Bioidentical Hormones:
Why Are They Still Controversial?

Estriol and Uterine Cancer

The increased risk of uterine cancer in users of non-bioidentical estrogen is well-established in the scientific literature.85-87 In contrast, the use of topical lower-potency estriol is not associated with an increased risk of uterine cancer.88 Other studies have demonstrated that the use of intravaginal estriol has low risk. A review of 12 studies determined that the use of intravaginal estriol did not result in endometrial proliferation (abnormal overgrowth of the cells lining the uterus with the potential to become cancerous). The authors of the study concluded that “single daily treatment with intravaginal estriol in the recommended doses in postmenopausal women is safe and without an increased risk of endometrial proliferation or hyperplasia.”89

Although several studies suggest that the oral route of administration of estriol appears relatively safe over the short term (e.g., less than five years), topical application is preferred for long-term use. For example, one study found an increased risk of endometrial atypical hyperplasia and endometrial cancer with oral use of estriol, but not with topically applied estriol over a five-year period. Compared with individuals who did not take estriol, those who took oral estriol for at least five years had a significantly greater risk of uterine cancer.88 Women using topical estriol for at least five years did not have any increased risk.88 As you will read in the “Safety” box, several studies suggest that the use of topical bioidentical progesterone cream may further reduce the risk to the endometrium.90-92

Safety Concerns

Most of the research cited in this article used oral estrogen as the route of administration. For enhanced safety, topical estriol would be a better choice. Several studies have shown that transdermal and transmucosal estrogen confers fewer health risks than oral estrogen.88,93-96 Clinical experience of many doctors over the past 20-30 years suggests that transdermal and transmucosal estrogen is also more effective for some women’s symptoms.97 One reason for this difference is the ‘first-pass effect’—meaning that orally ingested drugs are often first metabolized in the liver, before having any activity in the body. Orally ingested estrogen hormones are among these drugs that are first metabolized in the liver before exerting their effects in the body. Physicians experienced in hormone replacement often observe that women treated with oral estrogens show high levels of estrogen metabolites in 24-hour urine specimens, suggesting that most of the orally ingested hormones are metabolized and then excreted.64,98

In addition, several studies suggest that bioidentical estrogen has fewer health risks when given with low doses of bioidentical progesterone.99,100

Bioidentical Progesterone and Cardiovascular Health

The Women’s Health Initiative, a large randomized clinical trial, demonstrated that the addition of non-bioidentical progestins to non-bioidentical estrogen therapy resulted in a substantial increase in the risk of heart attack and stroke.1,26 Numerous studies, on the other hand, document that bioidentical progesterone has beneficial effects on cardiovascular health. In one trial published in the Journal of the American College of Cardiology, researchers studied postmenopausal women with a history of heart attack or coronary artery disease. The women were given estrogen in combination with either bioidentical progesterone or non-bioidentical progestin. After 10 days of treatment the women underwent exercise treadmill tests. Compared to the non-bioidentical progestin group, the amount of time it took to produce myocardial ischemia (reduced blood flow to the heart) on the exercise treadmill was substantially improved in the bioidentical progesterone group.131

The risk of a blood clot is a serious concern with the use of unnatural estrogen replacement therapy, especially by the oral route. This risk doesn’t occur when bioidentical progesterone is added to the mix. One investigation compared the risk of blood clots in postmenopausal women taking bioidentical progesterone to the risk in women taking non-bioidentical progestin. The group of women who used non-bioidentical progestin in combination with estrogen had a startling 290% greater risk of blood clots, compared to the group who never used HRT. In a reversal of fortunes, the group receiving bioidentical progesterone in combination with estrogen had a 30% decreased risk of blood clots, compared to women who never used HRT.132

Atherosclerosis (hardening of the arteries) is the leading cause of heart disease. Several studies have determined that non-bioidentical progestin promotes the formation of atherosclerosis.133-135 The story is quite different for bioidentical progesterone, where multiple animal studies have shown that bioidentical progesterone inhibits the process of atherosclerosis.135-137 To illustrate, scientists fed postmenopausal monkeys a diet which is known to cause atherosclerosis for 30 months. The scientists then divided the monkeys into groups that received estrogen alone, estrogen plus non-bioidentical progestin, or a control group that did not receive hormones. The control group developed substantial atherosclerotic plaque. The administration of estrogen resulted in a 72% decrease in atherosclerotic plaque, compared to the control group. Treatment with non-bioidentical progestin yielded disturbing results. The group that received estrogen combined with non-bioidentical progestin had a similar amount of atherosclerotic plaque as the control group, meaning that non-bioidentical progestin completely reversed estrogen’s inhibitory effects on the formation of atherosclerosis.135 In contrast, when the same investigators administered bioidentical progesterone along with estrogen, no such inhibition of estrogen’s cardiovascular benefit was seen.138

Is Cancer Risk a Reason to Deprive Aging Women of Natural Hormones?

