No auto mechanic in his right mind would replace worn parts in a Mercedes with new parts made for a Chevy. Unfortunately, many physicians (and pharmaceutical companies) seem to have less common sense than the average auto mechanic when it comes to treating menopausal women.

The “estrogen” replacement most doctors prescribe today for menopausal and premenopausal women is a pill known generically as conjugated equine estrogens (CEE). The best known brand of CEE is Premarin^®. Several studies suggest that in many women Premarin does help reduce symptoms of menopause, including hot flashes, vaginal thinning, memory loss and urinary incontinence. It also appears to reduce the risk of developing postmenopausal cardiovascular disease (the leading killer of women) and osteoporosis (the crippling progressive bone weakness). It also may help to prevent a significant proportion of Alzheimer’s disease and senile dementia.

So what’s wrong with CEE? Take a close look at the names. Notice the word “equine?” Yes, that is equine. Premarin is horse estrogen. It is derived from the urine of pregnant mares, hence, its brand name. Premarin works great in female horses, just as Chevy parts work great in Chevrolets, but replacing human estrogens with horse estrogens may be asking for trouble and here’s why.

In past centuries, the human female reproductive system has been running quite well on three separate estrogens: estriol, estrone and estradiol, which occur in an approximate ratio of 90 percent: 3 percent: 7 percent¹ (Fig. 1). Compare that with Premarin, which consists of estrone (75–80 percent), equilin (6–15 percent), estradiol + two other equine estrogens (5–19 percent).² Notice that in addition to having larger proportions of estrone and estradiol, Premarin also contains equilin and two other forms of estrogen found exclusively in horses.

The female human body contains all the enzymes and cofactors it needs to process estriol, estrone and estradiol—when they occur in their natural human proportions. On the other hand, it has none of the enzymes and cofactors required to metabolize equilin and the other horse estrogens, nor does it have enough of these important substances to deal with the excessively large amounts of estrone and estradiol found in Premarin (or in the 100 percent estradiol “patch”). Horses, of course, are well equipped to handle CEE. The difference in reproductive hormones is just one of many differences between horses and humans. You may have noticed that horses also have four hooves and a mane, whereas human females don’t.

It should come as no surprise, then, that the presence of Premarin in the human body induces a hormonal imbalance that can have important adverse consequences. To physicians who prescribe Premarin, this hormonal imbalance doesn’t seem to carry much weight. After all, the drug works doesn’t it? But as two leading reproductive physiologists point out, when women take Premarin, “Levels (of equilin) can remain elevated for 13 weeks or more post-treatment due to storage and slow release from adipose (fat) tissue. In addition, metabolism of equilin to equilenin and 17-hydroxyequilenin may contribute greatly to the estrogen stimulatory effect of (conjugated estrogen) therapy.” Another metabolite of equilin, 17-ß-dihydroequilin has been found to be eight times more potent than equilin for inducing endometrial growth, a possible precursor to cancer.³

As a result, Premarin produces “estrogenic effects” that are much more potent and longer lasting than those produced by natural human estrogens.

This explains why so many women feel “unnatural” on Premarin, why Premarin causes so many side effects and discomforts (see box). It even explains why Premarin has been associated with a significant risk of breast and endometrial cancer, because one of the primary effects of equilin, estradiol and estrone is to promote the growth of tissue in the endometrial (uterine) lining and also in the breast. This growth is important for preparing the premenopausal body for pregnancy and lactation, but if some of that tissue becomes cancerous or precancerous, look out. According to Premarin’s official labeling, taking it for a year (without also taking progesterone; see box), increases a woman’s risk of endometrial cancer by as much as 14 percent.²

• Breast tenderness
• Headaches
• Leg cramps
• Gallstones
• Worsened uterine fibroid and endometriosis
• Vaginal bleeding
• High blood pressure
• Blood clots
• Nausea and vomiting
• Fluid retention
• Impaired glucose tolerance
• Increased risk of endometrial cancer and breast cancer

Most conventional physicians, not to mention the pharmaceutical industry, are quick to rationalize the cancer and other risks of horse estrogens. Every treatment has its risks, they point out, but the risk of a postmenopausal woman dying of a heart attack or stroke, if she doesn’t take Premarin, are far greater than her risk of dying from cancer or an osteoporosis-related fracture if she does.

