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ESTROGEN DEPENDENT TUMORS AND HERBS:
How Modern Conditions Change Traditional Practices
A few years ago, if I were able to confidently provide women with an herbal therapy, especially one in a convenient form, that would boost their own production of estrogens, the demand for such an item would have been difficult to meet. For, at that time, millions of women were taking exogenous estrogens (or faced with the prospect of doing so in the near future) that were derived from animals or synthetically produced from plant precursors. These hormones have been used to alleviate menopausal symptoms for several decades, but there was a growing movement (among a minority of women, however) to reject that approach and seek something they deemed more natural as an alternative. Some were opposed to pharmaceutical interventions on general principle (that it is not natural and, therefore, harmful). One specific fear of the pharmaceutical estrogens was that they could increase the risk of breast cancer; this increased risk was interpreted, by most of these concerned women, as the result of using an unnatural product. Therefore, a natural means of increasing estrogen was thought to be safer.
For a while, women turned to certain products that were held out to be natural estrogens: for example, extracts of wild yam (Dioscorea sp. ) which were claimed to either contain natural estrogens or to provide precursors that the body could transform to estrogens. Today, most women have learned that this was a fallacy: wild yam neither contains estrogens nor does it contain precursors that can be modified by the body; however, it does contain precursors that can be modified in the pharmaceutical factories to yield estrogens. Other herbs have been described as containing phyto-estrogens, plant compounds that act like estrogen or can indirectly induce an estrogen-like response. As with wild yam, these herbs have been sought after by women, but most of the herbs have extremely weak estrogen activity, especially in the dosage form usually provided.
The situation has changed completely in the past few years. No longer does anyone ask if an herb therapy can provide estrogens, nor does anyone ask if an herb can increase the body's production of estrogens, unless they are hoping and praying that it won't do so. I am not asked for sources of estrogen enhancing herbs for women entering menopause, but, instead, I am asked to provide assurance that an herb therapy won't increase estrogen levels at all.
Why the change? Because modern research has shown that estrogen, whether naturally occurring in the body or introduced externally from any source, can stimulate the growth of breast cancer cells (and ovarian cancer cells; but with breast cancer being so much more common, it will be the focus of this article). Some breast cancer cells are more sensitive to estrogen than others: they have a relatively large quantity of a particular type of estrogen receptor; these cells are called estrogen-dependent or estrogen-receptor positive. While estrogen apparently doesn't cause cancer by itself, it has been learned recently that metabolites of estrogen (such as the 4-hydroxy derivatives) that are naturally produced in the body can transform normal cells to cancer cells. These metabolites are produced in varying amounts, dependent on factors that have not yet been fully determined (high alcohol consumption has been linked to higher risk of breast cancer and may be due to induction of liver enzymes that produce the 4-hydroxy estrogen derivatives). In addition, estrogen and its metabolites can increase the chances that a cell that already has the cancer-promoting genetic structure will multiply rather than disappear: this is the role of the estrogen receptors at the cell membrane. Thus, for women who fear experiencing breast cancer (for the first time or as a recurrence), avoiding estrogen-regardless of source-is the objective based on the current medical model.
Researchers and doctors have known for decades that there is a connection between estrogen and breast cancer, because it was known that removing the ovaries (which is the body's single largest source of estrogen) could inhibit breast cancer growth. But much more has been learned during the past decade, with testing now available to determine whether cancer cells (removed by biopsy or surgery) are highly estrogen-dependent or not. Such testing has not allayed the fears of those with the cancers that have low estrogen-activation; the word in the literature is that when a person has breast cancer, estrogen is bad.
While dietary cancer-promoting substances and environmental chemicals are sometimes blamed for the relatively high incidence of breast cancer observed in modern times, especially in the U.S., the change in child-bearing practices and the longer lifespan appear to be the dominant causes. Lifetime pregnancy rates have dropped dramatically over the past century and pregnancies are mostly occurring later in life than before. Epidemiological research shows that full-term pregnancy early in life is the most effective natural protection against breast cancer in women. Most breast cancer cases still occur late in life, even though the premenopausal cases are particularly of concern. The incidence of cancer in general, not just breast cancer, and the incidence of other life-threatening diseases increase with age due to a variety of age-related factors. The average female life span is now about 25 years past menopause-more than a decade longer than the average a century ago. The resulting change in breast cancer incidence related to these factors has led to intensive measures to warn women about every contributory risk known or suspected in relation to this disease. Herbal therapies have become one of the targets of this warning.
