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Life Extension Magazine October 2009
Reports

Bioidentical Hormones:
Why Are They Still Controversial?

White Paper Authored by the Life Extension Foundation® www.lef.org

How Bioidentical Estrogen-Progesterone Is Prescribed

Currently, widespread commercial availability of individually tailored bioidentical hormone prescriptions is lacking. As a result, many physicians utilize compounding pharmacies to dispense bioidentical hormone prescriptions for their patients. To obtain the phone number of a compounding pharmacist, call 1-866-864-3027.

Most practitioners use the level of estradiol in women’s blood, along with an assessment of the patient’s clinical symptoms to prescribe the initial dose of bioidentical estrogen. The estradiol blood level must be considered in context to the other hormones such as progesterone. A health care practitioner may also measure levels of estrone and estriol to obtain a more comprehensive assessment of a woman’s estrogen status.

In menopause, a woman typically has an estradiol blood level of 0-19 pg/mL. With the use of bioidentical estrogen topical cream (e.g., compounded estriol and estradiol), the blood estradiol level may go to 100 pg/mL or higher, which indicates to the prescribing doctor that the compounded estrogen formula is being absorbed and has increased the patient’s estradiol level to a more youthful range.

If the patient reports that her menopausal symptoms have resolved, most practitioners would continue the patient on the current program and conduct periodic follow-up.

If, however, the patient is still having symptoms, the bioidentical estrogen topical cream dose can be increased or additional tests ordered such as the total estrogen blood test or a urinary estrogen test to assess other estrogens and their associated metabolites. Based on findings from these tests, a more precise dose of estriol, estradiol, progesterone, and sometimes testosterone can be prescribed. A typical starting dose for bioidentical estrogen topical cream might read as:

How Bioidentical Estrogen-Progesterone Is Prescribed
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Please note that this is a general suggestion for an initial prescription. A physician experienced in bioidentical hormone replacement will tailor the prescription to the person’s individual needs.

The bioidentical estrogen topical cream dose can be increased when severe symptoms of estrogen deficiency are present.

Women given estrogen replacement should also be prescribed natural progesterone (in contrast to synthetic progestin drugs like Provera®) in a dose that achieves a youthful balance. Natural progesterone produces many benefits when properly balanced with estrogen. The typical dose for topical progesterone cream may vary between 50-200 mg, depending upon a woman’s unique, individual biochemical needs.

A typical starting dose for over-the-counter (OTC) progesterone cream is one-quarter teaspoon of a 2.5% strength progesterone cream applied to a different part of the body twice each day:

  • Premenstrual and perimenopausal women: 1/4 tsp. of a 2.5% progesterone topical cream (approximately 30 mg. natural progesterone) twice daily starting on day 12 of the menstrual cycle continuing up to day 28).
  • Menopausal women: 1/4 tsp. twice daily for 21 days followed by 7 days off.

The dose can be adjusted up or down depending on a woman’s symptoms and her response to treatment. If using natural progesterone cream from a pharmacy, a prescription could be written as follows for a postmenopausal woman:

How Bioidentical Estrogen-Progesterone Is Prescribed
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A prescription for a premenopausal woman could also read:

Testing Hormone Metabolites in the Urine
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Some physicians will prescribe topical progesterone in a similar way to estrogens, in milligrams per fraction of a cubic centimeter (cc).These dosages are “pressed out” of a syringe onto the skin, and have the dual advantages of more precise dosage adjustment and smaller volume of “crème,” which is less likely to make a mess on clothing.

A blood level target to strive for in aging women might be:

  • Estradiol 90-250 pg/mL
  • Progesterone 2.0-6.0 ng/mL
  • Free testosterone 1.0-2.2 pg/mL

Before a prescription for bioidentical hormones can be written, it is important to have a baseline blood test so the doctor knows what dose of bioidentical estrogens, progesterone, and possibly testosterone may be needed. To order a comprehensive Female Blood Test Panel that includes estradiol, progesterone, and free testosterone, call 1-866-864-3027.

Although this paper focuses on bioidentical estrogen and progesterone, it is important to also address testosterone levels in order to achieve optimal hormonal balance. Although testosterone is thought of as a male hormone, it plays an important role in women’s health as well. Testosterone levels decrease in women as they age. Low testosterone in women can have a negative impact upon sex drive, mood and well-being, bone and muscle mass, and cardiovascular health.180-183 A physician experienced in bioidentical hormone therapy will measure testosterone levels in women, and prescribe bioidentical testosterone if levels are low. Correcting low testosterone in women usually requires a 150 to 300 mcg patch or an individually prescribed testosterone cream.184 Since DHEA (dehydroepiandrosterone) can convert to testosterone in a woman’s body, a woman with low testosterone might be able to increase her testosterone level by taking 15 mg to 25 mg a day of DHEA, which is available as a low cost dietary supplement.185

Too much free testosterone in an aging woman induces abdominal weight gain,186,187 as does a deficiency of estradiol.188-191 Progesterone may be weight-neutral,192 though some complementary practitioners claim it helps facilitate weight loss. Some doctors seek to increase progesterone levels up to 15 ng/mL.