This reasoning is true as far as it goes but it ignores one hugely important fact—horse hormones are not the only choice human females have. What about human hormones? Wouldn’t it make more sense to replace human estrogens with human estrogens? Mercedes parts with Mercedes parts? Of course, it does. The real question is, why has no one thought of this before?

This realization occurred in 1982. All ob-gyn textbooks discussed the naturally occurring human estrogens—estriol, estrone and estradiol—but completely neglected to recommend their use for treating menopausal symptoms, inexplicably recommending horse estrogens instead.

The approximate circulating levels of the three estrogens were checked in human females. This information was used to design a combination estrogen replacement regimen that closely matched the natural conditions found in premenopausal women. The result was “triple-estrogen,” a combination of natural estriol, estrone and estradiol—using molecules identical in structure to those produced in the human body—in as close-to-natural quantities and proportions as could be calculated.

Triple estrogen was formulated by a compounding pharmacist friend, Ed Thorp of Kripps Pharmacy, Vancouver, B.C., and the rest is history. In the 16 years since triple estrogen was first prescribed, thousands of other progressive physicians—and their grateful patients—have found that it works as well as or better than conventional ERT regimens, while producing far fewer unwanted side effects.

You may have noticed that one estrogen, estriol, is completely absent from Premarin and other forms of conventional estrogen replacement regimens, although it comprises as much as 80–90 percent of triple estrogen. This is not an insignificant omission. Estriol has long been dismissed as a weak and unimportant estrogen by most conventional physicians and pharmaceutical researchers. They have considered it to be primarily a metabolite of estradiol and estrone, which are far more potent in producing estrogenic effects, such as inducing endometrial tissue growth. “Why go through all the trouble of putting estriol into a pill if you don’t really need it?” seems to be their reasoning.

Well, potency isn’t everything. In fact, estriol is vitally important precisely because it is a weak estrogen. A number of studies, published over four decades, have demonstrated that estriol’s unique and perhaps most important role may be to oppose the growth of cancer, including cancer promoted by its more potent cousins, estrone and estradiol. We’ll talk more about this.

Estriol plays far more than just a defensive role, though. European physicians have been more open to the potential benefits of estriol in menopausal women than those in the U.S. As a result most of the clinical research evaluating estriol has been conducted in Europe. In general, these studies show that menopausal women who use natural estriol to replace their natural estrogen experience a reduction in typical menopausal symptoms like hot flashes and thinning of the vaginal tissue (vaginal atrophy).⁴

• In one major trial, 22 practicing gynecologists from 11 large hospitals in Germany treated 911 perimenopausal women with estriol and evaluated them regularly for five years. They found estriol to be “very effective” against common menopausal symptoms and “well-tolerated” with “no significant side effects.”⁵
• A Swedish study evaluated 40 postmenopausal women with urinary incontinence (leaky bladders) for up to 10 years. The researchers found that estriol treatment resulted in significant improvement in 75 percent of the women, including eight whose ability to regulate urination completely returned to normal.⁶
• The same Swedish study found that symptoms of vaginal atrophy disappeared in 79 percent of the women after just four months of estriol treatment. After 12 months all but one woman were symptom free.⁶

There is no doubt that reasonable doses of horse estrogens and 100 percent estradiol patches and creams stimulate excessive proliferation of endometrial cells, a precursor to endometrial cancer. It is to reduce this risk that any woman taking these drugs must also take natural progesterone or a synthetic progesterone substitute (or “progestin”) like the Provera^® (see box). This is in contrast to estriol, which appears actually to antagonize the proliferative effects of estrone and estradiol, while having far less tendency to stimulate endometrial proliferation itself. Studies in experimental animals have shown that the proliferative dose of estriol (the dose that produces full endometrial growth) is at least double that of horse estrogens and estradiol.⁷

