A Closer Look at Hormones
By Joel Fuhrman, M.D. www.drfuhrman.com
Claims Made For Bio-Identical Hormones Are Not Backed By Facts!
Bio-identical hormones or so-called “natural hormones” are plant-derived hormones that are similar in structure to hormones produced by the body. Because these hormones have low absorption with oral administration, they are frequently formulated as a gel to be applied topically to the skin. They include estradiol, estriol, estrone, and progesterone. Some physicians add DHEA, testosterone, and cortisol to the preparations as well.
The theory is to recreate hormone levels similar to those found in an average young women. Physicians can order customized dosages of each ingredient to meet individual requirements and preferences. Compounding pharmacies are special pharmacies that customize the capsules, creams, and gels to the prescribing doctor’s specification. This customization makes the products relatively more expensive.
There are three types of estrogen: estradiol, estriol and estrone.
Estradiol—Estradiol is the major estrogen in humans. It is produced mostly in the ovaries, but also in the adrenal glands, the testes in males, and by our fat cells. Estradiol is the most potent naturally occurring estrogen. For this reason, it is also the hormone that is potentially the most dangerous for promoting breast cancer and heart disease. Overweight people produce more estradiol. Deactivation and removal from the body is performed by the liver and kidneys. It involves conversion of the estradiol to the less biologically active estrogens, especially estriol. Estriol is more readily excreted by the kidneys.
Compounds derived from eating cruciferous vegetables aid the body’s deactivation of estrogen, lessening the growth-promoting risks to estrogen-sensitive tissues such as the breasts. There is no reason to expect that bioidentical estradiol will be less risky than the estradiol contained in conventional formulas such as Premarin. Premarin, which is derived from the urine of pregnant horses, is mostly estradiol, but it also contains a small amount of the other estrogens. The reason Premarin works so well at relieving women’s menopausal symptoms is because it, too, is almost bioidentical to human estrogen. But, as explained in the previous article, that doesn’t make it safe.
Bio-identical estradiol is available in pill form and as vaginal creams. Estradiol used vaginally for postmenopausal vaginal dryness and urethra and vulva-vaginal atrophy exposes women to lower risk of stimulating breast tissue because it results in lower amounts of total circulating hormones than when it is taken orally.
Estriol—Estriol is produced only in insignificant amounts, except during pregnancy when it is made by the fetal liver. It is sometimes measured during pregnancy as a marker of fetal health. It has been suggested to be less breast cancer carcinogenic compared with the other estrogens, which makes sense because it only has less than one-tenth the estrogen strength as estradiol.
Creams and gels made with estriol can be helpful for menopausal symptoms, although a larger dose is needed to be effective compared with estradiol. Studies that track estrogen levels and estrogen use generally show estradiol as the primary culprit in promoting breast cancer, not estriol. The claim that estriol has no breast cancer-promoting effects does not appear to be accurate; rather, the effects are just milder.
If estriol is going be considered as an estrogen for hormone replacement therapy, it is important to recognize that it can stimulate breast, uterus and other tissues. Its own tissue- stimulating effects are weaker than those of estradiol, but that bit of relative safety may be undermined if the estriol dosage is increased.
Researchers have noted that vaginal use of a daily dose of estriol and estradiol have the same effect if the estriol dose is increased sufficiently. But when the dosage of estriol is increased, there are no clear differences between vaginal estradiol and estriol regarding the effects on vaginal and uterine tissues. The main reason estriol may be a safer estrogen is because it is weaker. It is comparable to using a lower dose of estradiol, but it should not be considered harmless. When you use estriol in amounts large enough to achieve a strength comparable to estradiol, you most likely will get similar negative effects with respect to the stimulation of breast tissue.