While breast cancer can strike at a relatively early age (usually because of strong genetic factors), most cases occur after age 40. At this stage of life, there are usually several signs of aging compared to earlier years, such as dryness of skin and hair, graying of hair, weakening of bones, loss of muscular tone, lowered stamina, and, for many people, onset of some degenerative conditions, perhaps affecting connective tissue, the vascular system, or the nervous system. If a woman goes to a practitioner of Chinese medicine at this time in her life, regardless of her specific medical complaint, the remedy is likely to be one that includes the "anti-aging" type of herb ingredients. The inclusion of such medicinal materials need not be based on any patient request to deal with a specific concern about aging, but, instead arises because the diagnosis will almost always take into account factors that are characteristic of the persons advanced age. Many of these herbs are classified as tonics, though not all of them are in that category.
In the pre-modern era of Chinese medicine, the treatments for men and women of this age group were aimed, at least in part, at nourishing the kidney and liver and replenishing the essence (and/or preserving the essence from loss). When modern scientific investigation of Chinese herbs was introduced during the 20th century, Chinese researchers designed experiments to determine what the herbs do, from a biochemical and physiological viewpoint, when they provide this anti-aging effect. One of the findings is that they enhance the endocrine system functions: they help to restore earlier levels of hormones that had declined with age (see: The endocrine impact of Chinese medicine). Thus, for example, here is a statement from an article on anti-aging herbal medicines (6):
The functional status of the endocrine system is also closely related to aging. To various extents, most of the endocrine functions deteriorate along with the increase in age. Derangement of any of the regulatory steps in the neuro-endocrine set-up, whether neurotransmitters, releasing hormones, stimulating hormones, or target hormones, will inevitably accelerate the aging process....Some of the herbs known to possess gonadal hormone-like effects or gonadotropic effects include epimedium, gecko, deer antler, cordyceps, and ginseng. Galenicals [formulas] such as Zhibao Sanbian Wan, Kangbao, Huangjingjian, and Shoutao Wan can elevate the body gonadal hormone levels. A point worth mentioning here is that all these individual herbs and compound prescriptions have been traditionally employed as 'kidney-replenishing' medicines.
Many people in the West involved with anti-aging approaches are aware of the potential benefit of hormones such as DHEA (dehydroepiandrosterone; an adrenal hormone, precursor to testosterone and other sex hormones), melatonin (pineal gland hormone that regulates the sleep cycle), growth hormone (usually referred to as human growth hormone), and, the sex hormones testosterone, estrogen, progesterone, and their variants. All of these hormones are present in relatively larger amounts early in life (before age 30), and decline, sometimes dramatically, later in life. Administering these hormones can sometimes alleviate characteristic signs of aging; Western conferences and publications on slowing the aging process are filled with reports on the use of hormones. The increased level of hormones in the bodies of older persons is what the Chinese had accomplished through administering herbs, rather than administering hormones (see: The treatment of menopausal syndrome with Chinese herbs). Had isolated or partially purified hormones (including estrogen) been accessible to the Chinese in ancient times, there is little doubt that they would have been used and proclaimed "first class" remedies.
Herbal therapies are not the only Chinese medical practices said to increase endocrine function and improve estrogen levels. In a report on the anti-aging effect of qigong practice, it was reported that menopausal women who practiced qigong would experience a substantial increase in the level of estradiol (the estrogen compound which is deemed one of the strongest promoters of breast cancer of all the naturally-occurring estrogens). This increase in estradiol is reported as evidence of the benefits of qigong practice. The authors state that: "This finding is particularly important in anti-aging treatment, especially for post-menopausal patients, as it has generally been accepted that ovary degeneration and decreased estradiol level in this period of life is an irreversible process."
As with the proposed effect of qigong, a therapeutic result of taking herbs that is characterized by increase in endocrine function and more hormones flowing through the blood would have been hailed as a great contribution to natural health care only a few years ago. Indeed, in a 1998 publication showing that kidney tonic herbs (mainly rehmannia, epimedium, dioscorea, cuscuta, cornus) could raise estrogen levels substantially during menopause and even 10 years after menopause, the authors wrote: "The results indicated that the hormonal disorders in post-menopausal females could be corrected by kidney tonic herbs by way of raising the levels of estrogen and calcitonin, and reducing the levels of parathyroid hormone." The authors took the view that the problem with hormone replacement therapy was the use of a single hormone which can present side effects, where as "kidney tonic herbs mobilize all positive factors through general regulation."
Now, as a result of publicized concerns about the impact of estrogen on cancer, all women who wish to avoid having any more estrogen in their system must avoid the use of Chinese herbs (perhaps qigong as well), at least many of the herbs that are aimed at treating the characteristic symptoms the woman is facing at this stage in her life. The reason that many of the herbs-rather than just tonic herbs-come into question is that there is theoretical and clinical evidence to support the ability of herbs other than tonics to accomplish the same goal. Tonic herbs are just the most frequently used group of herbs to treat the deficiency syndrome that often characterizes menopause.
In the book Aging and Blood Stasis (7), menopausal syndrome is described by differentiation in three categories: heart spirit bewildered and chaotic; heart blood deficiency; and liver qi depression and binding. In each case, consistent with the thesis of the book that aging involves blood stasis syndrome, a significant portion of the formula involves herbs that "quicken the blood and transform stasis," such as salvia, tang-kuei, cnidium, carthamus, and persica. According to the author, these herbs may be combined with others that have functions such as calming the heart (spirit) and regulating the liver qi. Regardless of the specific ingredients, if the therapy is successful, it is possible, perhaps even likely, that the endocrine system has responded and produced a somewhat higher amount of estrogen.
In the continuation of their article on anti-aging Chinese herbs (mentioned above), Chen and Li list the following herbs as having an "estrogen action:" curculigo, cuscuta, schizandra, rubus, lily, cyperus, soja (processed soy bean), and rhubarb. These herbs come from several therapeutic categories of the Materia Medica and not all of them fit the usual concept of anti-aging remedies as tonics. In one recent study, a therapy claimed to consist of Chinese herb extracts to be used for prostate cancer patients was reported to have a strong estrogenic activity, similar to that of standard medical hormone therapy (see: Questionable cancer therapies). Only one of its ingredients, ganoderma, might fit into the usual category of anti-aging herbs.
Most of the concern related to estrogen levels and herbs is currently focused on women who have a diagnosis of breast cancer (even if it is fully in remission) or ovarian cancer. In these cases, Chinese herbs cannot be advocated as part of the therapeutic regimen. The same restriction would apply to other herbs that are not classified as Chinese, and also to men with prostate cancer who are concerned about the adverse impact of testosterone on cancer development (certain testosterone metabolites stimulate growth of prostate cancer cells). While herbalists may believe that the beneficial effects of the herbs outweigh any risk (associated with raising estrogen levels), there is a lack of convincing evidence that this is actually the case; therefore, one cannot make a reliable claim.
In the near future, one can expect the concern about use of these herbs to be raised for any woman who is deemed at elevated risk of getting breast or ovarian cancer, such as those who have a family member that experienced the disease. This is especially so in light of the recent studies suggesting that estrogen metabolites produced in the body can actually cause cancer (8). As hormone replacement therapy advances, the large scale clinical trials will demonstrate that there are some combinations of hormones that have a high rate of effectiveness for alleviating menopause-related problems (e.g., osteoporosis) with a very low rate of risk for breast cancer, ovarian cancer, and other disorders (in current medical practice, the risk of these cancers is only marginally elevated or not at all, depending on the study). In addition, new non-hormone treatments for osteoporosis and other menopausal concerns are becoming available. Women and their physicians will naturally ask if the Chinese herbs administered for similar purposes have the same effects and the same lack of risks, and it will have to be admitted that there is inadequate evidence to determine whether or not they are comparable.
There is no easy way out of the conundrum. One recent laboratory animal experiment, designed to show that a food component, tangeretin (found in citrus fruits) might inhibit breast cancer in the same manner as Tamoxifen does (based on initial in vitro experiments), turned out to indicate that this natural compound canceled out the effect of Tamoxifen. While the results of this initial study may not end up applying to humans due to some differences in the metabolic pathways, at this time, there is no evidence to contradict the concern that the study raises. Most doctors and their patients would rather err on the side of caution.
Tangeretin is a citrus flavonoid; other flavonoids might also have this effect, they simply haven't been tested yet. Flavonoids are found in several herbs and in some herbs they are major active constituents; the Chinese rely on more than a dozen citrus materials in making herbal prescriptions (see: Synephrine: Is chih-shih toxic?), and each of them contains flavonoids that either include tangeretin or molecules very similar in structure and effect. The citrus materials are used by the Chinese to aid digestion, help resolve breast lumps, and regulate the bowels, all of which are areas of concern in menopausal women. Thus, women with breast cancer or at risk for breast cancer who are taking Tamoxifen might be cautioned about taking herbs (or including the otherwise healthful citrus fruits in their diet).
Many women with breast cancer take anti-depressants: having a diagnosis of breast cancer may, in itself, be depressing; the Chinese medical view is that depression is one of the contributors to developing cancer (see: Oriental perspectives on cancer and its treatment; and How emotions may contribute to cancer). Doctors caution against taking anything that inhibits an enzyme system called MAO (monoamine oxidase; an enzyme system that helps transform some of the neurotransmitters, which are monoamines, into an inactive form) when taking the anti-depressant drugs. This caution, which is applied especially to some drugs that are strong MAO inhibitors themselves, is made to avoid having the antidepressant (or other) drug therapy yield harmful levels of the neurotransmitters. Recently, a popular Western herbal remedy for depression, St. John's Wort (also traditionally used by the Chinese, but not for depression), was reported to inhibit MAO, which led to quick calls for avoiding its combination with Western drugs and separating its use from that of drug therapies by three weeks time. It appears that this report was fallacious, but the response to it made it quite clear that use of herbs in this circumstance has become a serious concern.
With aging, MAO levels increase. This increase in the enzyme causes the level of neurotransmitters to decline, with resulting losses in memory, clarity of thought, and neuromuscular control. Thus, the MAO increase contributes to some of the symptoms of aging, including those that women complain about during menopause. Anti-aging herbal approaches may inhibit MAO; as with the increases in hormones, this is regarded, by Chinese researchers, as an advantage to the use of the herbs (restoring MAO levels closer to those of youth). Even if an herb therapy is at a dosage that is too low to affect MAO (see: MAO inhibition and Chinese herbs), the effective level for the herbs is not well-defined and doctors may advise erring on the side of caution. Therefore, here is yet another reason to avoid Chinese herbs-or other herbs-in women with breast cancer.
At this time, there is no direct evidence that use of Chinese herbs increases the risk of breast or ovarian cancer (or prostate cancer in men), nor that Chinese herbs cause harm when combined with anti-depressant drugs. Rather, the concerns are based on pharmacology research and its connection to clinical and epidemiological observations. This is one of the ways in which modern conditions affect the practice of traditional medicine. Not everyone will worry about the potential interactions of herbs with the hormonal system and drug therapies, but these are questions increasingly raised. Certainly, the impact of Chinese herbs is expected to be dependent on the dosage administered. In terms of affecting risk factors for a disease that will occur much later, such as the role of increased estrogen on breast cancer, the biggest concern will be the duration of use. Though short-term administration of low to moderate doses of herbs may still cause some people to be worried, the practice is less likely to produce any adverse effect than either high dosage or long-term administration of herbs.
Epidemiologists have noted a lower incidence of breast cancer in Japan compared to the U.S., an incidence level that usually changes when Japanese women move to the U.S. Originally, the difference in incidence rate was thought to be due to a difference in saturated fat intake. However, a recent large-scale evaluation of diet and breast cancer has indicated that the role of dietary fat was probably overestimated and may be minor (elevated dietary fat is still believed to have an impact on cardiovascular disease, colon cancer, obesity, and other health problems). It is now proposed that one reason for the lower Japanese incidence of breast cancer in Japan is the elevated use of soy products in Japanese cuisine (see: The role of dietary and herbal flavonoids in gastro-intestinal health). Age-adjusted breast cancer death rates are 2-8 times higher in Western countries (U.S. and Western Europe) than in Asian countries (China, Japan, Korea). On average, women in the Orient consume 20-50 times more soy products than women in Western countries. The countries with relatively high soy intake also have lowered incidence of prostate and colon cancers. Prostate cancer, like breast cancer, is often hormone-dependent; colon cancer is strongly influenced by dietary components, since the unabsorbed components have direct contact with intestinal cells.
Soybeans contain substantial amounts of two isoflavones, one is genistein and the other is daidzein (see: Soybeans for cancer patients; Soybeans for health; & Legumes). Daidzein is metabolized in the intestines to produce equol, which may be the most potent of the isoflavones in terms of alleviating menopausal symptoms, but genistein has been studied most intensively in relation to cancer and it appears to be of some potential benefit to women who are concerned about estrogen dependent tumors.
Genistein is classified by some as a phytoestrogen. This term is somewhat misleading, in that genistein neither has a chemical structure like estrogen nor does it act in the body in the same way as estrogen. It does interact with estrogen receptor sites, but it appears to interact preferentially with a subclass of estrogen receptors that do not stimulate tumor cells. That is, genistein can interact with receptors that will alleviate some estrogen-deficiency symptoms (e.g., hot flashes) with little stimulus to the receptors that affect the tumors. In addition, it appears that genistein can inhibit the growth of breast cancer cells by promoting the internally-programmed cell death, which is otherwise halted by the cancerous condition (9).
Therefore, by consuming genistein, women may be able to help alleviate menopausal symptoms (but, certainly, not all aging symptoms) without the risk of stimulating breast cancer cell growth. Genistein is found in most legumes, but especially in peanuts, soybeans, and yellow peas. Genistein-enriched soy products, and encapsulated or tableted genistein products are also available. Effective levels for treatment are not firmly established, but ingestion of soy isoflavones in the dosage range 60-180 mg/day appears reasonable with the current state of knowledge.
The research is still preliminary. But, for those who are initially seeking Chinese herbs as a remedy and who are concerned about their potential estrogenic effects, the practitioner may wish to shift the emphasis away from the use of Chinese herbs to a genistein-based therapy. It will be necessary for both practitioners and patients to keep up with the emerging literature in order to assure that the most appropriate therapy is followed. As with all traditional, alternative, and complementary therapies, the evidence for effectiveness and safety is limited and views are subject to change, as has been described above.
Breast cancer cells alter their metabolism and growth (production of new cells) in response to various stimuli. Not all growth stimulants have been identified, but two stimulant groups are the estrogens (the main one being estradiol, called E2) and the peptide growth factors (such as epidermal growth factor, EGF). When one of the growth stimulants interacts with a cancer cell surface receptor, a cascade of signal transducers lead to DNA stimulation, which then manages the reproductive cycle of the cell. It is here, in the DNA, that abnormalities in growth and life cycle characteristic of the cancer cell are stored. One of the steps in the pathway to the DNA is an enzyme called tyrosine protein kinase (TPK). Genistein has been shown to inhibit both estrogen- and peptide-growth-factor-stimulated growth of breast cancer cells.
Cancer cells not only have the ability to grow more rapidly under certain stimuli, but there are other stimuli can inhibit cancer cell growth. For example, the p53 protein induces cell death (apoptosis) in cancer cells. Studies have shown that people with a genetic background that leads to low p53 levels are more susceptible to experience cancer and die from it. Genistein has been shown to help induce apoptosis of breast cancer cells via the p53 protein. Further, cancer cells have a mechanism for protection against apoptosis; this protective mechanism includes the production of stress proteins. The stress response is inhibited by genistein. In human breast cancer cells, another protein, p21, is especially important to the reproduction of the cells. In vitro experiments show that genistein induces expression of p21, resulting in arrest of the cancer cell cycle.
These various mechanisms of action, mostly observed in laboratory studies and not yet in humans, may help explain the reduced incidence of breast cancer among women who consume a considerable amount of soy products on a regular basis. It may also indicate a means of aiding the treatment of breast cancer, probably relying on a larger dosage of genistein than is characteristic of dietary levels that help prevent cancer. The in vitro studies usually rely on levels of genistein that exceed (by a factor of 10 or more) the levels experienced by cancer cells in the breasts of women who consume soy foods.
The fact that soy isoflavones reduce menopausal symptoms and yet may help prevent or even help treat breast cancer seems contradictory. It has been postulated that this apparent contradiction may arise from different binding capabilities or different primary binding sites for phytoestrogens compared to estrogen. In rat tissues, the isoflavones tend to bind more strongly to estrogen receptor beta (ER-b), while it is estrogen receptor alpha (ER-a) that estrogen binds to in producing several estrogenic effects; breast tissue is mainly supplied with ER-a receptors; there is only weak expression of ER-b in human breast tumor cells. Therefore, while an estrogen-like action is observed in relation to menopause, the estrogen-dependent tumor cells remain unstimulated.
A nutrient substance, coenzyme Q10 (CoQ10), has been investigated since 1957 by a research group headed by Karl Folkers (who was involved in the initial isolation, identification, and animal testing of the compound). The researchers have been pursuing the possibility that CoQ10 may have preventive and therapeutic effects in the treatment of cancer for more than ten years, and much of their efforts have focused on breast cancer. Coenzyme Q10 is best known for its effects on cardiac muscle, which is where this substance is concentrated (CoQ10 is utilized mainly in the mitochondria of all cells; this organelle carries out energy transformation, and is needed to keep the heart pumping). Originally, tiny amounts of CoQ10 were obtained from beef hearts; a technology for large scale production in batch culture was developed in Japan in 1974, which made it possible for CoQ10 to be utilized as a therapeutic substance.
CoQ10 already has a limited role in breast cancer therapy. It can be used to protect the hearts of patients who are being treated with chemotherapy regimens that includes the commonly-used drug adriamycin (as well as analogues with similar properties), which produces significant risk of heart damage. Evidence for the possibility that CoQ10 might have some additional value for women with breast cancer, regardless of estrogen receptor status, includes the following:
Unlike some other proposed natural therapies for cancer (see: Questionable Cancer Therapies I: PC-Spes), this one has been pursued at several research institutes and the effort has been joined by investigators aside from the original group (from Denmark). CoQ10 is already an approved drug (listed in the Physicians Desk Reference, but not indicated for cancer therapy at this time) and is a well-established food supplement (unregulated; available for sale without prescription). This substance is currently under investigation for possible therapeutic benefits in the treatment of atherosclerosis and heart disease, early-onset diabetes, deafness, Parkinson's disease and other degenerative neurological disorders. It is not purported to be a cure for cancer or any of these other diseases, but a contributor to improved outcomes.
The therapeutic dosage may be as low as 60 mg per day in some cases, but the most recent studies with women having breast cancer relied on 390 mg per day (a few practitioners have tried even higher doses, but there is no evidence to support the need for more than this amount). Although CoQ10 is a natural product, the doses given therapeutically are higher than occur naturally. The dietary levels are normally only a few milligrams per day; this fat soluble compound is mainly found in beef and pork, fatty fish (such as sardines and mackerel), wheat germ, and soybean and sesame oils. Women pursuing a low fat and mostly vegetarian diet aimed at maintaining health and reducing cancer risk may have very low dietary intake of this nutrient. CoQ10 is also produced in the human body from tyrosine, but the combination of dietary sources and biosynthesis will yield a blood plasma level that usually does not exceed 1 ug/ml in healthy individuals, while supplementation at 390 mg of CoQ10 daily has been shown to increase the level to over 3 ug/ml in patients with breast cancer.
There is no known impact of CoQ10 on hormone levels and, at this time, no reason to suspect a significant effect on estrogens or other sex hormones. CoQ10 administration is currently considered safe by most authorities and there are few adverse effects (at the high dosages, some nausea or bloating may occur, which is generally alleviated by dividing the dosage into smaller amounts taken more times per day; there may be some changes in the urine at doses of 200 mg or more per day). In laboratory animals, life-long feeding of high levels of CoQ10 did not produce any evident adverse effect and did not affect life span (16).
Although there are several natural substances that are under consideration for prevention of cancer (4, 17), CoQ10 is one of the few that has been specifically aimed at use in treatment of breast cancer. Therefore, as with soy isoflavones, this substance is of potential interest to practitioners who are pressed to natural therapies that are not likely to increase the perceived risk associated with endocrine system enhancement.