Estriol apparently accomplishes its protective role by benignly binding to estrogenic receptors in the uterine lining and possibly the breast. Unlike the more potent estrogens, though, it does not stimulate growth nearly as much. At the same time, receptors covered by estriol are shielded from more carcinogenic estrone and estradiol.⁴ This is thought to be the same mechanism by which other weak estrogens, such as those found in soy products, protect against cancer. In laboratory animal studies totaling more than 500 rat-years, estriol has been shown to be the most protective estrogen ever tested against cancers of the breast induced by several potent carcinogenic agents, including radiation.^{8, 9}

There is important evidence dating back to the 1960s suggesting that estriol may protect against breast cancer as well. At that time, Henry Lemon, M.D., who was head of the division of gynecologic oncology at the University of Nebraska College of Medicine, hypothesized that some women who develop breast cancer have too little estriol relative to estradiol and estrone circulating in their bodies. To test his hypothesis, Dr. Lemon ran a preliminary study in which he employed a urinary estrogen quotient (EQ), which was simply a measure of the ratio of estriol to the total of estradiol + estrogen in the urine over a 24-hour period; the higher the quotient, the more estriol there is relative to estradiol and estrone.¹⁰

In a small study of 34 women with no signs of breast cancer (Fig. 2), Dr Lemon found the EQ to be a median of 1.3 before menopause and 1.2 after menopause. Only 21 percent of the women had an EQ <1.0 (ie, estriol was less than estradiol and estrone combined). For 26 women with breast cancer, however, the picture was quite different. Their median EQ was 0.5 before menopause and 0.8 after menopause; 62 percent of these women had an EQ <1.0. Thus the women with breast cancer seemed to be making substantially less estriol relative to the other estrogens, compared with the women without breast cancer.

Over the years some researchers have published work disputing Dr. Lemon’s findings, while others have supported him. The issue is complicated by the fact that a woman’s level of estriol when breast cancer becomes apparent may not be as important as a deviation from the norm in her estriol levels as a young woman.

Clearly, much more research, including large-scale, long-term human trials, are needed to answer the many unanswered questions regarding estriol’s role in cancer. In the meantime there can be little doubt that an estrogen replacement regimen that includes the three human estrogens in triple estrogen—estriol, estrone and estradiol—in identical-to-natural proportions is a superior choice for perimenopausal and postmenopausal women, compared with the horse estrogens and 100 percent—estradiol patches and creams the pharmaceutical industry promotes.

This sentiment was echoed in a 1978 editorial in the Journal of the American Medical Association titled, “Estriol, the Forgotten Estrogen?” in which Alvin H. Follingstad, M.D., bemoaned the lack of large clinical trials on estriol that would earn it an FDA stamp of approval. “Do we as clinicians have to wait the years necessary for the completion of these trials before estriol becomes available to us?” he asked. “I think not. Enough presumptive and scientific evidence has been accumulated that we may say that orally administered estriol is safer than estrone and estradiol.”¹¹

Two decades later we are still waiting for those clinical trials; and what Dr. Follingstad said then is even more true today. There’s nothing to be gained by waiting. If a woman is concerned about her risk of cancer from estrogen replacement (and who isn’t?), then the logical choice (considering both modern scientific research and hundreds of thousands of years of human experience producing and metabolizing estrogens) is an estrogen formula containing a majority of estriol—in other words, triple estrogen.

Natural hormone formulations like triple estrogen are normally available in the U.S. only from compounding pharmacies with a physician’s prescription; they cannot be found at standard pharmacies. You can also order triple estrogen cream from some overseas pharmacies. For a listing of reliable sources contact Smart Publications and request their Directory of Sources. (See address at the end of this article.)

What about estrogen “patch” and “cream” products? These are composed of 100 percent estradiol, the most potent, and most carcinogenic, of the estrogens. The estradiol is derived from the same source as the estradiol in triple estrogen, the wild yam, so in that sense these products can be considered “natural.” However, because they are 100 percent estradiol, with no estrone, and most importantly, no estriol, these products must be considered unnatural once inside the human body. The human physiology is designed to work with three forms of estrogen—estriol, estrone and estradiol—in a ratio of about 90:7:3. Exposing the body to 100 percent estradiol creates an unbalanced and therefore unnatural and potentially dangerous situation.