A recent case-controlled study confirmed that estriol use was associated with lobular breast cancer.7 If a natural estrogen is absolutely necessary during menopause, then estriol cream or gel is the safest to use, although it still has some risk, especially in women who might be prone to breast cancer. Furthermore, estriol should not be used without also using progesterone. When used alone, estriol has been demonstrated to increase risk of endometrial cancer.8
The “natural estrogen” community publicizes that estriol may actually have protective effects against breast cancer because this “weaker” estrogen can block the cancer-stimulating effects of the more powerful estrogens. Some self-proclaimed “antiaging” doctors test the estriol/estradiol ratio in a patient’s urine or blood and then prescribe additional estriol to create a higher estriol/estradiol ratio than would be typical for the patient’s age. Some doctors test the saliva, but this method is not generally as accurate because hormonal levels vary greatly at various times of the day, and the window when measured may not reflect overall levels throughout the entire day.
Remember that there are still no long-term data on the safety of even weak, exogenously administered estrogens like estriol. The fact that it can be used to decrease symptoms of estrogen deficiency is because estriol binds to estrogen receptors, which can promote breast cancer. As early as 1977, researchers found that the binding effect of estriol was capable of partially overcoming the anti-estrogenic effect of Tamoxifen (an antiestrogen drug) and could stimulate human breast cancer cells. The researchers concluded that “estriol can bind to estrogen receptors and stimulate human breast cancer in tissue culture. Our data do not support an anti-estrogenic role for estriol in human breast cancer.”9
Estrone—Estrone is produced in small amounts and not during pregnancy. Of the three estrogens, estrone is produced the least. Its relevance is that it is held in reserve and can be converted to estradiol when needed. Because of dramatic decline of estradiol after menopause, estrone is the only one of the three estrogens that is naturally present in any significant quantity after menopause. It is generally not as strong an estrogen as estradiol, but stronger than estriol.
Progesterone—Progesterone is the other type of steroid hormone that governs women’s reproductive cycles. It is produced almost exclusively in the ovaries. Progesterone is sometimes called “the hormone of pregnancy,” and it has many roles relating to the development of the fetus. Progesterone thickens the lining of the uterus (endometrium), preparing it to accept the egg for implantation. If pregnancy does not occur, progesterone levels will decrease, leading to menstruation. Normal menstrual bleeding is progesterone withdrawal bleeding.
An additional source of progesterone is milk products. They contain much progesterone because on dairy farms cows are milked during pregnancy, when the progesterone content of the milk is high. After consumption of milk products, the level of bioavailable progesterone goes up. This could be a contributor to certain medical issues in humans and the early development of puberty, which in turn increases rates of breast cancer.
Provera—Provera is a progestin, which is a synthetically produced progesterone. Synthetic progestins have a variety of negative cardiovascular effects.10 They also promote breast cancer, whereas natural progesterone does not.11 Natural progesterones seem advantageous over the older synthetic compounds, and although the use of progesterone as a cream or gel along with estrogen has not been adequately studied to determine full benefits and risks, enough evidence suggests the natural compound is safer than the synthetic (but better absorbed orally) progestins. Natural progesterones are poorly absorbed orally, but are available in creams and gels by compounding pharmacies. Prometrium is a natural progesterone commercially available as a pill. It is mixed with peanut oil for better oral absorption.
Using progesterones with the estrogen component is FDA-approved to reduce the risk of endometrial hyperplasia and subsequent risk of uterine cancer. In other words, when estrogen is used,progesterone should be taken simultaneously or for a prescribed number of days each month to protect against the continual endometrial stimulation that could lead to endometrial cancer. Another advantage is that progesterone has been shown to improve sleep and mood in postmenopausal women.12
Testosterone—Just as men’s bodies manufacture small amounts of estrogen, women’s bodies produce testosterone from the ovaries and adrenal glands. Testosterone is thought to boost both libido and energy and to help maintain muscle and bone mass. Due to the gradual drop in testosterone levels with aging and diminishing levels after menopause, many doctors, especially the anti-aging doctors and bio-identical hormone advocates, add testosterone to women’s postmenopausal formulas.
