Life Extension Magazine

Life Extension Magazine October 2004

What You Don't Know About Estrogen

LE Magazine October 2004
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What You Don't Know About Estrogen

There are many misconceptions about what estrogen really is and how it works in the body. This widespread confusion exists in the minds of the lay public as well as the medical community. The result is poor choices being made about what women should be doing to maintain youthful hormone balance while also protecting against cancer.

This article uncovers the basic facts about estrogen that are so often overlooked by doctors today. It then reveals dietary modifications that women should consider if they are taking an estrogen drug. The science underlying this article is extremely complex. In order to make this information comprehensible to the lay reader, we have made a special effort to translate these new findings about estrogen metabolism into a version that most people will understand.

Nevertheless, some people may have difficulty understanding a few technical areas of this article. This information is so critically important, however, that we urge you to re-read paragraphs you do not understand in order to gain a full grasp of these crucial anticancer concepts.

The word estrogen strikes fear into the hearts of many. Women equate it with breast cancer, scientists equate it with “endocrine disruptors,” and doctors equate it with hormone replacement. Are these perceptions accurate?

Estrogen is many things. It includes the body’s natural estrogenic hormones and things that look like the body’s natural hormones. As long as something behaves like an estrogen in the body, it is an estrogen, or is, quite simply, “estrogenic.” The strongest natural estrogen in the human body is estradiol. Premarin® is an example of an unnatural estrogen—unnatural, at least, to the human body. It is made from estrogens excreted in the urine of pregnant horses. Chemical estrogens that behave badly once they are inside the body are known as “endocrine disruptors” for their adverse effects on development. All of these estrogens interact with the body’s innate hormonal system. They do not, however, provoke the same responses.

Photomicrograph of estradiol crystals. Estradiol, the most potent of the natural estrogens, is used in its natural or semisynthetic form to treat menopausal symptoms.

What Makes Estrogen Tick
“Estrogen receptors” are rarely talked about unless a woman is diagnosed with breast cancer (or a man with prostate cancer), but they are critical to how an estrogen behaves. For example, tamoxifen is a “known human carcinogen” due to its estrogenic effects, yet it is marketed as an “estrogen blocker” because of its estrogen-blocking effects. It has beneficial effects on bone, but negative effects on the circulatory system.1,2 It blocks estrogen-driven breast cancer growth temporarily, yet later becomes estrogenic in the same tissue, promoting new breast cancer. How can one “estrogen” do all these things?

The answer is, partly, estrogen receptors, which are proteins in the body that react to estrogen. Estrogen is like fuel, and estrogen receptors are like machines. When fuel meets machine, things happen.

Unfortunately, what happens depends on which area of the body is in question. The receptors of different parts of the body are different. In other words, although all the machinery runs on some type of estrogen, not all the machinery does the same thing. Estrogen does different things in different parts of the body. It does one thing in the brain and another in the breast. It might surprise you to learn, for example, that the pituitary gland is second after the uterus as the most estrogen-responsive area of the body.3 So it is not accurate to think of estrogen as the thing that makes breast cancer cells grow.

Just a few years ago, researchers believed that there were two types of estrogen receptors: alpha and beta. That made things fairly simple. Estrogen hits receptor alpha and Y happens. Research focused mostly on the strong estrogen—estradiol—and it seemed that progress could be made in understanding how estrogen affects at least breast tissue, though strange things continued to happen, such as the estrogen “blocker” tamoxifen causing the growth of tamoxifen-dependent cancers. With the discovery of a much larger picture, those days are over and a lot of research is now out the window. As a researcher at Columbia recently lamented, “where will it end?”4 There is more to it than anyone ever imagined.

The Plot Thickens
It has now been discovered that there is an entire new class of estrogen receptors called estrogen-receptor-related receptors. These receptors do not respond to the body’s natural estrogen.5,6 They are instead activated by xenoestrogens (estrogens from the outside, or from the environment).7 Pesticides and tamoxifen are two examples of xenoestrogens that activate estrogen-receptor-related receptors.8,9 The extraordinary thing about these receptors is that they represent a whole new class of estrogen machinery, previously unknown. Not only can these receptors do everything the estrogen receptors that respond to “natural” estrogen can do, but they also have a major impact on how an estrogen—any kind of estrogen—behaves.6 The discovery of this new class receptors will enable researchers to understand, for the first time, how environmental estrogens (“endocrine disruptors”) interfere with the body’s normal metabolism, and to better define the use of natural estrogen.

Estradiol Stops Cancer Cell Growth
How can this “strong” hormone—estradiol—stop hormonally responsive cancer cells from multiplying? The answer to that question first appeared in the Journal of the National Cancer Institute,10 and has been known since at least 1977.11 The cancer cells that estradiol stopped from growing had been treated with tamoxifen. Tamoxifen works two to five years after breast cancer treatment to block estrogen and prevent cancer recurrence, and then usually does the opposite.12-14 When it starts doing the opposite of what it is supposed to do, so does estradiol. How can this puzzle be solved?

In 2001, researchers reported for the first time that tamoxifen breakdown products interact with one of the newly discovered estrogen-receptor-related receptors, and keeps it from activating certain genes normally activated by estrogen.8,15 This opened a whole new vista for understanding how tamoxifen and other synthetic estrogens work. Important clues have already been found.

Estrogen Cofactors Discovered
In addition to interacting with estrogen-receptor-related receptors, tamoxifen and other xeno-estrogens interact with yet another new discovery.

