~Female Hormone Modulation

~Female Hormone Modulation
Reprinted with permission of Life Extension®.

Menopausal symptoms are related to a decline in the production of certain hormones such as estrogen, progesterone, testosterone, and DHEA, and this hormone reduction varies from individual to individual. Hormonal imbalance results in the menopausal miseries experienced by so many women as they age past 45. Restoration of the proper balance of hormones can relieve the menopausal symptoms, enabling a woman to feel like her youthful self again. Restoring a youthful hormone balance also helps protect against osteoporosis, mental depression, thinning skin, immune dysfunction, and a host of other age-related diseases and discomforts.

How Widespread Is the Problem?

According to the North American Menopause Society (NAMS), no hard data exist concerning the number of women in the United States who are menopausal. Based on the year 2000 U.S. Census report, an estimated 41.75 million women are over age 50 (the average age of spontaneous menopause). Estimates are that another 1.8 million women became menopausal in the year 2000 (4200 per day) (Pinn et al. 2002). As a large population of female baby boomers approaches the menopausal years, concern about how to treat "the change of life" is expected to grow exponentially.

Concern about the potentially life-threatening side effects of synthetic hormone drugs has caused many women to deprive themselves of the benefits of safer, natural hormone replacement therapy. Proper hormone modulation can prevent degenerative disease and improve functioning in 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 were made in a timely manner. Numerous female health problems are also tied to inadequate hormone balances.

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. Quality and quantity of life for these women will be determined by how well they (and their doctors) understand and manage hormone replacement.

The Estrogen Dilemma

  • Estrogen Drugs Have a Bad Reputation
  • Dangerous Estrogen Drugs
  • Synthetic Estrogen

Between the ages of the early forties to mid-fifties, 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 can cause a wide variety of menopausal miseries, including hot flashes, depression, vaginal dryness, anxiety, and forgetfulness. The menopausal decline in production of all hormones, including the estrogens, is believed to be a direct cause of premature aging and an increased risk of osteoporosis.

Estrogen replacement therapy (ERT) remains controversial. FDA-approved estrogen drugs have been documented to cause cancer and increase cardiovascular disease risks. The first conclusive report showed that women taking estrogen and a synthetic progestin drug had a 32-46% increase in their risk of breast cancer (Colditz et al. 1995). A more recent study (called the Women's Health Initiative, WHI) showed a 29% increase in breast cancer, along with a sharply higher risk of heart attack, stroke, and pulmonary embolism in women taking a popular estrogen/progestin drug combination for only 5.2 years (Rossouw et al. 2002).

The report that women had a 32-46% increase in their risk of breast cancer while using estrogen alone, or estrogen and a synthetic progestin (Colditz et al. 1995), was based on 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, data from the Breast Cancer Detection Demonstration Project suggested that relative risk is increased by 20% after even 4 years of use, compared to no hormone treatment, and that surprisingly there was a 40% increased risk of breast cancer when both estrogen and progestin were combined, compared to only a 20% increase for estrogen alone (Smart et al. 1997). The implications of these findings remain to be seen as other studies are analyzed and compared with this one. The hormone combination of estrogen and progestin that was used in the study consisted of a form of estradiol called Premarin´┐Ż that is derived from the urine of pregnant mares (one of the strongest estrogens) and a synthetic form of progesterone called medroxyprogesterone (progestin). The combination is sold under the name Prempro´┐Ż.

Increased risk of breast cancer is not the only danger associated with use of 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 postmenopausal women. After adjusting for other risk factors, women who used estrogen for 6-8 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 8 women, up from 1 in 30 women in 1960. Conventional ERT and estrogen-based oral contraceptives have been used extensively since 1960. Clearly, an alternative is needed to provide the antiaging and health-enhancing benefits of estrogen, while protecting against its cancer-causing and cardiovascular risks.

Why Estrogen Drugs Have a Bad Reputation

Traditionally, the estrogen prescribed by physicians was a synthetic form of estradiol. (Estradiol is a strong estrogen made in the body and it usually falls dramatically during menopause.) However, current belief by innovative doctors is that all of the hormones (the three main estrogens--estradiol, estriol, and estrone--along with progesterone and the androgens testosterone and DHEA) should be balanced in the postmenopausal years to achieve the greatest overall well-being for an individual woman and to keep risks of side effects to a minimum.

It has been hypothesized that the cause of the increased incidence of breast, ovarian, and uterine cancer might be the imbalance of the replaced hormones during menopause. Furthermore, too much estradiol and progestin often were prescribed in the past, because the doses of each were not individualized. This common misdosing was simply the "standard of care" of the day.

Another cause of the increased incidence in cancer could have been due to the fact that most physicians were not taught to follow hormone levels after menopause. Once the diagnosis of menopause was made, the patient was placed on a generous standard dose of estradiol with or without a standard dose of progestin. If symptoms persisted, the doses would be adjusted based on the few available strengths, or a synthetic testosterone would be added to the regimen. However, blood or tissue levels of hormones were not monitored. If they had been, physicians would have been surprised by the large amounts of estrogens that were present in women who were given those standard doses.

The standard starting dose of Premarin was 0.625 mg daily. This dose was adjusted by halving or doubling that amount as determined by patient's symptoms. Finally, most of the hormones previously prescribed were either synthetic or extracted from pregnant mare's urine, rather than a formulation that was bioidentical to the hormones made naturally in the human body. In some instances, estrace, an estradiol made from soybeans, would be prescribed at a starting dose of 0.5 mg.

A newer state-of-the-art method to approach this problem is to prescribe a compounded bioidentical hormone preparation that is either applied topically in the form of a cream, gel, or patch or is delivered sublingually or orally. The goal is to achieve a minimal dose of each hormone to meet a woman's individual needs, based on her hormone levels and her symptoms (how she feels). Sometimes other methods of administration are used, such as an intravaginal cream or suppository or a rectal suppository. Approaches to treatment will be discussed later in this protocol.

Dietary factors must also be considered when considering hormone replacement therapy. For example, a woman who consumes large amounts of soy might have higher serum levels of estrogens and would require less supplemental estrogen, or none at all. Similarly, some women receive sufficient benefits from using soy isoflavone extracts and other natural supplements such as DHEA.

Finally, testing has revealed that a small percentage of women still will continue to make adequate amounts of hormones even in the postmenopausal years, regardless of diet. These women might only need replacement of either estrogen, testosterone, or progesterone, or nothing at all. Hormone status can change with time; therefore, symptoms should be monitored and blood or tissue hormone levels should be checked if symptoms begin to occur.

Dangerous Estrogen Drugs

The most popular estrogen drug in the United States has been Premarin, which--as mentioned earlier--contains estrogens derived from the urine of pregnant mares. Besides the fact that the process of collecting urine from mares is an inhumane procedure, the form of estrogen it produces is one of the most dangerous kinds and is foreign to the human body.

Premarin is a "conjugated" estrogen that nature never intended for the human body. Other popular estrogen drugs are sold under the names Estrace and Estraderm. These estrogen drugs 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 and more recently in the Women's Health Initiative Randomized Controlled Trial (Rossouw et al. 2002), to be discussed later in the protocol, the combination of Provera and Premarin in the standardized doses used in the study may actually increase the risk of estrogen-induced breast cancer and cardiovascular disease (Weiss et al. 2002).

Estrogen and progestin drugs have well-documented side effects that cause many women to avoid using them. In addition to increased risk of cancer, some 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)

In mid-2002, the largest randomized, controlled trial on hormone replacement therapy conducted on healthy women with an intact uterus was halted prematurely. This study was called the Women's Health Initiative (WHI) and was launched by Dr. Bernadine Healy and the National Institutes of Health (NIH). This landmark study was reported in the July 2002 issue of JAMA (Rossouw et al. 2002). The reason the trial was stopped was that it became clear that there was a significant difference between the placebo group and the treatment group receiving Prempro, a one-drug combination containing both conjugated equine estrogen (Premarin) and medroxyprogesterone acetate (Provera).

These differences had to do with the risk of coronary heart disease, stroke, venous thromboembolic (blood clots in the legs) disease, and cancer of the breast. The rate of women experiencing coronary heart disease events (such as a heart attack) was increased by 29% for women taking estrogen plus progestin relative to the placebo group. The rate of women experiencing stroke was 41% higher in women receiving estrogen plus progestin. Women in the estrogen plus progestin group also had a twofold increase in the rate of venous thromboembolism as well as deep vein thrombosis and pulmonary embolism individually (Rossouw et al. 2002).

Although previous studies of estrogen and/or progestin combinations suggested that Premarin can protect against coronary heart disease, these studies usually reported results from less than 10 years of combination therapy. In the WHI study, which was halted after 5 1/2 years, the numbers indicate that the risk of developing coronary heart disease and pulmonary embolism clearly begins within the first year of use and continues for at least 5 years. In contrast, the risk of stroke and invasive breast cancer rises only significantly after 3-5 years of medicating with these synthetic hormones.

The WHI study is significant in that it involves a large number of women who were randomized from the beginning into the two groups. The study also reported that there was a reduction in osteoporotic fractures by about 25%. The authors of the study reported:

Results from the WHI indicate that the combined postmenopausal hormones CEE [Conjugated Equine Estrogen - Premarin], 0.625 mg/d, plus MPA [medroxyprogesterone - Provera] should not be initiated or continued for the primary prevention of CHD [coronary heart disease]. In addition, the substantial risks for cardiovascular disease and breast cancer must be weighed against the benefit for fracture [reduction] in selecting for available agents to prevent osteoporosis (Rossouw et al. 2002).

In another study in the same issue of JAMA, a strong association between estrogen-only therapy and ovarian cancer was reported, especially in those who have taken the replacement hormone for more than 10 years (Lacey et al. 2002).

Considering these latest developments in the research of hormone replacement therapy, what is our advice to women who are already taking Premarin and Provera? Visit your physician and try to find another means of controlling menopausal symptoms such as some of those suggested later in this protocol.

Why Women Still Choose Synthetic Estrogen

Despite unpleasant and sometimes lethal side effects, many women use estrogen drugs because of the ability of estrogen to reduce the unwanted effects of menopause and for the anti-aging properties of estrogen. Estrogens are steroid hormones that promote youthful cell division in target organs of the body. In women, 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 (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 from Alzheimer's disease (Resnick et al. 1997; DeGregorio et al. 1998)
  • Enhanced immune function
  • Greater feeling of well-being

The benefits of estrogen 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? One alternative to potent hormone drugs is natural estrogen supplements produced from plant sources. These safe 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 shown to reduce hot flashes and protect against age-related diseases such as osteoporosis, heart disease, and cancer (Vincent et al. 2000). Additional plant-derived extracts that help alleviate menopausal symptoms such as depression, anxiety, insomnia, and vaginal atrophy must be looked at as well.

Natural Dietary Approaches to Menopause

  • Soy Estrogens
  • Phytoestrogens Prevent Osteoporosis
  • Benefits of Soy Estrogens
  • Soy Estrogens Are Readily Available

Before we go into the specifics of natural hormone replacement, it is important to understand that natural hormones or hormone analogues by their nature are 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. Significant in the Oriental diet are the large amount of soybean products consumed and the low intake of fat. It is likely that both of these factors, and probably others that we do not know about yet, have given rise to a very low incidence of menopausal disorders in that part of the world.

Hormones are messengers, carrying a signal 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 (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, e.g., in 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 the 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 does not fit in the lock and the door will not open. Being certain that we take in a good balance of saturated and unsaturated fats (which include omega-3 oils) and eliminate trans fats will go a long way toward ensuring 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, active estrogen may be circulating unnecessarily. Any chronic digestive or liver condition and indeed any imbalance of 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 other healthy diet, it should be moderate in protein and complex carbohydrates, with 15-20% of the calories coming from fat. Saturated fat from animal products should be low, and unsaturated fats should come from cold water fish (e.g., salmon, tuna, mackerel, and herring), with a good portion of the diet containing fresh fruits and vegetables. Keeping the bowel bacteria in balance by taking probiotics such as Lactobacillus acidophilus on a regular basis is also recommended.

Soy Estrogens Versus 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 to be about 50 mg a day. On the other hand, the typical Western diet provides only 1-5 mg a day of the soy isoflavones that may protect against several forms of cancer.

At a conference in Brussels, Belgium (September 15 to 17, 1996), entitled "The Role of Soy in Medicine," numerous clinical studies were presented, showing that soy phytoestrogens in doses ranging from 40-160 mg a day produced rapid and significant reductions in menopausal symptoms. Other studies presented at this conference also reported that in countries where soy is a major constituent of the diet, women do not experience uncomfortable menopausal symptoms in the way Western women do (Ostman 1997). This data indicates that soy phyto-estrogens may be safe(r) and almost as effective as FDA-approved estrogen drugs.

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 daily 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/day will increase bone mass and will lower low-density cholesterol and triglycerides (Wagner et al. 1997; St. Germain et al. 2001), but will 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 that 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 of 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 soy protein containing phytoestrogens or milk-derived protein that contained no phytoestrogens. The soy protein group was divided into two groups, which were given two different concentrations of phytoestrogens. The results showed significant increases in bone density and bone mineral content of the lumbar spine in the women receiving the higher dose of phytoestrogens derived from soy protein diets (which provided 2.25 mg of isoflavones) compared to the group receiving casein- (milk) derived protein, which demonstrated no increase in bone density. 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 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 noncognitive effects of menopause (Somekawa et. al. 2001). It is important to note that these studies have suggested that an adequate amount of soy must be consumed in order to have any impact on bone density and that soy may not be sufficient on its own to improve bone density of skeletal structures such as the hip, an important bone to protect against fractures in the elderly. Additionally, the long-term effect of soy on bone density has not been established. Women who are at high risk for osteoporosis should not rely only on soy phytoestrogens to maintain their bone density. (Refer to the Osteoporosis protocol for complete information about maintaining healthy bone integrity.)

More Benefits of Soy Estrogens

The widespread use of insecticides, fungicides, chemicals used in manufacturing, and chlorine-based substances that mimic and mutate estrogen might be a major cause of the breast cancer epidemic. 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 residues 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 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).

Considering the increased risk of breast cancer and uterine cancer in women using estrogen drugs, one alternative for women might be to include more phytoestrogens in the diet, such as soy-based products containing isoflavones, daidzein, or genistein, which have been shown to protect against breast cancer, uterine cancer, and cardiovascular disease (Hawrylewicz et al. 1995; Goodman et al. 1997; Anthony et al. 1998; Cline et al. 1998). The amount of soy isoflavones needed to provide positive hormonal effects is approximately 40-60 mg/day. Just 4 oz/day of a fermented soy product such as tofu or tempe will provide this. Fermented soy product is preferred over other soy food preparations because it is more easily digested and absorbed. If soy food products do not appeal to your palate, soy isoflavones and soy protein concentrate can also be taken as a supplement in capsule form.

In a study using Cynomolgus female monkeys with 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 with soy and E2 (beta-estradiol), such that animals consuming soy protein and E2 had the least arterial cholesterol ester content. These results suggest that ERT combined with dietary soybean protein has beneficial effects on cardiovascular risk factors (Wagner et al. 1997). Life Extension believes that additional agents (discussed later in this protocol) are needed to protect against the increase in cardiovascular risk caused by estrogen drugs.

In another study with male and female Cynomolgus monkeys, it was shown that isoflavone-intact soy protein significantly improved both LDL and HDL cholesterol. Compared to the other substances tested, it also showed 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). However, this 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 has been difficult and expensive in the past to obtain the amount of genistein and other soy isoflavones that scientists say might treat menopausal symptoms.

In October 1997, a soy extract concentrate was introduced that contained enough phytoestrogens from soy to provide 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 that observed in people on Asian diets.

Continued . . .

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