Many clinicians believe that the diminished energy, decreased sexual desire, and “flatness” of mood that some women experience during and after menopause are directly related to declining levels of testosterone. Oral testosterone lowers “good” HDL cholesterol and raises “bad” LDL cholesterol in the blood, so it may not be heart disease-favorable.
The largest concern with testosterone use is the increased risk of breast cancer. Adding testosterone to the estrogen replacement therapies has been shown to substantially increase the risk of breast cancer.13 The same study reported that women receiving testosterone in their hormonal replacement mix had a 17 percent increased incidence of breast cancer. Overall, long-term studies on the safety of postmenopausal testosterone by women are lacking. I cannot recommend testosterone replacement for women.
DHEA—Dehydroepiandrosterone (DHEA) is the most abundant androgen (male steroid hormone) secreted by the adrenal glands and, to a lesser extent, by the ovaries and testes. DHEA also is converted into other steroid hormones, including testosterone and estrogen.
Considerable interest in DHEA has developed in recent years with reports that it may play a role in the aging process. Its levels peak at age 25 and then steadily decline with age. DHEA levels in 70-year-old individuals tend to be roughly 80 percent lower than those in young adults. DHEA is touted as an anti-aging hormone with profound beneficial effects, and it is available in health food stores without a prescription. Its easy availability may have lots to do with its promotion. But, keep in mind, just because something is produced in higher quantity when we are young does not mean high amounts are beneficial for us when we are older. In fact, the reduction of hormones with aging may be protective in many ways and encourage a longer life span.
Because it is a steroid hormone, DHEA has been shown to be helpful for patients with lupus or MS and possibly other autoimmune diseases to lessen the need for medication. It acts like a natural steroid, so it is not a cure.
Supplementary DHEA, which is available in pill or cream form, can increase testosterone levels by one-and-a-half to two times. So it’s not surprising that DHEA provides many of the same therapeutic benefits, including increased sexual interest and enhanced physical and mental satisfaction. Since DHEA increases testosterone in women, too, there is a risk of developing signs of masculinization (such as loss of hair on the head, deepening of the voice, hair growth on the face, weight gain around the waist, or acne).Also, men should be aware of the risks of excess testosterone (such as shrinkage of the testicles, aggressive tendencies including sexual aggression, male pattern baldness, and high blood pressure).
A large and extensive recent study appears to refute anti-aging claims for DHEA. Researchers from the Mayo Clinic examined the effect of DHEA supplementation on markers of aging such as muscle strength and physical performance. The scientists concluded that men and women age 60 and older who took the hormone for two years showed no measurable improvements in the signs of aging, including body fat, physical performance, insulin sensitivity, and quality of life—despite the fact that their body content of DHEA increased to levels they likely hadn’t seen since their 20s. Researchers concluded that their data provided “no evidence that either DHEA or low-dose testosterone is an effective anti-aging hormone supplement and argue strongly against the use of these agents for this purpose.” The main concern here is that this steroid hormone is still classified as a dietary supplement and sold without regulation or concern. This is a real steroid hormone with just as much risk as estrogen and testosterone. DHEA has been shown to increase risk of breast cancer.14
When taken by mouth, DHEA is rapidly absorbed into the circulation and converted to its storage form DHEA-S. DHEA levels themselves fluctuate widely during the day and from day to day, depending on stress levels and the need to manufacture other hormones. DHEA is stored in a reservoir of DHEA-Sulfate (abbreviated DHEA-S), which remains relatively constant from day to day. DHEA-S blood levels, therefore, reflect the overall adequacy of DHEA. Measurements of DHEA-S in blood are the most reliable indicators of DHEA metabolism.
Other adverse effects of DHEA that have been reported include high blood pressure and reduced high density lipoprotein (HDL or “good”) cholesterol. The International Olympic Committee and the National Football League recently banned the use of DHEA by athletes because its effects are very similar to those of anabolic steroids.