In the laboratory, researchers can get estrogen, by itself, to activate estrogen receptors. In other words, in a laboratory setting, any estrogen fuel will activate the estrogen machinery and set things in motion. In real life, this does not happen. In real life, estrogen is only one of many factors that coordinate as a group to activate estrogen receptors.

The body makes proteins known as “coactivators” and “corepressors.” These proteins attach themselves to estrogen and other hormones such as thyroid, creating big, complex “globs.” It is these globs—not estrogen alone—that activate or suppress what was previously attributed to estrogen alone. In other words, studies showing what an estrogen does in the laboratory may have little to do with what actually occurs in the human body; in real life, other proteins run the show. This is bold new territory for hormone research.

Here is an example of just how important these coactivator and corepressor proteins are in determining how estrogen behaves. Corepressor SSN6 blocks estrogen’s effects in cells. In other words, the SSN6 protein shuts the machinery down. The estrogen fuel can be available (estrogen could be floating all around), but the machinery will not start as long as corepressor SSN6 is working. It neutralizes the effects of estrogen. If something interferes with this protein, however, instead of dampening the effects of estrogen, it enhances them. In addition, estrogen blockers turn into estrogen enhancers.16 Sound familiar? The importance of coactivators and corepressors cannot be overstated. They interact with both estrogen receptors and the newly discovered estrogen-receptor-related receptors. As you will soon read, there may be natural ways for women to regulate these “coactivators” in a manner that reduces breast cancer risk.

Estrogen Imposters
The three principal types of estrogen manufactured by the human body are estradiol (17 beta-estradiol), estriol, and estrone. Estradiol is the most feared because it is the strongest and is associated with the growth of cancer cells. Estrone is a metabolite of estradiol, and is less potent. Estriol is another metabolite, but is considered so mild mannered that it is recommended as a safe hormone replacement.17-19 In addition, the human body contains 11 other estradiol metabolites that hardly anyone ever mentions.

Premarin® and Prempro™ are drugs made of 17 beta-estradiol and more than a dozen estrogen metabolites from horses.20 These manmade drugs should not be confused with any estrogen manufactured by the human body, with other estrogen drugs, or with estrogen in general. The data from studies of women taking these drugs cannot, and should not, be extrapolated to other hormone replacement drugs or therapy. This is an important point: Premarin® is not estrogen, but instead is an estrogen—one of many estrogens. Different estrogens produce different effects. The manufacturer of Premarin® and Prempro™ has argued that its horse estrogens have unique effects in humans, and undoubtedly they do.

Dozens of studies demonstrate important differences between the effects of Premarin® on the human body and the effects of other estrogen products. Transdermal estradiol, for example, may decrease triglycerides and LDL oxidation, whereas Premarin® may do the opposite.21 Premarin® may increase C-reactive protein (a negative for the heart) while transdermal estradiol may not.22 Changing from Premarin® to transdermal estradiol may reduce triglycerides significantly.23 Estrogen patches may reduce blood pressure, whereas oral estrogen may not.24 These and dozens of other studies show different effects depending on which estrogen drug is being evaluated. Not only are there differences between Premarin®/Prempro™ and other drugs, but there are differences between other drugs as well.

Neutralizing Estrogen: The Asian Advantage
Japanese women have been reported to have higher levels of estradiol in their blood than Americans, yet they have a much lower risk of breast cancer.25,26 Why? Researchers believe it has more to do with environmental factors than genetics. When Japanese and other Asians adopt a Western lifestyle, risk increases.27,28 The Asian diet may contain things that modulate the response to estrogen, and strong evidence indicates that how the body handles estrogen is far more important than how much estrogen it handles. Research indicates significant differences between Japanese and Western women in their number of estrogen receptors and in their response to xenoestrogens.29-31 These differences suggest the involvement of the newly discovered estrogen coregulators. Dietary factors can activate or deactivate these factors, which means that every woman can regulate her own estrogen, to a certain extent.

Researchers have extensively investigated three aspects of the Asian advantage: soy, vegetables, and green tea. Each is associated with a dramatically lower risk of breast cancer.

Drinking 36 ounces of soy milk a day can reduce levels of estradiol by 20-27% within weeks.32,33 Soy contains isoflavones that neutralize “strong” estrogens, converting them to estrogen metabolites that protect against breast cancer.34 When mice implanted with human breast tumors were given soy concentrate and green tea, tumor size was reduced by 72%.35 Estrogen receptor alpha was also reduced, an indication that the combination of soy and green tea was working at the genetic level, probably with estrogen cofactors. Forty milligrams of isoflavones a day significantly decreased “strong” estrogen levels in women, according to a study from the H. Lee Moffitt Cancer Center in Tampa, FL.36 These are only a few of the many studies demonstrating the beneficial effects of soy.

In another experiment that shows the hormonal benefits of soy on the effects of chemical estrogens, when female monkeys were given birth control pills, their cortisol shot up, and their DHEA and testosterone plummeted. When they were given Premarin®, the same thing happened. When the monkeys were given soy protein with isoflavones, however, their hormones normalized.37

Several years ago, there was concern about genistein, an isoflavone in soy, when research showed that it activated estrogen-related genes. Some people took this to mean they should avoid consuming soy, which would be unfortunate given the overwhelmingly positive data about soy’s benefits to humans. Genistein has been called the “good estrogen” for its beneficial effects against estrogen-responsive breast cancer.38 It subsequently emerged that most of the negative research on genistein was generated by one researcher, under conditions that would not exist in real life (such as extremely high levels of genistein put into cancer cells that were deprived of all other estrogen).