Osteoporosis is the bone-thinning disease that commonly occurs following menopause. It appears to be due to a loss of both estrogen and progesterone. Replacing estrogen will usually help slow or even halt the thinning process, but it does nothing to restore bone that has already been lost.

Dr. Lee took regular bone mineral density measurements of 62 postmenopausal women who were taking either Premarin + progesterone (in a cream base) or progesterone alone for a period of at least three years. The women also took calcium supplements and maintained a diet and life style designed to minimize bone loss. He found that natural progesterone replacement resulted in a remarkable increase in bone mineral density. Some of Dr. Lee’s patients increased the density of their lumbar vertebrae by 20 to 25 percent in the first year. Over the three years of the study, the mean increase in bone mineral density was 15.4 percent. According to other studies, including PEPI, a 4 to 5 percent decrease in bone density would have been expected in women not using natural progesterone. Not surprisingly, Provera appears to provide no protection against osteoporosis and definitely does not enhance bone growth.

Natural progesterone creams are widely available over the counter, usually at health food stores as well as mail order vitamin suppliers. For a listing of reliable sources on this, please request the Directory of Sources from Smart Publications.

Natural Hormone Replacement for Women Over 45 by Jonathan V. Wright, M.D. and John Morgenthaler is available in book stores, health food stores and direct from the publisher for $9.95 plus $3.95 shipping and handling (U.S. addresses). Overseas orders inquire about shipping rates. California residents add 7.5 sales tax. Smart Publications, Box 4667, Petaluma, CA 94955. Phone: 800-976-2783. Fax: 707-763-3944.

References

1. Scliesman B., Robinson L. “Serum estrogens: quantitive analysis of the concentration of estriol campared to estradiol and estrone.” Meridian Valley Laboratory (1997). Kent, WA:Data on file.
2. Premarin® (conjugated estrogen tablets). Wyeth-Ayerst Company. Physicians' Desk Reference, 52^nd Edition. Montvale, N.J.: Medical Economics Company (1998). pp. 3111-3
3. Barnes, R., Lobo, R “Pharmacology of Estrogens,” in Mishell D, Jr, ed. Menopause: Physiology and Pharmacology. Chicago: Year Book Medical Publishers, Inc. 1987.
4. Heimer, G. “Estriol in the postmenopause.” Acta Obstet Gynecol Scand. (1987). Suppl 139: 1-23
5. Lauritzen, C. “Results of a 5 years prospective study of estriol succinate treatment in patients with climacteric complaints.” Honn Metabol res. (1987). Vol. 19:579-84.
6. Iosif, C. “Effects of protracted administration of estriol on the lower genito urinary tract in postmenopausal women.” Arch Gynecol Obstet. (1992). Vol 251:115-20.
7. Utian, W. “The place of oestriol therapy after menopause.” Acta Endocrinol (1980). 233 (suppl):51-6.
8. Lemon, H. “Oestriol and prevention of breast cancer.” Lancet. (1973). Vol. 1:546-7
9. Lemon, H. Kumar, P. Peterson, C, Rodriguez-Sierra, J. Abbo, K. “Inhibition of radiogenic mammary carcinoma in rats by estriol or tamoxifen.” Cancer (1989). Vol. 63:1685-92.
10. Lemon, H. Wotiz, H. Parsons, L. Mozden, P. “Reduced estriol secretion in patients with breast cancer prior to endocrine therapy.” JAMA (1966). Vol. 196:112-20.
11. Follingstad, A. “Estriol, the forgtten estrogen?” JAMA (1978). Vol. 239:29-30.
12. The Writing Group for the PEPI Trial. “Effects of estrogen or estrgen/progestin regimens on heart disease risk factors in postmenopausal women: The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.” Jama 1995. Vol. 273:199-208.
13. Lee, J. “What Your Doctor May Not Tell You About Menopause.” New York: Warner Books, 1996.
14. Lee, J. “Is natural progesterone the missing link in osteoporosis prevention and treatment?” Medical Hypotheses (1991). Vol. 35:316-8.