From The August 1999 Issue of Nutrition Science News
by Michael L. Bennett, Pharm.D.
What's the fuss about designer estrogens when nature makes a better fit?
Seldom has the public, the media and the medical profession been so bewildered by a term as they are by "estrogen." Almost every day a news release or article extols the benefits or dangers of using estrogen. The generic use of this word feeds the confusion. Accurate use of terms is critically important because each individual estrogen in the group of estrogens has specific biological actions depending on its chemical structure.
The categories of estrogens covered in this review are threefold: the natural human estrogens, the so-called xenoestrogens and the phytoestrogens. Within each of these categories are several specific chemical species.
Although estrogens are used by women for many reasons such as birth control and managing menstrual problems, this discussion will concentrate on postmenopausal women's use of estrogens to restore their hormonal balance, thus staving off symptoms such as hot flashes and osteoporosis. To counter the increased risk of endometrial cancer as a result of using estrogen in this way, progesterone is normally added to drug formulations to balance the hormonal effect. 
Hormone levels can be tested in a variety of ways. Ideally, tissue levels are measured directly, but that is impractical and invasive. Blood also can be tested, but many proteins and lipoproteins carry hormones in the blood, which makes detection complicated. Urine testing is another method but does not reflect the sum of all metabolic reactions taking place and does not give time-specific hormone levels. Currently, the best testing method uses saliva to measure whole-blood and tissue hormone levels and permits analysis of biologically active amounts.
Natural Human Estrogens
This category consists of the naturally occurring estrogens made by the human body, both male and female. There are only three natural human estrogens: estrone (E1), estradiol (E2) and estriol (E3). E2 packs more estrogenic potency than E1, which in turn is much more estrogenic in action than the relatively weak E3.
These three are part of what is called natural hormone replacement therapy, or NHRT. A combination of E1, E2 and E3 is used by a growing number of physicians and is called tri-estrogen, or triest. There is also a biest formula that contains just E2 and E3. Biest formulas leave out E1 because E1 and E2 are interconverted in the body, so some clinical researchers believe only E2 is needed for replacement. Interestingly, all three of these human estrogens are derived from either stigmasterol (in soy) or diosgenin (in Mexican wild yam, Dioscorea composita). Once extracted, however, these plant precursors must be chemically transformed into the bioidentical human estrogens E1, E2 and E3.
As women age, their fat mass tends to increase while their lean body mass decreases. The body produces estrone (E1) in relatively large quantities in postmenopausal women, mostly because fat cells (as well as adrenal glands) produce estrone, which converts to estradiol in the liver. The interconversion of estrone to estradiol provides a source of estrogens to estrogen-dependent tissues such as the brain. 
This estradiol (E2) produced mostly by the liver spurs cell growth in the breast, uterus and other tissues.  Estradiol is the main estrogen influencing the menstrual cycle, and its levels fluctuate tremendously. Many postmenopausal women produce more E2 than progesterone. These women with an estrogen-dominant condition commonly experience bloating, breast swelling or tenderness, fatigue, headaches and irritability. From this it should be obvious that excess estrogen has become a problem and more is not needed. Still, many women are commonly prescribed Estrace or Estraderm, which are pure estradiol in pill and patch forms, respectively. Instead, what is needed to rebalance the progesterone-to-estradiol ratio is a diet rich in phytoestrogens. These plant estrogens compete for estrogen receptor sites, thus blocking the effects of much more potent estrogens. Many cancers such as breast cancer are associated with high levels of estrogen.
Estriol (E3) is the safest of the three human estrogens because it has the least estrogenic effect on the body.  It has been called "the forgotten estrogen" by Alvin H. Follingstad, M.D., in a seminal piece written more than 20 years ago in the Journal of the American Medical Association.  In Europe, estriol is the estrogen of choice for vaginal dryness and is also favored by many dermatologists for its smoothing effects on the skin. It is also said to have antiwrinkle effects. Some progressive physicians use estriol in women who are at high risk for breast cancer yet still need extra estrogen. Estriol vaginal cream, suppositories and topical estriol can be obtained only by prescription.
The prefix xeno means foreign. Xenoestrogens are a rather large group of compounds, and not all are recognized by human metabolism. This category is four-fold and consists of selective estrogen receptor modulators (SERMs) now being promoted by the pharmaceutical companies; Premarin (pregnant mare's urine); Cenestin, a new Food and Drug Administration (FDA)-approved plant-derived mixture of nine estrogens; and estrogenic pesticides and herbicides. Each has unique biological activity based on its structure.
SERMs are synthetic "designer estrogens" created to have selective estrogenic actions in certain tissues. For example, tamoxifen is a drug that has estrogenic actions in the uterus yet has antiestrogenic actions in breast tissues. Zeneca, a large pharmaceutical manufacturer based in England, boasts in several medical journals that "tamoxifen is now the only drug proven to reduce breast cancer by 44 percent in women at high risk of developing the disease."
However, tamoxifen's new indication approved by FDA was not for prevention. The Oncologic Drugs Advisory Committee to the FDA, and finally the FDA itself, rejected use of the word "prevention," yet the media continues to use it.  The headline in my local newspaper read, "Drug may prevent breast cancer." However, the published report states, "Although tamoxifen prevented the appearance of a substantial number of breast cancers over the duration of this study, the term 'prevention' does not necessarily imply that the initiation of breast cancers has been prevented or that the tumors have been permanently eliminated." 
Tamoxifen may slow the rate of cancer growth, but prevention and risk reduction are two different things. Tamoxifen should not be thought of as a preventive agent, as FDA correctly concluded. Diet, for example, is a much better preventive course. Tamoxifen is also not without side effects, which include doubling or tripling the risk of uterine cancer and tripling a woman's chances of developing blood clots in the legs and lungs.
