~ The Estrogen Dilemma

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® 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®.

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 post-menopausal 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 anti-aging 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 post-menopausal 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 and cruel 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 ovar-ian 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.

The proper intake of hormone-modulating plant extracts, phytoestrogens, DHEA, natural progesterone, and other natural hormones may provide significant health benefits.

A woman approaching menopause or postmenopause should consult her physician before commencing any hormone replacement therapy program. The following nutrients, drugs, and blood tests can be taken to restore hormone balance:

1. ProFem (natural progesterone cream): Apply topically to the skin (follow directions as outlined in this protocol).

2. Natural Estrogen (multi-ingredient phytoestrogen formula containing soy isoflavones, black cohosh, licorice root extract, Dong Quai, and vitex extract): Take one capsule, two times daily.

3. DHEA: Take one 15-mg or one 25-mg capsule daily in the morning on an empty stomach. Some women may require 50 mg each morning. Refer to the DHEA Replacement Therapy protocol for specific information.

4. Mega Soy extract: Take one 135-mg (40% isoflavones) capsule twice daily. This is not required if Natural Estrogen is taken.

5. Melatonin: Take 300 mcg to 6 mg only at bedtime.

6. Indole-3-carbinol (I3C): Take 200 mg, twice daily. Women weighing over 180 pounds require higher amounts.

7. Vitamin E: Take 400 IU daily along with a supplement that provides at least 200 mg of gamma tocopherol.

8. Vitamin C: Take 2.5-6 grams daily as a prophylactic dosage.

9. Vitamin D3: Take 400-1500 IU daily.

10. Vitamin B complex (including folic acid): Take three capsules of Life Extension's Complete B Complex daily in divided doses.

11. Alpha lipoic acid: Take two 250-mg capsules early in the day.

12. Calcium: Take 1000 mg daily; magnesium: take 400 mg daily in a combined dose to prevent bone loss.

13. Ipriflavone may be considered to prevent bone loss in a dose of 200 mg, 3 times daily.

14. CoQ10: Take 100-300 mg daily (those over 40).

15. Essential fatty acids help to maintain eicosanoid balance and healthy hormonal receptor sites. Omega-3 and omega-6 essential fatty acids from cold water fish and plant derivatives should be considered as follows:

* Omega-6 fatty acids providing at least 900 mg daily of gamma linolenic acid may be obtained from borage oil or evening primrose oil.

* Omega-3 fatty acids may be obtained from perilla oil, 6000 mg daily, or flaxseed oil, 6000 mg daily. Super EPA contains an omega-3 formulation rich in EPA and DHA from fish oil concentrate. Four 1400-mg capsules provide 1600 mg of EPA and 1200 mg of DHA.

17. Consider estriol, Bi-est, or Tri-Est drugs if menopausal symptoms are not alleviated by nonprescription therapies. Blood or saliva testing may also indicate the need for additional estrogen or proges-terone. Blood or saliva testing after 60-90 days is mandatory to verify that you are taking the proper dosages. These drugs are available from compounding pharmacies, but require a physician prescription.

18. Blood, saliva, or 24-hour urine tests can evaluate a woman's need for modulation of hormones such as estrogen, progesterone, testosterone, DHEA, etc. Testing can greatly assist a knowledgeable physician in balancing a woman's hormone profile. These tests can be ordered by calling 1-800-208-3444.

19. The 2/16a Estrogen Metabolite Ratio urine test measures the ratio of 2-hydroxy- to 16-hydroxyestrone (2/16). Only one urine specimen is required and the results come with an interpretation, such as consuming indole-3-carbinol and eating more cruciferous vegetables if levels of the bad estrogen metabolite (16a-hydroxyestrone) are too high or if levels of the good estrogen metabolite (2-hydroxyestrone) are too low. The optimal time to measure the 2/16a ratio is in the follicular or preovulatory phase of the menstrual cycle (Bradlow et al. 1995a,b, 1996) To inquire about this simple urine test, call (800) 208-3444.

Editor's note: Significant portions of this were contributed by Michele Morrow, D.O., F.A.A.F.P. and Edward Leyton, M.D.

For more information, contact the National Institute on Aging, (800) 222-2225.

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