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Life Extension Magazine October 2009
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Bioidentical Hormones:
Why Are They Still Controversial?

Bioidentical Hormones

As women enter the menopausal years, they face a difficult decision. Their bodies’ production of estrogen, progesterone, and other hormones needed to maintain youthful vitality rapidly declines.

While individual effects of menopause vary widely, many women suffer because their bodies no longer produce sex hormones at sufficient levels required to optimally sustain critical physiological processes. Depression, irritability, and short-term memory lapses are common menopausal complaints, along with hot flashes, night sweats, insomnia, and weight gain.

Health problems encountered during menopause may adversely affect a woman for the rest of her lifetime in the absence of appropriate hormone replacement. Yet maturing women today are often told by their doctors to limit prolonged use of hormone drugs, only long enough to obtain relief from menopausal symptoms and then no more. Unfortunately, this advice fails to recognize the critical differences between hormone drugs foreign to women’s bodies and hormones identical to those naturally produced by women’s bodies.

The understandable, factual concern espoused by many mainstream doctors is that FDA-approved estrogen-progestin hormone drugs have been shown to increase the risk of cancer and cardiovascular disease. The dilemma facing aging women is that their bodies may still benefit from youthful hormone levels, but many of their doctors say “no.”

There is, in fact, a body of scientific evidence indicating that natural progesterone (as opposed to synthetic progestin drugs) and the natural estriol form of estrogen may help protect against the very diseases caused by unnatural estrogen-progestin drugs that are foreign to the human body.

Mainstream medical practitioners (many of whom prescribed unnatural hormone drugs for decades) and the FDA (which still allows these dangerous unnatural hormones to be sold) are now at the forefront urging aging women to avoid their prolonged use.

Overlooked by mainstream medicine is a plethora of research findings indicating that women may more safely benefit from individualized doses of natural estrogens and progesterone over their lifetime. Almost completely ignored are lifestyle changes (such as assuring optimal vitamin D status and cruciferous vegetable intake) that may prevent and even reverse the kind of damage to cell regulatory genes inflicted by some estrogenic compounds.

In this comprehensive white paper, we present data showing how women may more safely benefit from comprehensive approaches that naturally restore youthful hormone balance, while protecting aging cells against carcinogenic and atherogenic insults.

The Rise and Fall of non-bioidentical Hormone Replacement Therapy

Few topics have attracted as much attention in recent years as hormone replacement therapy (HRT) among postmenopausal women. For decades, physicians were prescribing patented non-bioidentical estrogen and progestin drugs such as Premarin®, Provera®, and Prempro®—to combat the symptoms of menopause. Non-bioidentical hormones are not identical in structure or activity to the hormones naturally produced within the body.

The Rise and Fall of non-bioidentical Hormone Replacement Therapy
Polarised light micrograph of progesterone crystals. Progesterone is derived from pregnenolone.
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Doctors also prescribed non-bioidentical hormones to protect postmenopausal women against osteoporosis and heart disease. The rationale behind heart disease prevention was simple: during their reproductive years, women enjoy lower rates of heart disease than men, supposedly because of the protective effect of estrogen. It seemed only logical to mainstream medicine that by replacing the effect of estrogens lost at menopause with non-bioidentical hormones, women would retain some of their protection against heart disease.

Unfortunately, the logic of non-bioidentical hormone replacement therapy (HRT) turned out to be fatally flawed. In 2002, the results of the Women’s Health Initiative were released early. This landmark study followed more than 16,000 women and assessed the effects of non-bioidentical hormone replacement therapy (HRT), including estrogen-only therapy and therapy that combined non-bioidentical estrogen and progestin. The findings were shocking: the estrogen/progestin arm of the study was terminated early because the non-bioidentical hormone therapy not only failed to protect against heart disease, but was shown to increase the risk of heart attack and breast cancer.1 These alarming findings led a team of researchers to boldly state in the prestigious Journal of the American Medical Association that “…the results indicate that this regimen [non-bioidentical estrogen/progestin] should not be initiated or continued for primary prevention of coronary heart disease.”1

In 2004, the non-bioidentical estrogen-only arm of the study was terminated as well because hormone replacement therapy (HRT) with conjugated equine (horse-derived) estrogen was found to increase the risk of stroke.2 These findings had an immediate impact on the millions of women taking non-bioidentical HRT, of whom up to 50% discontinued their use of non-bioidentical HRT.3

The Bioidentical Hormone Option

The Bioidentical Hormone Option
Molecular model of the hormone progesterone: carbon (blue), hydrogen (gold), and oxygen (red).
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Bioidentical hormones have the same exact molecular structure as the hormones produced naturally within the body. The body does not distinguish between supplemental bioidentical hormones and the hormones produced within the body.4 As a result, bio-identical hormones are properly utilized, and are then able to be naturally metabolized and excreted from the body. The use of bioidentical HRT has increased during the last several years as women have sought out a more natural approach to restoring hormonal balance.