Concern about cancer is an important reason why more aging women do not restore their hormones to more youthful levels. Hormones like estrogen and testosterone affect cell growth and proliferation. Does that mean aging women should simply accept the sex hormone deficiencies they face as a part of “normal” aging? Based on the data suggesting beneficial effects upon cell growth and maturation, as well as favorable ways to affect estrogen metabolism that point to cancer prevention (by consuming generous amounts of cruciferous vegetables like kale and broccoli, for example), restoring hormones to more youthful levels appears to be an important strategy that should not be ignored. As we describe later in this article, large human population studies show major reductions in cancer risk and often specific protective mechanisms against hormone-responsive cancers like breast and prostate cancer when vitamin D,101-103 cruciferous vegetables,104-112 (a source of indole-3-carbinol, or I3C), soy,113-117 D-glucarate,118-121 and lignans122,123 are consumed. Dramatic cancer rate reductions also occur when red meat, high-fat dairy, and other deleterious foods are reduced or eliminated from the diet.124,125 Misconceptions generated by misinterpreted studies and associated media hype have created an environment in which aging people suffer the agonies caused by sex hormone imbalances, yet do nothing to correct this because of fear of cancer. When one looks at what the real cancer risk factors are, it would appear that altering one’s lifestyle at any age—including properly restoring natural hormone balance to reflect a more youthful range—would result in significant reductions in malignant disease. The Real Cause of Breast Cancer To fully understand the carcinogenic effects of aging, we have reprinted a chart showing women’s breast cancer risk by age.126 A quick look at this chart clearly documents that aging is a primary cause of breast cancer, not hormones like estrogen. If estrogen caused breast cancer, then we would expect to see very high rates of breast cancer in young women of childbearing age, with a dramatic decrease in breast cancer after menopause. This is not observed. The good news is that many of the gene expression changes involved in the development of breast and other cancers can be favorably altered by taking low-cost nutrients like vitamin D103,127,128 in the dose of 1,000 IU to 10,000 IU/day, based on individual response. Risk of Developing Breast Cancer by Age126 By age 25: 1 in 19,608 By age 30: 1 in 2,525 By age 40: 1 in 217 By age 45: 1 in 93 By age 50: 1 in 50 By age 55: 1 in 33 By age 60: 1 in 24 By age 65: 1 in 17 By age 70: 1 in 14 By age 75: 1 in 11 By age 80: 1 in 10 By age 85: 1 in 9 Why Young Women with High Estrogen Seldom Develop Breast Cancer During women’s younger years, when breast cancer risk is relatively low compared with advancing age, they enjoy high levels of sex hormones (estrogen, progesterone, dehydroepiandrosterone, and testosterone). As they age and hormone levels decline, breast cancer risk increases. The reason cancer risk increases with “aging” is that the genes in cells that help regulate healthy cell growth can mutate and directly cause cancer. In fact, mutations in cells’ regulatory genes are an underlying cause of cancer.129 It is encouraging to know that there are low-cost nutrients that favorably restore healthy gene function and reduce cancer risk in the process. One study cites evidence that vitamin D can exert its cancer-preventing effect by counteracting the growth-promoting effect of estrogens.130 Vitamin D also exerts its cancer-preventive influence by helping to control cell differentiation and inducing normal programmed cell disposal (apoptosis).130 Strategies to protect against breast and other cancers can easily be incorporated into a woman’s lifestyle. We provide a more complete description of what all women (whether or not they choose to take estrogen) should do to reduce their risk of developing breast and other cancers later in this article. Visit www.lef.org

Bioidentical Progesterone and HDL

High-density lipoprotein (HDL) functions to remove cholesterol from the arterial wall and thus helps protect against the development of atherosclerosis.139 Low HDL is a proven risk factor that contributes to heart disease. Non-bioidentical progestin is known to cause reductions in HDL levels.140-145 One mechanism by which bioidentical progesterone enhances cardiovascular health is its ability to maintain or even increase HDL levels in women receiving estrogen replacement therapy.141,142,146-148 In one study published in the Journal of the American Medical Association, 875 postmenopausal women were randomized to receive estrogen alone, estrogen combined with non-bioidentical progestin, estrogen combined with bioidentical progesterone, or placebo. The results demonstrated that the group receiving bioidentical progesterone experienced significantly higher HDL levels than the group receiving non-bioidentical progestin.141 These results confirm earlier preliminary data provided by researchers who administered estrogen combined with either non-bioidentical progestin or bioidentical progesterone to postmenopausal women. The use of non-bioidentical progestin resulted in an undesirable 15% decrease in HDL levels, whereas there was no decrease in HDL levels in those patients prescribed bioidentical progesterone.142

Estriol and Cardiovascular Health

Growing evidence suggests that estriol may offer benefits to the cardiovascular system. For instance, Japanese scientists found that a group of menopausal women given 2 mg/day oral estriol for 12 months had a significant decrease in both systolic and diastolic blood pressure.149 Another study compared the use of oral estriol at a dose of 2 mg/day for 10 months in 20 postmenopausal and 29 elderly women. Some of the elderly women had decreases in total cholesterol and triglycerides and an increase in beneficial HDL.150

To examine the effects of estriol on atherosclerosis, researchers conducted an experiment in which female rabbits were fed a high cholesterol diet with or without supplemental estriol. The rabbits had their ovaries removed surgically to mimic menopause. Remarkably, the group receiving estriol had 75% less atherosclerosis than the group fed the high cholesterol diet alone (without estriol).151