No Absolute Safety
The reality is that no hormone is completely safe. Nevertheless, compounded plant-derived hormones, recently called bio-identical, may have certain benefits and risks comparable to the more commonly prescribed commercial formulas marketed by pharmaceutical companies. Estriol, especially, and natural progesterone seem to be a better choice for postmenopausal hormonal replacement when considering the risks and benefits. However, we must realize that while estriol has the benefits of other estrogens, it also has the risks of other estrogens.
The Endocrine Society’s October 2006 Position Statement says, “...many ‘bio-identical hormone’ formulations are not subject to FDA oversight and can be inconsistent in dose and purity. As a result of unfounded but highly publicized claims, patients have received incomplete or incorrect information regarding the relative safety and efficacy of hormone preparations that are referred to as ‘bio-identical.’” The problem here is that the bio-identical hormone hype found in magazine articles and books and touted by anti-aging physicians clearly has been inaccurate and has led women to mistakenly think that these hormones have no risks.
Every Woman Unique
Menopause affects women differently. Some women have no detectable estrogen and have no hot flashes, and others have high, almost premenopausal levels and have terrible symptoms. The practice of measuring a woman’s hormone levels and custom-compounding a prescription for her to maximize so-called benefits is in direct contradiction to evidence-based guidelines.
Women’s hormone levels change from day to day and even throughout the day. These tests are useful to tell if a women is in menopause or not, but they have not been shown to be useful for adjusting hormone therapy dosages. There is too much scientific uncertainty behind this practice, and the only supported prescribing method is to use the least amount of hormone possible to adequately control symptoms for women who still request the treatment after they have been informed of the potential risks.15 Physicians who prescribe hormonal replacement should be wary of adding testosterone (and DHEA) to the mix, and doctors should strive to prescribe the lowest effective dose of hormone possible when used for women in postmenopausal distress.
We must recognize that hormonal replacement should not be called “anti-aging” medicine. It should not be promoted as having no risks because it actually carries some significant risks, especially for breast cancer. Hormonal replacement increases the risks of some diseases and decreases the risks of others. Unfortunately, the risks exceed the benefits for most women. The risks can be minimized for women who are not at high risk of breast cancer and who are eating a high-nutrient diet, if the therapy is limited to minimal amounts for a minimal amount of time.
1. Rosenberg LU, Magnusson C, Lindström E, et al. Menopausal hormone therapy and other breast cancer risk factors in relation to the risk of different histological subtypes of breast cancer: a case-control study. Breast Cancer Res 2006;8(1):R11.
2. Emons G, Huschmand-Nia A, Krauss T, Hinney B. Hormone replacement therapy and endometrial cancer. Onkologie 2004;27(2):207-10.
3. Lippman M, Monaco ME, Bolan G. Effects of estrone, estradiol, and estriol on hormone-responsive human breast cancer in long-term tissue culture. Cancer Res 1977;37(6):1901-7.
4. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principle results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288(3):321-333.
5. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA 2003;289(24):3243-3253.
6. Fitzpatrick LA, Pace C, Witta B. Comparison of regimens containing oral micronized progesterone of medroxyprogesterone acetate on quality of life in postmenopausal women: a cross-sectional survey. J Womens Health Gend Based Med 2000:9(4): 381-387.
7. Tamimi RM, Hankinson SE, Chen WY, et al. Combined estrogen and testosterone use and risk of breast cancer in postmenopausal women. Arch Intern Med 2006;166(14):1483-9.
8. Tworoger SS, Missmer SA, Eliassen AH, et al. The association of plasma DHEA and DHEA sulfate with breast cancer risk in predominantly premenopausal women. Cancer Epidemiol Biomarkers Prev 2006;15(5):967-71.
9. Cirigliano M. Bioidentical hormone therapy: a review of the evidence. J Women’s Health 2002; 16(5):600-31.