The overall objective is to achieve a more youthful hormone balance to improve the patient’s appearance, state of health, and well-being. The use of estrogen drugs is contraindicated in women with existing estrogen receptor-positive cancer.

Testing Hormone Metabolites in the Urine

Some physicians prefer to follow their initial bioidentical hormone prescription with a comprehensive hormone analysis performed on a urine specimen collected over 24 hours. This much more complete evaluation allows not only evaluation of the levels of the hormones in the prescription, but also whether the patient metabolizes the hormones into other estrogen metabolites as safely as possible.

This follow-up automatically measures two ratios important to assessment of estrogen-related cancer risk: the “2/16 hydroxyestrogen ratio,”110,193,194 and the estrogen quotient, or “ EQ,” which is a mathematical calculation of estriol/estrogen+estradiol. The follow-up also includes levels of 2-methoxyestradiol, an estrogen with potent anti-carcinogenic potential, and 4-hydroxyestrone, an estrogen metabolite with strong pro-carcinogenic tendencies. With this comprehensive evaluation, your physician can more precisely recommend appropriate vitamins, minerals, and botanicals to correct your estrogen metabolism profile if necessary to optimize the safety of hormone therapy. (A more in-depth explanation of the 2/16 hydroxy-estrogen test appears later in this paper.)

The comprehensive hormone evaluation also includes measurement of testosterone, DHEA, progesterone, and some of their metabolites, once again checking for both hormone levels and “hormone safety.” Cortisol, cortisone, aldosterone, and other important natural steroids and some of their metabolites are measured as well. To obtain information about this 24-hour comprehensive urine test, call 1-866-864-3027 or visit www.lef.org.

Why Skeptics Are Still Concerned About Estriol

Based on what you have read so far, topical estriol appears to be a safe and optimal antidote to correct estrogen deficits. Not everyone agrees, however.

Some doctors are concerned that the long-term use of estriol might increase cancer risk. These doctors seem unaware of the evidence indicating that estriol may reduce breast cancer incidence, or of documented methods to protect against estrogen-induced side effects.

Bioidentical Progesterone vs. non-bioidentical Progestin for the Treatment of Menopausal Symptoms

Unlike cynics who view any form of estrogen as a carcinogen, the Life Extension Foundation® has examined the published studies to ascertain what real risks may exist when supplementing with estriol (and other estrogens).

One concern about all estrogens is that they undergo alterations in the body that can result in these estrogens cascading into either pro-carcinogenic or anti-carcinogenic compounds. The good news is that one can affect whether estrogens increase or decrease cancer risk via their diet and/or supplement intake.

Skeptics view estriol supplementation in a vacuum, as if women will take estriol and do nothing else. You have already read extensive documentation about how natural progesterone significantly protects against estrogen-induced cancers. What you will read next is what all women should do to reduce breast and other cancer risk (whether or not they take supplemental estrogen).

These recommendations are based on large human population studies showing huge reductions in cancer risk and specific protective mechanisms against estrogen’s negative pathways when vitamin D, cruciferous vegetables, soy, D-glucarate, and/or plant lignans are consumed. These cancer rate reductions also occur when red meat, high-fat dairy, and other deleterious foods are reduced or eliminated from the diet.

Anticancer Nutrients That Complement Bioidentical HRT

Critical Importance of Vitamin D

Young women (under age 30) almost never develop breast cancer. As women age, their cell growth-regulatory genes accumulate mutations. As our bodies age, we become less proficient at rapidly repairing (or removing) damage to the cells and tissues of our bodies. When genes that regulate cell division undergo mutation, the result can be uncontrolled cell propagation that results in tumor formation. Aging women experience a dramatic rise in cancer incidence, even as their estrogen levels plummet.

In the presence of changes to genes involved in the growth and proliferation of breast tissue cells, estrogen can promote cancer cell propagation. The good news is that the ingestion of vitamin D, cruciferous vegetables, and other compounds can prevent and help repair gene mutations and thus reduce cancer risk. All women (including those who maintain youthful estrogen levels) should make sure they are ingesting optimal amounts of vitamin D and other compounds that favorably alter gene expression.

How Bioidentical Estrogen-Progesterone Is Prescribed

Vitamin D confers significant protective effects against breast cancer. Laboratory studies have shown that vitamin D suppresses growth of breast cancer by 1) blocking signals that stimulate cancer cell growth, 2) by enhancing signals that inhibit cancer cell growth, and 3) by favorably altering gene regulators of the cell cycle.195-198 This three-pronged effect of vitamin D can prevent mutated cells from becoming malignant and even induce cancer cell death (apoptosis).

Studies have found a strong correlation between blood levels of vitamin D and the risk of breast cancer. A case-control study comparing 1,394 postmenopausal breast cancer patients with 1,365 controls showed that low blood levels of vitamin D were significantly related to breast cancer risk. In fact, women with the highest levels of vitamin D had a nearly 70% reduction in their risk of breast cancer, compared to women with the lowest vitamin D levels.199

Similar research examining the relationship between blood levels of vitamin D and breast cancer risk revealed that women with blood vitamin D levels of approximately 52 ng/mL had a 50% lower risk of breast cancer compared with women who had vitamin D levels below 13 ng/mL.101

In a one report, the effects of administering 1,100 IU a day of vitamin D (with calcium) was evaluated in 1,180 postmenopausal women.127 After only four years, the risk of developing any cancer was 60% lower in the vitamin D (and calcium) group, compared with those who received calcium only. The scientists then performed a more detailed analysis of the data. When excluding cancers diagnosed in the first year of the study, which would have included pre-existing cancers present at the time participants began taking vitamin D, they found an astounding 77% reduction in cancer incidence in the group receiving vitamin D, compared with placebo.

Ensuring vitamin D blood levels over 50 ng/mL is a critical step in reducing cancer risk. Life Extension® is finding that many people require 5,000 IU a day of supplemental vitamin D3 and higher to achieve these optimal blood levels. These doses have been shown to be both effective and safe in human trials.200,201 The heavier one is, the more supplemental vitamin D they often require. (Note that vitamin D status in the body is measured as serum 25-hydroxyvitamin D.)

Cruciferous Vegetables Protect Against Tumor-Proliferating Estrogen Metabolites

Scientists have identified compounds in cruciferous vegetables (broccoli, cauliflower, Brussels sprouts, cabbage, kale) that specifically neutralize dangerous breakdown products of estrogen that promote cancer growth.104,202 Cruciferous vegetable compounds also help neutralize the many carcinogens we are inevitably exposed to each day.106-109,203 One of the best-studied cruciferous vegetable compounds is called indole-3-carbinol (I3C). Women seeking to restore youthful hormone balance should make sure to obtain enough I3C from their diet or by taking standardized supplements. The reason for this is that I3C increases levels of a cancer-protective estrogen metabolite (2-hydroxyestrone), while suppressing a dangerous estrogen metabolite (16-alpha-hydroxyestrone) that promotes breast and other cancers.193,194

To emphasize the critical importance of indole-3-carbinol (I3C), please understand that aging women still produce estrogen. All the estrogen in women’s bodies (both endogenously produced and supplemental) can follow two primary metabolic pathways in the body. If estrogen is converted to 16-alpha-hydroxyestrone, then the risk of breast and other cancers is increased. If on the other hand, the estrogen is converted to 2-hydroxyestrone, then the risk for breast and other cancers is decreased.204,205

I3C can readily be obtained by eating lots of cruciferous vegetables and/or taking I3C in dietary supplement form.

To confirm the theory that certain estrogen metabolites can contribute to cancer, researchers analyzed data gathered from over 10,000 Italian women over more than five years. The objective was to determine how dietary and hormonal factors influence breast cancer risk. They found that among premenopausal women, higher levels of 2-hydroxyestrone were associated with protection against breast cancer.204 This same finding has been shown in additional studies of different populations.206,207

The toxic estrogen metabolite 16-alpha-hydroxyestrone acts as a breast tumor promoter.110 By contrast, estrogen metabolized via the 2-hydroxyestrone pathway does not exhibit adverse estrogenic activity in breast tissue.110 Additionally, a form of this less active estrogen metabolite is believed to prevent the formation of blood vessels necessary to feed growing cancers, thus helping to arrest tumor growth.208

Cruciferous vegetable compounds (such as I3C) are effective in shifting estrogen metabolism to the more beneficial pathway, thus reducing levels of toxic 16-alpha-hydroxyestrone and increasing levels of protective 2-hydroxyestrone.110-112,205

This beneficial modulation of estrogen is associated with reduced risk of breast and other cancers, including cervical and head and neck cancers.106,204,205 Cruciferous vegetable compounds thus play an important role in fighting cancer. To illustrate, research conducted at the University of California at Berkeley documented that I3C in combination with the anti-estrogenic chemotherapeutic agent tamoxifen inhibited the growth of human breast cancer cells by an astounding 90%.209

Interestingly, an assay study performed at the National Cancer Institute determined that I3C was superior to 80 other natural substances with regard to anti-cancer potential.210

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