Scientific Evidence Suggests Bioidentical Progesterone Does Not Increase the Risk of Breast Cancer

The well-established body of literature demonstrating the harmful effects of non-bioidentical hormones might lead some women to fear taking bio-identical hormones as well. A review of the published scientific literature indicates those fears are misunderstood and unfounded. For example, thirteen studies document that non-bioidentical progestin significantly increases estrogen-stimulated breast cell replication and growth.5-17 In stark contrast; seven studies have shown that bioidentical progesterone does not induce estrogen-stimulated breast cell proliferation.18-24

Numerous studies have demonstrated an increased risk of breast cancer with the use of non-bioidentical progestins.1, 5, 25-48 However, the use of bioidentical progesterone has not been associated with an increased risk of breast cancer. Quite the contrary, research has revealed that bioidentical progesterone decreases the risk of breast cancer. In a study published in the journal Breast Cancer Research and Treatment, 80,000 postmenopausal women using various forms of HRT were followed for more than 8 years. Women who used estrogen in combination with non-bioidentical progestins had a 69% increased risk of breast cancer, compared to women who had never used HRT. However, for women who used bioidentical progesterone in combination with estrogen, the increased risk of breast cancer was completely eliminated with a significant reduction in breast cancer risk compared with non-bioidentical progestin use.49

In another investigation, these same researchers found a 40% increased risk of breast cancer for women who used estrogen with non-bioidentical progestin. Interestingly, in women who used estrogen combined with bioidentical progesterone, there was a promising trend toward a reduced risk of breast cancer, compared to women who had never used HRT.25 In essence, bioidentical progesterone appeared to protect women against the development of breast cancer. These findings confirm work done six years earlier that found a trend toward a reduced risk of breast cancer in 1,150 women using bioidentical progesterone, compared to non-users of progesterone.50

What You Need to Know: Bioidentical Hormones
  • Non-bioidentical hormones are not identical to the hormones naturally produced within the body. The use of non-bioidentical estrogen and progesterone is associated with the risk of breast cancer, heart attack, and stroke.
  • Bioidentical hormones have the same molecular structure as the hormones produced naturally within the body. The body does not distinguish between supplemental bioidentical hormones and the hormones produced within the body. As a result, bioidentical hormones are properly utilized, and are able to be naturally metabolized and excreted from the body.
  • Studies suggest that bioidentical progesterone is not associated with an increased risk of breast cancer. Current literature indicates the use of bioidentical progesterone is associated with a decreased risk of breast cancer.
  • Three types of estrogen are produced in the body: estriol, estrone, and estradiol. The scientific literature suggests the use of estriol is not associated with an increased risk of breast cancer. While non-bioidentical estrogen replacement therapy is known to increase the risk of uterine cancer, topical estriol is not.
  • Research on bioidentical progesterone has shown beneficial effects on cardiovascular health, including decreasing the risk of blood clots, protecting against atherosclerosis (hardening of the arteries), and maintaining healthy HDL levels.
  • A review of the scientific literature suggests that bioidentical progesterone may be superior to non-bioidentical progesterone in treating menopausal symptoms. Estriol is also highly effective in the treatment of menopausal symptoms.
  • Estriol has been shown to improve bone density, promote youthful skin, and enhance sexual and urinary health.
  • Foods and nutrients with scientific evidence to potentially protect against the development of breast cancer include green tea, soy isoflavones, fish oil, vitamin D, plant lignans, indole-3-carbinol (I3C; found in cruciferous vegetables), and D-glucarate. Visit www.lef.org

Compelling research offers further insight into natural progesterone’s ability to defend against breast cancer. In a fascinating study, scientists administered estrogen alone, bioidentical progesterone alone, estrogen plus bioidentical progesterone, or placebo to 40 women prior to surgery to remove a breast lump. The hormones were applied topically to the breast for about 12 days before surgery. As expected, when given alone, estrogen caused a 62% increase in breast cell proliferation rates compared to placebo. Conversely, the addition of bioidentical progesterone to estrogen resulted in a significant decrease in the estrogen-induced increase in breast cell proliferation rates. Even more impressive was the finding that the group receiving bioidentical progesterone alone had a 66% lower breast cell proliferation rate compared to the placebo group.18

What You Need to Know: Bioidentical Hormones
Hormone replacement therapy (HRT) pills in their dispensers and patch.
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A growing body of literature has documented a strong connection between a woman’s progesterone levels and her subsequent risk for breast cancer. A trial reported in the International Journal of Cancer in 2004 measured blood levels of progesterone in 5,963 premenopausal women. Incredibly, the analysis of the data revealed that those women with the highest blood levels of progesterone levels who had regular menses experienced an 88% decreased risk of breast cancer.51 These findings corroborate another study in which 1,083 women treated for infertility were followed for upwards of 33 years to determine their subsequent breast cancer risk. Compared to women with normal progesterone levels, those deficient in progesterone had a 540% increased risk of premenopausal breast cancer, and were 10 times as likely to die from any cancer.52

Similarly, researchers at the University of North Carolina School of Public Health measured progesterone levels in pregnant women, who were then followed for upwards of 32 years. The researchers discovered that those women with the highest blood levels of progesterone during pregnancy had a promising trend toward a lower risk of breast cancer, compared to women with the lowest levels of progesterone during pregnancy. When the researchers analyzed the risk of breast cancer in women under age 51, those with the highest progesterone levels had a staggering 70% decreased risk compared to the group with the lowest progesterone levels.53

Findings from two other investigations revealed that survival rates for breast cancer are strongly correlated with the patient’s progesterone levels at the time of surgery.54,55 One study noted that 65% of women with a progesterone level of 4.0 ng/mL or more on the day of their surgical treatment of node-positive cancer were alive 18 years later, while only 35% of women with low progesterone levels on the day of surgery were still living after 18 years. The scientists noted that progesterone lowers the expression of vascular endothelial growth factor, which promotes the increase in new blood vessels (angiogenesis) that is essential for tumor growth. These scientists concluded: “This study has confirmed that a raised level of progesterone at the time of tumor excision is associated with an improvement in prognosis for women with operable breast cancer.”55

Estriol and the Risk of Breast Cancer

When discussing estrogen it is important to note that “estrogen” is an umbrella term for many different estrogens including estriol, estrone, and estradiol. All three of these estrogens are produced in the body and have physiological effects. In the past, estriol was believed to have little physiological significance due to its weak estrogenic activity when compared with estrone and estradiol. Nonetheless, research suggests that estriol’s weakness may confer certain beneficial effects in contrast with more potent estrogens.

The benefits of estriol may, in part, be explained by its mixed pro-estrogenic and anti-estrogenic effects. Scientists investigated the mixture of stimulating and non-stimulating effects produced by estriol on estrogen receptors. When estriol is given together with estradiol, the estradiol-specific stimulation to cells is decreased.66 This little-appreciated scientific fact helps to explain how estriol can reduce pro-carcinogenic effects of more powerful estrogens like estradiol. Experimental studies suggest that estriol has a protective effect against radiation-induced cancer of the breast.67

Estriol and the Risk of Breast Cancer

A greater understanding of estriol’s anti-estrogenic activity becomes apparent when examining the differing effects of the three primary estrogens upon estrogen receptor binding activity. There are two distinct estrogen receptors that estrogen hormones bind on breast cells: estrogen receptor alpha and estrogen receptor beta.68-73 The binding of estrogen hormones to estrogen receptor alpha promotes breast cell proliferation, which can lead to breast cancer development. Conversely, the binding of estrogen hormones to estrogen receptor beta inhibits breast cell proliferation and prevents breast cancer development.74-79

Estrone and estradiol bind to and activate estrogen receptor alpha, thereby explaining the known breast cancer-promoting effects of these two hormones.80,81 Estriol, on the other hand, binds to and activates estrogen receptor beta.80,81 This critical fact helps to explain estriol’s anti-estrogen activity, which led a noted researcher in hormone replacement therapy to state: “This unique property of estriol, in contrast to the selective ER [estrogen receptor] alpha binding by other estrogens, imparts to estriol a potential for breast cancer prevention, while other estrogens [estrone and estradiol], would be expected to promote breast cancer… Because of its differing effects on ER alpha and ER beta, we would expect that estriol would be less likely to induce proliferative [potential cancerous growth] changes in breast tissue and to be associated with a reduced risk of breast cancer.”82

A study published in the International Journal of Cancer in 2004 reported on the use of hormone replacement therapy (HRT) and breast cancer incidence in 31,451 postmenopausal women. The analysis of the data determined that women who used estriol did not have an increased risk of breast cancer, compared to women who never used HRT.83 Additional evidence of estriol’s safety was provided by a study that compared use of HRT in 3,345 women over age 50 with breast cancer to 3,454 women without breast cancer. Those women who used non-bioidentical estrogen had a risk of breast cancer that was double that of women who never used HRT. However, women who used low-dose oral or topical estriol did not have an increased risk of breast cancer, compared to women who never used HRT.33

Intriguing research has uncovered that estriol might confer a protective effect against the development of breast cancer. This was demonstrated in an unpublished 35- to 40-year prospective study of 15,000 women who had pregnancies between 1959 and 1967. The women had samples of their blood frozen for 30 years or more. In 1997, the researchers thawed the blood and measured hormone levels to determine the relationship between estriol levels during pregnancy and subsequent incidence of breast cancer. The researchers found that breast cancer risk was reduced by 58% among women with the highest estriol levels compared to those with the lowest estriol levels.84 This study has important implications, as the findings suggest that having optimal estriol levels can play a pivotal role in the prevention of breast cancer.

Natural Progesterone (Bioidentical) Versus Synthetic Progestins (Non-Bioidentical)

In this article, we define natural progesterone as bioidentical progesterone and synthetic progestins as non-bioidentical progestins. It is important that the reader know that non-bioidentical progestin are not the same as bioidentical progesterone.

What Is Natural Progesterone?

Bioidentical natural progesterone is made in the body or made (not extracted) in the laboratory from either soybeans or the Mexican wild yam (Dioscorea villosa). The process was discovered in the 1930s by Pennsylvania State University professor Russell Marker, who transformed diosgenin from wild yams into natural progesterone.56 Natural progesterone refers to bioidentical hormone products that have a molecular structure identical to the hormones our bodies manufacture naturally. One of the most effective forms of bioidentical progesterone is called micronized progesterone. The process of micronization allows for steady and even absorption of the medication.57 Accordingly, both the micronized progesterone and other commercially available progesterone creams contain bioidentical progesterone.

What Are Synthetic Progestins?

Unlike natural progesterone, non-bioidentical synthetic progestins are not molecularly identical to the hormones found naturally in the body. Synthetic progestins were first developed for use as contraceptive agents. Because the half-life of natural progesterone is very short, researchers sought an agent that would produce longer-lasting, more potent effects than natural progesterone. Birth control pills usually contain a synthetic progestin and a synthetic estrogen. Synthetic progestins are very potent, with just a small dose preventing ovulation and thus functioning as birth control. A slight change in the chemical structure of progesterone has allowed pharmaceutical companies to create patentable and highly profitable birth control products.

One of the most common progestins, medroxyprogesterone acetate (Provera®), has been linked to blood clots, fluid retention, acne, rashes, weight gain, depression, certain cancers, and other disorders.58, 59 Non-bioidentical progestins are also able to bind to glucocorticoid, androgen, and mineralocorticoid receptors, which may explain the wide range of adverse side effects many women experience while taking synthetic progestins.60,61 The vast majority of research studies have been conducted using progestins rather than natural progesterone, which helps explain the disparity and negativity of the results.

The FDA has also approved a drug called Prometrium®, an oral pill containing 200 mg of natural micronized progesterone taken daily. Because orally administered progesterone is metabolized by the liver, it may be contraindicated in patients with certain liver conditions. Initial liver metabolism of progesterone (called “first-pass” metabolism) also creates higher levels of certain metabolites of progesterone than transdermal or transmucosally administered progesterone.62

How To Best Administer Natural Progesterone

Natural progesterone cream may be more efficiently used, since lipophilic (fat-soluble) molecules allow it to be better absorbed through the skin. This is called “transdermal” administration. Even better absorption is obtained if the progesterone is rubbed into a mucous membrane surface (inner aspects of labia or intravaginally), called “trans-mucosal” administration. Another advantage of topical natural progesterone cream is that individualized dosing can be easily facilitated by varying the amount of cream applied.63-65

As one can readily discern from the peer-reviewed published literature, adverse side effects are clearly associated with non-bioidentical progestins, whereas several health benefits have been observed with the use of bioidentical progesterone. Visit www.lef.org

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