Another SERM now approved by FDA for osteoporosis is raloxifene. This drug has selective estrogenic effects on bone yet spares other tissues such as the uterus and breast. The maximum increase in bone density during a two-year study period was 2 percent, which is less than that provided with natural estrogen therapy.  A recent meta-analysis concludes raloxifene increases bone mineral density to a lesser degree than does estrogen. In addition, raloxifene users commonly experience hot flashes.  More effective alternatives, with fewer side effects, are available, including isoflavones, natural progesterone, natural human estrogens and weight-bearing exercises. In a new book, The Osteoporosis Solution, author Carl Germano, R.D., outlines a nutrition-oriented complementary approach that could well exceed a 2 percent increase in bone density. Adequate calcium intake and exercise are important adjuncts to other therapies but by themselves do not prevent osteoporosis in most women. 
Premarin is another form of supplemental estrogen. It is derived from horse urine and is technically called conjugated equine estrogens. The company that makes Premarin claims it comes from "natural sources," meaning horses.  Horses are natural creatures, but not all their estrogens are natural to humans. Recently, FDA required the maker to fully characterize all the estrogens in Premarin. Reportedly, of the 10 to 30 or more estrogens in Premarin, only two are bioidentical to human estrogens.  Remember, there are only three human estrogens. The effect of taking nonhuman estrogens is unknown.
Cenestin was recently approved by FDA for controlling women's short-term vasomotor symptoms such as hot flashes and sweating.  The manufacturer claims that women now have another choice of estrogen, and this one is "plant-based" rather than "animal-based." Cenestin contains nine estrogens, only two of which are natural to humans.  Just because an estrogen is plant-based does not make it better. That is, estrogens not natural to the body may have effects that we don't know about yet. It is a good idea to avoid them whenever possible. I suggest women avoid these conjugated estrogens altogether and stick with the true natural human estrogens (E1, E2 and E3)and then only if needed as determined by a saliva test.
Pesticides and herbicides can be estrogenic to all tissues in the body. The chemical structures resemble part of the natural estrogen estradiol, and some are more potent. Environmental pollutants contain estrogenic compounds suspected of increasing endocrine interference and reproductive failure.  Petrochemicals, solvents and pesticides, including lawn and garden sprays as well as flea sprays for the family dog, should be minimized if not avoided. Many people are exposed to these substances dailysimple gardening practices can expose a person to harmful chemicals. Washing food, eating organic products and avoiding hormone-laced meat and dairy products all can help. 
Phytoestrogens: Nature's SERMs
Are there natural SERMs? The search for the perfect SERM is now consuming several pharmaceutical companies' time and money. While they try to outwit nature, many isoflavone alternatives and other phytoestrogens already exist in food.
Isoflavones found in red clover, soy and certain other legumes are nature's SERMs because they have selective effectsplus they are probably safer than their synthetic counterparts. Their benefits are well known. Basically, isoflavones act as weak estrogens at estrogen receptor sites, strong enough to promote bone formation and reduce cardiovascular disease risk, yet not potent enough to induce cancer. [17,18]
Flax lignans and yam sapogenins are plant compounds that behave like estrogens. Lignans from whole flaxseed are what I call nature's tamoxifen because of their activity against breast cancer. Instead of using tamoxifen to prevent breast cancer, I recommend women at high risk grind and eat up to a quarter cup of flaxseed each day. Rat and human studies at the University of Toronto confirm the positive effects of flaxseed on the preliminary stages of breast cancer.  Whole ground flaxseed is better than flax oil, even the high-lignan type, which does not contain sufficient amounts of lignans to have therapeutic effectslignans are associated with the protein meal part and not the oil fraction. Flax has greater amounts of lignans than any grain, including rye.
The value of yam sapogenins has been largely forgotten, yet they have weak estrogenic activity and are phytoestrogens in their own right. Several yam-product manufacturers, however, not only confuse consumers by using the wrong species of yam, but also claim unverifiable sapogenin concentrations. For example, one large supplier states its yam cream is a "10% wild yam extract," which does not necessarily mean it contains 10 percent wild yam sapogenins. Identifying the sapogenin contentspecifically diosgenin, the primary medicinal sapogenin in Mexican wild yamshould be the most important item on product labels.
The yam species used by nearly all manufacturers is Dioscorea villosa, which has very little sapogenin and hence very little estrogenic activity. Contrast this to the Mexican wild yam, D. composita, which is such a rich source of diosgenin (a sapogenin) that it has been used by pharmaceutical companies for more than 50 years to make natural human estrogens. D. composita has weak estrogenic effects because it contains sufficient amounts of sapogenins. I have done HPLC analysis on both species and found D. composita to have a 4 to 5 percent sapogenin content, whereas D. villosa shows a sapogenin content of less than 0.1 percent.
When I do saliva monitoring of patients using true Mexican yam extract I observe increased levels of E2 and E3, which suggests it has effects, either at estrogen receptor sites or other pathways. However, D. villosa extracts do not increase natural estrogen levels. More research is needed to characterize these observations.
It is clear from the literature and from the progress of thousands of women who have switched therapies that natural hormones are superior to synthetics. Remember, "natural" means naturally occurring in the human body. The only natural estrogens to humans are estrone, estradiol and estriol.
Michael L. Bennett, Pharm.D., is owner of Optimal Natural Pharmacy and author of "Wild Yam: Nature's Source of Phytohormones" and "The Flaxseed Revolution: Nature's Source of Omega-3s, Lignans and Fiber" (Optimal Healthspan Publications, 1997, 1998).
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