same relationship exists with young women, too. And, eating lots of fruit in childhood may protect bones throughout life—something that was not found for milk intake, as I’ve explored before in my video Is Milk Good For Our Bones?

Bone health isn’t just about calcium. There are several key nutrients found in vegetables, fruits, and beans that are associated with better bone mineral density, but does that translate into lower hip fracture risk? The Singapore Chinese Health Study found that a “diet rich in plant-based foods, namely vegetables, fruit, and legumes such as soy, may reduce the risk of hip fracture.” But, why?

“The underlying mechanism in postmenopausal osteoporosis (PO) is an imbalance between bone resorption [disappearance] and formation,” and oxidative stress may play a role in this balance.

There are two types of bone cells: “the bone-forming osteoblasts and the bone-dismantling osteoclasts.” Osteoblasts are continually laying down new bone, while osteoclasts chisel away old bone, using free radicals as the molecular chisel to chip away our bone. Too many free radicals in our system, though, may lead to excessive bone breakdown. Antioxidant defenses appear “markedly decreased in osteoporotic women,” and “elderly osteoporotic women had consistently lower levels of all natural antioxidants tested than controls.”

“Because excessive [free radicals] may contribute to bone loss, it is important to elucidate the potential role antioxidant-rich fruits play in mitigating bone loss that leads to the development of osteoporosis.” The thought is that fruits up-regulate the bone building cells, and down-regulate the bone-eating cells, tipping the balance towards greater bone mass. So, let’s put a fruit to the test. Which one do we pick? Dried plums were chosen because they have among the highest antioxidant ranking among commonly consumed fruits and vegetables—and because the researchers received a grant from the California Dried Plum Board!

When you think of prunes, you think of bowels, not bones, but, over a decade ago, researchers at Oklahoma State tried giving a dozen prunes a day to a group of postmenopausal women, using a dozen dried apple rings as a control. After three months, only the subjects who consumed the prunes had significant elevations in an enzyme marker of bone formation, although prunes didn’t seem to affect markers of bone breakdown. So, prunes may help more with building bones than preventing bone loss. However, the reverse was found with almonds, so maybe a little prune-and-almond trail mix is in order. 

With this bump in bone formation indices, one might expect that if they did a longer study, we would actually see an impact on bone mineral density. And nine years later, just such a study was done: 12 months on dried plums versus apples. Both dried fruit regimens appeared to have “bone-protective effects,” though the prunes seemed to work better in the arm bone and spine.

So, the dried plum marketing board wants everyone to know that dried plums are “the most effective fruit in both preventing and reversing bone loss,” but only two fruits have ever been tested: plums and apples. If this pans out for other plants, though, “a ‘fruit and vegetables’ approach may provide a very sensible (and natural) alternative therapy for osteoporosis treatment, one that is likely to have numerous additional health-related benefits.” All we have to do is convince people to actually do it.


For more on bone health, see:

What else can prunes do for us? Check out Prunes vs. Metamucil vs. Vegan Diet.

Apple rings have their own benefits. See Dried Apples vs. Cholesterol.

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: