FEMALE HORMONE MODULATION THERAPY

Women need to be concerned about steroid hormonal levels at two major intervals in their lifetime. The first is from the onset of Menses until menopause, and the second is from menopause to death - in other words, for most of their life! In both of these life phases changes in hormonal levels can wreak havoc with a woman's feeling of health and well-being. The primary issues in the first phase are with dysmenorrhea and preMenstrual syndrome [PMS]; and in the second phase with increased risk to cardiovascular disease, osteoporosis, and a host of menopausal symptoms related primarily to lack of estrogen production. This protocol discusses the options for managing Menopause. See also the separate protocol on PMS and Menstrual Irregularities for more information on properly managing hormone levels during child-bearing years.

Concern about the life-threatening side effects of synthetic hormone drugs has caused many Women to be deprived of the benefits of safe natural hormone replacement therapy. Presently, only 20-30% of postmenopausal Women in the United States take conventional HRT using estrogen alone or in combination.

Proper hormone modulation can prevent degenerative disease and improve functioning in both the physical and emotional spheres of life, both at menopause and throughout life. For example, many sexual "dysfunctions," including lack of desire, can be mitigated when hormone levels are naturally restored to a youthful profile. Menopause might also be delayed and be less traumatic if hormone adjustments are made in time. Numerous female health problems are tied to inadequate hormone balances, as we will show.

Approximately 45 million Women are menopausal in the United States today; another 1.8 million Women will become menopausal this year. Based on life expectancy trends, Women face the prospect of spending the last one-third to one-half of their lives in a state of hormonal imbalance. The quality and quantity of life for these Women will be determined by how well they (and their doctors) manage their hormone replacement.

Hormone Deficiencies: Estrogen

Starting around age 45 to 50, Women face a perplexing dilemma regarding estrogen, one of the primary sex hormones. The amount of estrogen naturally produced by their bodies dwindles. This estrogen deficiency causes a wide variety of menopausal miseries, including hot flashes, depression, vaginal dryness, anxiety, and forgetfulness. The menopausal decline in estrogen production is a direct cause of premature aging, increased risk of cardiovascular disease, and increased risk of osteoporosis.

Estrogen replacement therapy (ERT) remains controversial. FDA-approved estrogen drugs have been documented to cause cancer. The most conclusive report showed that Women taking estrogen and a synthetic progestin drug had a 32 to 46% increase in their risk of breast cancer (Colditz et. al. 1995). These estrogen and progestin drugs carry warning labels listing a shocking array of dangerous side effects.

Although estrogen increases the risk of some types of cancer, it also has critical anti-aging benefits, including the prevention of osteoporosis and heart disease and the reversal of some aspects of neurological decline. Many doctors don't believe that estrogen can cause cancer, while others think that combining estrogen with a synthetic progestin neutralizes the risk. Some studies show that estrogen does not cause cancer in the short-term, but in Women taking estrogen and/or a synthetic progestin for more than 10 years, there appears to be a significantly elevated risk of breast, ovarian, and uterine cancers (Colditz et al 1995; Rodriguez 1995; Negri et al. 1999).

The report that Women had a 32 to 46% increase in their risk of breast cancer while using estrogen alone, or estrogen and a synthetic progestin, was based upon data from the famous Nurses' Health Study conducted at Harvard Medical School. This study showed that the carcinogenic risk of estrogen-progestin replacement therapy became most pronounced when it was used for 10 or more years. However, recent data from the Breast Cancer Detection Demonstration Project suggest that relative risk is increased by 20% even after four years of use compared to no hormone treatment, and that surprisingly there was a 40% increased risk of breast cancer using both estrogen and progestin combined, compared to only 20% increase for estrogen alone. This latter finding goes against theoretical beliefs and prior research that combining estrogen with a synthetic progesterone would mitigate against an increased risk due to the "anti-proliferative" effect of progestin (Schairer et al. 2000).

Increased breast cancer risk is not the only danger of using estrogen drugs. A report published by Rodriguez et al. (1995) showed that long-term estrogen replacement therapy increased the risk of fatal ovarian cancer. This 7-year study included 240,073 pre- and post-menopausal Women. After adjusting for other risk factors, Women who used estrogen for 6 to 8 years had a 40% higher risk of deadly ovarian tumors, while Women who used estrogen drugs for 11 or more years had a startling 70% higher risk of dying from cancer of the ovaries. The increased carcinogenic risk from estrogen is a serious concern. Cancers of the breast, uterus, and ovaries account for 41% of cancer incidence in U.S. Women. Breast cancer is running at epidemic levels, striking 1 in 9 Women, up from 1 in 30 Women in 1960. Conventional estrogen replacement therapy and estrogen-based oral contraceptives have been used extensively since 1960. Clearly, an alternative is needed to provide the anti-aging and health-enhancing benefits of estrogen, while protecting against its cancer-causing effects.

Dangerous Estrogen Drugs

The most popular estrogen drug in the United States is Premarin, which contains estrogens derived from the urine of pregnant mares. Besides the fact that the process of collecting mares' urine is an inhumane and cruel procedure, the form of estrogen it produces is the most dangerous kind. In humans, estrogen has three different forms, one of which, estriol, is safe and effective. Premarin contains no estriol. Instead it is a "conjugated" estrogen, never intended for human bodies. Other popular estrogen drugs are sold under the names Estrace and Estraderm - these are pure estradiol and are not conjugated. Estrace is derived from soybeans. Provera is the name of a popular synthetic progestin often given with Premarin to help prevent estrogen-induced uterine cancer. Unfortunately, as noted above, it does not seem to prevent estrogen-induced breast or ovarian cancer.

Estrogen and progestin drugs have well-documented side effects that cause many Women to avoid using them. In addition to increased cancer risks, some of the other risks of estrogen/progestin drugs include

Weight gain.
Abnormal blood clot formation (thrombosis).
Increased risk of gallstones, fibroid tumors, and headaches.
PreMenstrual-type symptoms (irritability, fluid retention).

Despite these unpleasant and sometimes lethal side effects, many Women use estrogen drugs because of their ability to reduce the unwanted effects of menopause and for their anti-aging properties. Estrogens are steroid hormones that promote youthful cell division in target organs of the body. The anti-aging benefits of estrogen replacement therapy include

Enhanced skin smoothness, firmness, and elasticity (Castelo-Branco et al. 1998)
Enhanced moistness of skin and mucous membranes.
Enhanced muscle tone.
Reduced genital atrophy and enhanced sex drive in Women (Head 1998)
Reduced menopausal miseries such as hot flashes and anxiety (Vincent 2000)
Reduced risk of heart disease and osteoporosis (Kaufert et al. 1998; Sites 1998)
Reduced risk of colon cancer.
Improved memory and neurological function (Sherwin 1994; Jacobs et al. 1998)
Protection against Alzheimer's disease (Resnick et al. 1997; DeGregorio et al. 1998)
Enhanced immune function.
A greater feeling of well-being.

Estrogen's benefits make it desirable for most menopausal Women to maintain youthful levels of this hormone. The question is, can the anti-aging benefits of estrogen be obtained without increasing the risk of cancer and arterial blood clots? There are preferable alternatives to these synthetic hormones. Estrogen supplements may be produced from plant sources. These safe and effective estrogens are known as "phytoestrogens," and they have been studied in great detail. A review of the published literature reveals some interesting findings about plant-derived estrogens. Phytoestrogens from soy have been documented to reduce hot flashes and protect against age-related diseases such as osteoporosis, heart disease, and cancer (Vincent et al. 2000). There are additional plant-derived extracts that have been shown effective in alleviating menopausal symptoms such as depression, anxiety, insomnia, and vaginal atrophy that must be looked at as well.

Natural Dietary Approaches to Menopause

Before we go into the specifics of natural hormone replacement, it is important to understand that natural hormones or hormone analogues are by their nature weaker than synthetics. Natural hormones require, as much as possible, a supportive environment in which to function optimally. Because of this, a balanced nutritional program will help to optimize any natural therapy that you undertake. Natural hormone replacement therapy concepts came about as a result of population studies in Asia showing that many of the menopausal disorders of Western civilization were absent in the East. What is significant about the Oriental diet is the large amount of soybean products consumed, and the low fat intake. It is likely that both of these factors, and probably others that we don't know about yet, have given rise to a very low incidence of menopausal disorders in that part of the world.

Hormones are simply messengers, carrying a message from one organ to another or from one organ to a group of cells. For example, estrogen is a proliferative hormone that creates growth of the endometrium or lining of the uterus. Any hormone sends its message by 'locking on' to the cell wall of a target organ at a place called the receptor site. Once locked in position it causes changes in the cellular metabolism of that particular cell by turning on or turning off certain genes that code for the manufacture of specific proteins. These messages are then translated by the genes of those cells in such a way as to produce some kind of effect-in this case growth of the uterine lining to prepare for implantation of a fertilized egg.

While this is the effect of estrogen on the lining of the uterus, estrogen may play a significantly different role in other organs, for example bone where it helps maintain bone mineral density. In order to do this effectively, the structure of the cell wall must be such that it accepts the hormone molecule completely. The cell wall structure is dependent upon the kind of food that we eat, particularly the kind of fat. Imbalances of dietary fat cause changes in the three-diMensional structure of the cell wall such that the receptor site's configuration or shape is changed. Thus, when the hormone comes along to transmit a message it does not fit into the cell wall correctly and a message, is either changed or not sent. Think of the receptor site as a lock, and the hormone as a key. If the lock is changed the key simply doesn't fit in and the door will not open. Making sure that we take in a good balance of saturated and unsaturated fats and eliminate trans fats will go a long way towards making sure that receptor sites are of good quality.

Any hormone that has transmitted a message must then be deactivated. This is what happens when we detoxify something-our body changes it so that it is deactivated and excreted. In the case of estrogen this takes place in the liver by a process called glucuronidation or conjugation. If this process is not working efficiently, then active estrogen may be circulating unnecessarily. Any chronic digestive problem, and indeed any imbalance of the healthy bowel bacteria will lead to this situation. Keeping our digestive system in a healthy state may seem a long way from menopausal hormones and hot flashes; however, it is an integral part of the whole process.

What should your diet be like as you enter menopause? Like any healthy diet it should be moderate in protein and complex carbohydrates, with 15 to 20% of the calories coming from fat. Saturated fat from animal products should be low; unsaturated fats should come from cold water fish (salmon, tuna, mackerel and herring for example); with a good portion of your diet coming from soybeans. Tofu contains the highest amounts of genistein and daidzein, which are the estrogen look-alikes (see below). We would also recommend keeping the bowel bacteria in balance by taking Lactobacillus acidophilus, on a regular basis.

Soy Estrogens Versus Estrogen Drugs

A soy extract that provides at least 50 mg of soy phytoestrogens is a key ingredient for effective natural estrogen replacement therapy. Compelling research findings show that soy phytoestrogens may be safer and almost as effective as FDA-approved estrogen drugs.

Based upon records of dietary soy consumption in Japan, where breast cancer incidence is very low, daily soy isoflavone intake has been estimated at 50 mg a day. The typical Western diet, on the other hand, only provides 1 to 5 mg a day of the soy isoflavones that may protect against several forms of cancer.

At a conference in Brussels, Belgium (Sepember 15 to 17, 1996), entitled "The Role of Soy in Medicine," numerous clinical studies were presented, showing that soy phytoestrogens in doses ranging from 40 to 160 mg a day produced rapid and significant reductions in menopausal symptoms. Other studies presented at this conference showed that, in countries where soy is a major constituent of the diet, Women do not suffer discomforting menopausal symptoms the way Western Women do.

According to peer-reviewed scientific studies, soy isoflavones protect against menopausal disorders that are normally treated by FDA-approved estrogen drugs. Unlike these synthetic drugs, phytoestrogens from soy have been shown to

Prevent cancer at multiple sites.
Prevent gallstones.
Protect kidney function.
Stimulate bone formation.
Lower cholesterol levels.
Inhibit the oxidation of LDL cholesterol.
Inhibit the development or progression of atherosclerosis.

Unlike estrogen drugs, phytoestrogens have a balancing effect on the body. When estrogen levels are too low, their very mild estrogenic effect raises total estrogenic activity. When estrogen levels are too high, they compete with estrogen at cell membrane receptor sites, thus lowering total estrogenic activity.

In a study by Cassidy et al. (1994), 27 Women with a mean age of 56 years were studied in a double-blind cross-over trial to assess whether supplementation with soy phytoestrogens could reduce the frequency of hot flashes. These Women were given 80 mg of soy phytoestrogens or placebo for 2 months. The authors concluded that soy phytoestrogens demonstrated greater estrogenic hormonal activity and reduced hot flashes compared to placebo.

However, not all studies support the clinically positive effects of phytoestrogens. Most studies are in agreement that soy intake at levels of greater than 50 mg a day will increase bone mass, will lower low density cholesterol and triglycerides (Wagner et al. 1997; St. Germain et al. 2001), but have clinically no estrogenic effect on the vaginal and uterine epithelium. Also, while there have been frequent positive anecdotal reports on the effect of soy on menopausal symptoms such as hot flashes, clinical studies have not wholly supported these benefits over a long period of time.

Phytoestrogens Prevent Osteoporosis

At the University of Kentucky in Lexington, Dr. Paolo Fanti studied the effects of genistein (one of the active components from soy) on bone loss in ovariectomized rats. Dr. Fanti found the mechanism of action of genistein (the most abundant soy phytoestrogen) appears to differ from that of estrogens. The protective action of genistein seems to depend on stimulation of bone formation rather than estrogen's effect of regulating bone resorption (Fanti et. al. 1998).

A 6-month study on 66 postmenopausal Women was conducted at the University of Illinois at Urbana-Champaign to investigate bone density and bone mineral content in response to soy therapy. In this study, postmenopausal Women received, on a daily basis, either phytoestrogens derived from soy protein or milk-derived protein (that contained no phytoestrogens). The results showed significant increases in bone density and bone mineral content for the lumbar spine in the Women receiving the phytoestrogens derived from soy protein diets compared to the control diet. Increases in other skeletal areas also were noted in the Women on the soy diets. Dr. Erdman, the lead scientist, concluded that soy isoflavones show real potential for maintaining bone health (Potter et. al. 1998).

More recent studies on postmenopausal Japanese Women consuming at least 50 mg/day of soy isoflavones confirmed the positive effect on bone density (Horiuchi et al. 2000), the lowering of low density cholesterol, and amelioration of the non-cognitive effects of menopause (Somekawa et. al. 2001).

More Benefits of Soy Estrogens

A major cause of the breast cancer epidemic may be widespread use of insecticides, fungicides, manufacturing chemicals, and chlorine-based substances that mimic and mutate estrogen. These fat-soluble substances called "hormone modulating pollutants" accumulate in the body over time, and are being recognized as a contributing factor in the development of hormone-related cancers. Women with breast cancer have high levels of estrogen-altering pesticide residue in their breast fat cells compared to Women who do not have breast cancer. Soy contains "friendly estrogens" that block estrogen-receptor sites on cells that are vulnerable to attack by carcinogenic "mutated" estrogens.

Kenneth D. Setchell, Ph.D., of Children's Hospital and Medical Center in Cincinnati, Ohio confirmed the estrogenic activity of the principal soy isoflavones daidzein, genistein, and glycitein (Setchell et al. 2001). Setchell et al. conducted research on the chemical structure and metabolism of soy phytoestrogens, and concluded that consuming modest amounts of soy protein results in relatively high blood concentrations of phytoestrogens and that this could have a significant hormonal effect in many individuals (Setchel 1998).

Dr. Sulistiyani of the Primate Research Center at Bogor Agricultural University in Indonesia stated that, in his opinion, one of the reasons estrogen replacement therapy is so effective in helping to reduce the risk of coronary heart disease in postmenopausal Women may be in part because of its antioxidant properties (Sulistiyani et al. 1997). Considering the increased risk of breast cancer and uterine cancer in Women using estrogen drugs, the researcher suggested that one alternative might be to include more is to take phytoestrogens in one's diet, such as genisteinsoy-based products containing isoflavones, daidzein or genistein, which have been shown to protect the heart against breast cancer, uterine cancer, and cardiovascular disease (Hawrylewicz et al. 1995; Goodman et al. 1997; Anthony et al. 1998; Cline et al. 1998).

In a study using Cynomolgus female monkeys who had their ovaries removed to simulate postmenopausal Women, it was shown that the soy protein isolate resulted in a significant improvement in lipoprotein concentrations and plasma lipids along with improvements in insulin sensitivity and glucose effectiveness. It was also shown that there was a significant interaction (p = 0.02) with soy and E2 (beta-estradiol), such that animals consuming soy protein and E2 had the least arterial cholesteryl ester content. These results suggest that both ERT and dietary soybean protein have beneficial effects on cardiovascular risk factors (Wagner et al. 1997).

In another study with male and female Cynomolgus monkeys, it was shown that isoflavone-intact soy protein significantly improved both LDL, and HDL. Compared to the other substances tested, it also had the least amount of atherosclerosis. The researchers concluded: "Potential mechanisms by which soy isoflavones might prevent atherosclerosis include a beneficial effect on plasma lipid concentrations, antioxidant effects, antiproliferative and antimigratory effects on smooth muscle cells, effects on thrombus formation, and maintenance of normal vascular reactivity" (Anthony et al. 1998). This however, has not been shown in humans.

Soy Estrogens Are Readily Available

While the health benefits of soy are well documented in the scientific literature, it used to be difficult and expensive to obtain the amount of genistein and other soy isoflavones that scientists say may treat menopausal symptoms and prevent age-related diseases.

The Life Extension Foundation introduced a soy extract (Mega Soy) in October 1997 that contains enough phytoestrogens from soy to provide double the amount of genistein, daidzein, and glycitein found in the typical Japanese diet. This soy extract is so concentrated that only a small amount is needed to obtain enough phytoestrogens to potentially provide effective estrogen replacement for many Women. This concentrated soy extract is now available in several commercial formulations. Thomas et al. (2001) found that bioavailability for soy isoflavones in supplement form is similar to those observed in people on Asian diets.

Ipriflavone and Bone Loss

Early reports on the synthetic isoflavone known as ipriflavone were positive for the prevention of bone loss, certainly in early menopause. This synthetic isoflavone is synthesized from daidzein, and has generated considerable interest in the hormone and bone loss research community (Gennari et al. 1998). In a multicenter double-blind 2-year trial tested Women 65 to 79 years of age with multiple forearm fractures. One-hundred eleven Women received 200 mg TID ipriflavone with meals or 1 g oral calcium daily. After two years, a significant increase in forearm bone density measured by dual photon absorptiometry was obtained after ipriflavone treatment (Agnusdei et al. 1997). Women receiving the calcium showed limited bone loss during the treatment. In addition, urinary hydroxyproline, a measure of bone loss, was significantly decreased suggesting a reduction in bone turnover rate. There was also a reduction in the incidence of vertebral fractures in the ipriflavone-treated group as compared to placebo.

The authors indicate that almost 3000 patients have been treated with ipriflavone for a total of over 3000 patients/years in 60 clinical studies from over three countries. The incidence of adverse reactions in the ipriflavone-treated patients was similar to that observed in subjects receiving placebo. They suggest long-term treatment with ipriflavone may be considered safe and may increase bone density and possibly prevent fractures in elderly patients with established osteoporosis (Agnusdei et al. 1997).

Halpner et al. (2000) found that urinary N-linked teleopeptides, another marker of bone breakdown, declined by 29% in those receiving ipriflavone supplement. Nozaki et al. (1998), at the Department of Gynecology and Obstetrics, Kyushu University in Japan tested conjugated estrogens and ipriflavone together. They reported that in ovariectomized Women, bone mineral density was reduced 48 weeks after treatment by the use of placebo, conjugated estrogen alone, and ipriflavone alone. However, a combination of conjugated estrogen and ipriflavone resulted in much less bone loss following ovariectomy. This is for acute short term bone loss following ovariactomy.

Contrary to the majority of trials, the most recent large-scale trial with a total of 474 postmenopausal osteoporotic participants, showed no changes over placebo in terms of bone loss or biochemical markers of bone metabolism. This group also found that ipriflavone caused lymphocytopenia in a significant number of Women although this appeared to be reversible. This latter side effect has not been reported before, and could represent a significant negative factor in considering treatment (Alexandersen et al. 2001).

The research on this product is presently in fairly early stages, and further studies are warranted before considering it in terms of alternatives or adjuncts to other hormonal treatments.

Black Cohosh-Another Safe Phytoestrogen

An important and widely studied plant component used to treat menopause is a standardized extract from the black cohosh plant, also known as Cimicufuga racemosa. This black cohosh extract is approved by the German Ministry of Health for the treatment of menopausal symptoms related to estrogen deficiency. Standardized black cohosh has been trademarked under the name Remifemin for sale as a drug in countries throughout the world. More than 1.7 million Women in Europe and Australia have used this natural herbal extract to treat menopausal symptoms. Clinical studies show that Remifemin alleviates not only hot flashes, but also depression, anxiety, vaginal atrophy, and a host of other menopausal-related disorders (Liske 1998).

A fascinating study involved 60 Women who were given either standardized black cohosh extract, Valium, or Premarin (synthetic estrogen) for menopausal symptoms. The Women in the black cohosh group were relieved of depression and anxiety more effectively than the Women in the Valium or Premarin group. This study was reported by Warnecke 1985.

Premarin and Valium have been among the best selling drugs on the U.S. market for decades, yet produce terrible side effects. European Women, on the other hand, have been using this safe natural herbal extract (black cohosh) that's been shown to work better in alleviating depression and anxiety than these two widely prescribed FDA-approved drugs.

Another study on black cohosh extract involved Women under age 40 who produced very little natural estrogen or progesterone because their ovaries had been removed (by hysterectomy). One group received estriol (a weak, but safe form of estrogen); the second group received Premarin; the third took Premarin and a progestin drug; the fourth was given black cohosh extract; and the fifth group received a placebo. This 24-week study rated Women according to symptoms that included hot flashes, irritability, heart palpitations, etc. The results of the study showed that Women experienced a 30% improvement in all groups receiving different forms of estrogen-progestin and black cohosh extract. There was no improvement in the placebo group. At the conclusion of the study, the majority of Women receiving the estrogen drugs or black cohosh extract were symptom-free. However, most importantly, the Women receiving the black cohosh extract reported fewer side effects. This study showed that phytotherapy with standardized black cohosh worked as well as estrogen drugs, but produced fewer uncomfortable and dangerous side effects. This research was reported by Lehmann-Willenbrock et al. (1988).

The most impressive study on the benefits of this phytoestrogen was carried out by 131 physicians on 629 menopausal Women. This study showed that black cohosh extract produced clear improvement in over 80% of patients within 6 to 8 weeks. Both physical and psychological symptoms improved. Here were the results of the changes in specific menopausal symptoms:

Symptom Percent of Women who became symptom-free Percent who showed improvement
Hot flashes 43.3% 86.6%
Profuse perspiration 49.9% 88.5%
Headache 45.7% 81.9%
Vertigo 51.6% 86.8%
Heart palpitation 54.6% 90.4%
Tinnitus 54.8% 92.9%
Nervousness/irritability 42.4% 85.6%
Sleep disturbances 46.1% 76.8%
Depressive moods 46.0% 82.5%

Most patients in the above clinical study reported noticeable benefits within 4 weeks. After 6 to 8 weeks, complete resolution of symptoms was reported in a high number of patients (Stolz 1982).

A placebo-controlled study by Duker et al. (1991) investigated the hormonal mechanisms by which black cohosh alleviates menopausal symptoms. The doctors conducting the study pointed out that hot flashes correspond closely with a surge of luteinizing hormone released from the pituitary gland in response to estrogen deficiency. Black cohosh was shown to suppress increased luteinizing hormone secretion in menopausal Women and this effect was specifically linked with a reduction in the incidence of hot flashes (Duker et al. 1991).

Black cohosh extract has shown estrogenic effects within the body in several studies, but it does not elevate estrogen levels in the blood. Black cohosh extract appears to bind to estrogen receptors in order to mimic the hormonal effects of the weak estrogen, estriol. Estriol has been shown to protect against the types of cancers that more potent forms of estrogen (estradiol and estrone) appear to cause. Black cohosh extract has been referred to as being "estriol-like" because of the rejuvenating effect it exerts on the vaginal, rather than the uterine, lining.

Liske (1998) states that black cohosh shows good therapeutic efficacy and tolerability profiles. Because of the impressive safety record of standardized black cohosh extract, it is has become a popular natural alternative to FDA-approved estrogen drugs.

More Estrogenic Plants

There are other, important plant-derived hormone modulators that are used by alternative physicians to treat menopausal symptoms. It is important to understand that estrogens are continually being modified as they circulate in the body. They are converted from one form to another and are outfitted with numerous other compounds that cause their biological activity to vary considerably. While it may appear that the combination of soy phytoestrogens and standardized black cohosh may provide complete estrogen replacement, there are other hormonal factors to adjust for if the metabolism of youth is to be maintained (or restored).

An extract from the licorice root called glycyrrhetic acid (GA) stimulates the natural conversion of testosterone to estrogen in the body (Takeuchi 1988). Glycyrrhetic acid is an antioxidant that is often used to protect the liver and suppress viral activity in hepatitis patients (Abe et al. 1994). Offshore cancer clinics prescribe high doses of GA in injectable form to patients because of studies showing that it modulates immune function and suppresses cancer cell replication. It is interesting to note that while FDA-approved estrogen drugs can cause abnormal blood clotting, the GA contained in licorice root inhibits the clotting factor thrombin (Francischetti et al. 1997), thus reducing the risk of a heart attack or stroke. Licorice root extracts have many disease-fighting applications, but for menopausal Women, the most important factor is that glycyrrhetic acid extracted from licorice is a safe source of natural estrogen (Rafi et al. 2000; Tamir et al. 2000). Numerous studies indicate that GA is an effective estrogen replacement therapy in humans. The Chinese have successfully used licorice extracts for more than 3000 years to treat menopausal disorders.

Dong Quai extract is the supreme female tonic in traditional Chinese medicine. It has been used successfully to alleviate PMS (preMenstrual syndrome) and menopausal symptoms by helping to normalize estrogen levels (Hardy 2000). Dong Quai extract has shown to have a muscle relaxant effect, and has been used as an analgesic and anti-inflammatory agent. Scientists believe that one unique mechanism of action of Dong Quai is to promote natural progesterone synthesis. Progesterone, which will be discussed in more detail below, is another hormone whose production declines at menopause. Progesterone may be more important than estrogen for preventing and treating osteoporosis because progesterone is directly involved in the production of bone-forming cells called osteoblasts. Many menopausal Women use a topical natural progesterone cream to provide for direct absorption of progesterone into the bloodstream.

Another hormone imbalance that Women encounter as they grow older is excessive prolactin secretion from the pituitary gland. Prolactin interferes with the beneficial effect of estrogen and may promote the development of estrogen-induced cancers. Prolactin secretion may be suppressed by a natural extract called vitex agnus castus. In a study by Milewicz et al. (1993), vitex agnus castus extract was shown to suppress excessive prolactin secretion and promote natural progesterone synthesis over a 3-month period. As with the other plant hormone-modulating extracts, no side effects were observed.

WARNING: Prolactin is so dangerous in patients with hormone-dependent cancers that the Life Extension Foundation advocates prolactin suppression drug therapy for breast and prostate cancer patients.

A Natural Estrogen Replacement Approach

When choosing a natural estrogen replacement program, make sure the ingredients are standardized to meet pharmaceutical potency. An investigation conducted in 1998 of natural estrogen products sold in health food stores showed that many companies were not using the standardized plant extracts that had been used in the published studies to treat menopausal symptoms. Telephone calls to these companies confirmed that many extracts were "one-to-one" ratios, which means that relatively little of the active ingredient was present. It should be pointed out that this investigation also found that respected brand-name supplement companies were using pharmaceutical-grade standardized extracts in their products to treat menopausal symptoms.

An ideal multi-ingredient phytoestrogen supplement should contain concentrated pharmaceutical extracts. If the active ingredients are not standardized, one cannot expect to obtain consistent biological activity.

Several natural hormone replacement formulas are available to Americans. A product called Natural Estrogen was formulated by the Life Extension Foundation to provide the complete hormone-modulating effects that can be obtained from plant sources. The Natural Estrogen formula provides phytoestrogens from soy, estrogenic plants such as licorice extract, and hormone- modulating plant extracts such as black cohosh (Cimicifuga racemosa), Dong Quai (Angelica sinensis), and vitex extract. More about how to safely use natural estrogen supplements will appear later in the protocol.

When Natural Estrogen is Not Enough

Some Women experience such severe menopausal symptoms that natural, safe forms of estrogen supplements do not provide sufficient relief. If this occurs, and a woman is afraid of the cancer risks and side effects of long-term therapy with estrogen drugs approved by the FDA, there is a third option. Estriol is used extensively in Europe for estrogen replacement therapy in menopausal and postmenopausal Women, but to date has rarely been used for that purpose in the United States. It can, however, be obtained in the U.S. from compounding pharmacies with a doctor's prescription.

Evidence suggests that estriol offers many of the benefits of more traditional estrogen-replacement therapies, but without the harsh side effects or longer term dangers often encountered by other substances and trademarked products (Head 1998). First, some background. The primary forms of estrogen synthesized by the body include three substances: estrone, estradiol and estriol. Estrone sulfate one form of estrogen found in Premarin, while 17-b-estradiol is the only form of estrogen found in the products Estrace and Estraderm. Estrone and estradiol, may significantly increase the risk of breast and ovarian cancer when taken for more than 10 years. According to the Merck Manual, conjugated estrogens are substances that even have been listed as known carcinogens, yet they are the unquestioned choices of too many physicians.

Estriol, on the other hand, is a weak estrogen that provides the anti-aging benefits of estrogen replacement therapy, apparently without the risk of cancer. Consider this evidence of its benignity: during pregnancy, huge amounts of estriol are secreted by the placenta to protect the fetus. Urinary assay of estriol is used to assess the viability of the fetus.

Since estriol is a weak estrogen, larger amounts must be used for estrogen replacement therapy. Estriol is used in doses of 2 to 8 mg a day. A dose of 2 to 4 mg of estriol is equivalent to, and often as effective as, 0.6 to 1.25 mg of conjugated estrogens such as Premarin. One of the most common side effects of standard estrogen therapy is endometrial hyperplasia, or hyperproliferation of the cells of the uterine lining, a condition that often turns into uterine cancer. This condition, which sometimes occurs at younger ages, will be described in more detail later. However, most investigators have found that the use of the alternative estriol therapy, even at the high dose of 8 mg a day, does not cause endometrial hyperplasia.

In one study by scientists at the Medical College of Georgia in Augusta, 52 Women with severe menopausal symptoms were given estriol succinate continuously for 6 months in doses of 2 to 8 mg a day. Significant improvements in symptoms were noted within 1 month of the start of the study, and they persisted as long as estriol therapy was continued. The degree of symptom improvement was directly related to the dose. Symptom relief was moderate at 2 mg a day, but marked at 8 mg a day.

Estriol therapy also reversed vaginal atrophy and improved the quality of cervical mucus. No breakthrough bleeding occurred in any of the subjects and biopsies of the inner mucous membrane of the uterus failed to show endometrial hyperplasia in any case, regardless of the dose of estriol used. The scientists concluded, "Estriol therapy may be employed in dosages up to 8 mg/day continuously, especially in those patients in whom other estrogens induce undesired side effects such as nausea, breakthrough bleeding, or endometrial hyperplasia, and the recurrence of hot flashes during cyclic therapy of more potent estrogens. . . . Being a weak estrogen, it does not induce endometrial proliferation or breakthrough bleeding of any consequence, while modifying menopausal symptoms."

A large, long-term study of estriol therapy for the symptoms of menopause was conducted by Lauritzen (1987) at the University of Ulm in Germany. The investigators concluded, "Estriol therapy was successful in 92% of all cases. In 71%, hot flashes and sweating were completely eliminated, in 21% they were ameliorated, becoming weaker and occurring more seldom. … Depressive moods were abolished in 24% of the cases, and in 33% they were ameliorated, so that an overall improvement occurred in 57%." The study also found that forgetfulness, loss of concentration, irritability, and heart palpitations were remarkably improved towards normal. Also, the number of patients suffering from migraine headaches decreased from 33 to 12, and atrophying of the vulva was completely eliminated in 44 of 61 cases, and showed improvement in 12 cases. "Remarkably," the scientists added, "the quality of the skin improved according to the subjective impression of patients and physicians in a high percentage of cases. . . . In no case, did a deterioration of symptoms occur."

As described above, one of the major benefits of estrogen therapy is prevention of the bone loss associated with menopause. Postmenopausal Women taking estrogen experience 50% fewer bone fractures than Women of comparable age who have not taken estrogen (Smetnik 1997).

Although no studies have yet been conducted in the U.S. to determine whether estriol therapy can prevent osteoporosis, a prospective double-blind study was conducted in 136 postmenopausal Women at the Chinese Great Wall Hospital in Beijing, China using nylestriol (CEE), a long-acting estriol derivative. The doctors found that the placebo group had significantly greater loss of bone mass and higher low-density lipoprotein levels when compared with the treated group. They concluded, "CEE is an effective estrogen for preventing bone loss and lipid disorders in postmenopausal Women, just as is the more popular conjugated estrogen (Premarin), but is more convenient. Long-term CEE medication, its effects on the endometrium and the regimen of progestin combination await further study."

There also is direct evidence from animal studies, and indirect evidence from human studies, that estriol can prevent breast cancer. Much of this work has been done by Dr. H. M. Lemon and associates of the Department of Internal Medicine at the University of Nebraska Medical Center in Omaha. In one study, they induced mammary tumors by radiation in female rats. In the control group, 75% developed tumors.

However, among those animals receiving estriol, just 48% developed tumors (Lemon et al. 1989). In another study by the Lemon team, estriol was shown to have "the most significant anti-mammary carcinogenic activity of 22 tested compounds [because] . . . estriol is less likely to induce proliferative changes in the target organs of cancer-prone Women than estrone or estradiol" (Lemon 1980).

Because of these anticancer effects of estriol in animals, Lemon looked at the question of whether estriol is related in any way to breast cancer in humans. He found that Women with breast cancer have low levels of estriol relative to other forms of estrogen (Lemon 1977). The evidence about estriol as a safe alternative estrogen therapy can be summed up well by the Medical College of Georgia scientists, who concluded, "Estriol deserves a place in our therapeutic resources."

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