estrogen print version
Let Your Doctor Give You Horse Urine! There Are Better Treatments For Menopause
By Jonathan Wright MD and John Morgenthaler
auto mechanic in his right mind would replace worn parts on a Mercedes with new
parts made from 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. Many studies suggest that in many women, Premarin does help reduce
symptoms of menopause, including hot flashes, vaginal thinning, memory loss and
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.
is horse estrogen derived from horse urine!
So what 's wrong with CEE?
Take a close look at the names. Notice the word "equine?" Yes, that
equine! Premarin is horse estrogen! It is derived from the urine of pregnant mares,
hence its name. Premarin works great in female horse just as Chevy parts work
great in Chevys. But replacing human estrogens with horse estrogens may be asking
for trouble, and here's why
For the last several million years, the
human female reproductive system has been running quite well on three separate
estrogens; Estriol, Estrone and Estradiol, which occur in an approximation of
90%; 3%; 7% (1) (Fig 1). Compare that with Premarin, which consists of Estrone
(75-80%), equilin (6-15%), Estradiol and two other equine estrogens (5-19%). (2)
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.
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 metabolizing 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% Estradiol "patch").
Horse, of course,
is well equipped to handle CEE. The difference in reproductive hormones is just
one of many differences between horse and humans. You may have noticed that horses
also have four hooves and a mane, whereas human females don't!
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 sloe release
from adipose [fat] tissue.
In addition, metabolism of equilin
to equilenin and 17-hydroxyequilenin may contribute to the estrogen stimulatory
effect of [conjugated estrogen] therapy." Another metabolite of equilin,
17-dihydroequilin has been found to be eight times more potent than equilin for
inducing endometrial growth, a possible precursor to cancer (3).
a result, Premarin produces "estrogenic effects" which are much more
potent and longer lasting than those produced by natural human estrogens.
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
According to Premarin's official labeling, taking it for
a year (without also taking progesterone, see box), increases a women's risk of
endometrial cancer by as much as 14% (2).
physicians, not to mention the self-serving 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.
not use human hormones for humans?
Well, this reasoning is true as far
as it goes, but it ignores one hugely important fact, that horse hormones are
not the only choice human females have. What about human hormones? Wouldn't it
make 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!
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 is "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.
estrogen was formulated by a compounding pharmacist friend- Ed Thorp of Kripps
Pharmacy, Vancouver BC, 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 regiments, while producing far fewer unwanted side effects.
the missing-in-action hormone
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% of triple estrogen.
This is not an insignificant omission. Most conventional physicians and pharmaceutical
researchers have long dismissed estriol as a weak and unimportant estrogen. 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.
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 in a moment.
plays more than just a defensive role though. European physicians have been open
to the potential benefits of Estriol in menopausal women than those in the US.
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)
* In one major trial, 22 practicing gynecologists from
11 large hospitals in Germany treated 911 premenopausal women with Estriol and
evaluated them regularly for 5 years. They found Estriol to be "very effective"
against common menopausal symptoms and "well-tolerated" with "no
significant side effect." (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% of the women, including eight whose ability to regulated urination completely
returned to normal. (6).
* The same Swedish study found that
symptoms of vaginal atrophy disappeared in 79% of the women after just 4 months
of Estriol treatment. After 12 months, all but one woman were symptom free (6).
in cancer protection
There is no doubt that reasonable doses of horse
estrogens and 100% Estradiol patches and creams stimulate excessive proliferation
of endometrial cells, a precursor to endometrial cancer.
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 stark contrast to Estriol, which appears
to actually antagonize the proliferate effects of Estrone and Estradiol, while
having far less tendency to stimulate endometrial proliferation, itself. Studies
in experimental animals have shown that the proliferate 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 1960's suggesting that Estriol may protect against breast cancer
as well. At that time, Henry Lemon, MD, 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 this 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
and estrogen in the urine over a 24-hour period. The higher the quotient, the
more Estriol there is relative to Estradiol and Estrone (10).
a small study of 34 women with no signs of breast cancer, Dr. Lemon found the
EQ to be a median of 1.3 before menopause and 1.2 after menopause. Only 21% of
the women had an EQ <1.0 (I.E. 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% 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.
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 premenopausal and
postmenopausal women. Especially when compared with the horse estrogens and 100%
Estradiol patches and creams the pharmaceutical industry promotes.
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, MD, 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)
later, we are still waiting for those clinical trials, and what Dr. Follingstad
dais then is even truer 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 is an estrogen formula containing a majority of Estriol,
in other words, triple estrogen.
Especially when you consider
both modern scientific research and hundreds of thousands of years of human experience
producing and metabolizing estrogens).
Natural hormone formulations
like triple estrogen are normally available in the US only from compounding pharmacies
with a physician's prescription; they can not be found at standard pharmacies.
You can also order triple estrogen cream from some overseas pharmacies (ed., -
note that IAS has the precise 90/7/3 natural estrogen cream researched and formulated
by Jonathan Wright MD, it is called ESNATRI).
If triple estrogen is so much better than Premarin, why have
so few people heard about it? The answer to this question can be summed up in
one word, patentability. Premarin is patentable, and hence, can be sold exclusively
only by its manufacturer and licensees, whereas triple estrogen is a natural product,
like vitamin C, and can be sold by anyone.
made Premarin a huge moneymaker for its manufacturer, Wyeth-Ayerst Pharmaceuticals.
For nearly 30 years, it has been at or near the top of the drug best seller list.
In just the first half of 1997, pharmacists filled 22.1 million prescriptions
for Premarin, amounting to revenues of $388.2 million in the United States alone!
Add in the rest of the world's women, and you get a sense of the high stakes involved
in the business of menopause.
These enormous financial resources
have provided Wyeth-Ayerst the muscle to practically corner the estrogen market.
Through advertising, sponsorship of clinical trials, and conferences, free samples
and other common marketing techniques, they have created an atmosphere in which
physicians virtually equate estrogen replacement with Premarin.
physicians, who have little enough time to keep up with the world of double blind,
placebo-controlled drug trials reported in medical journals (which are supported
largely by pharmaceutical advertising) are completely in the dark about the use
of triple estrogen and other natural hormones. Their use is not taught in medical
schools, nor do any large pharmaceutical companies promote it
no money available to pay the enormous costs, the large, definitive studies that
might demonstrate the efficacy and safety of these natural hormone regimens will
likely never be done.
What makes a hormone natural?
The word "natural" gets thrown around a lot in discussions of hormone
replacement therapy. Premarin, for example, is widely considered to be a "natural
hormone." So is the Estradiol in the estrogen "patch" and "cream"
products. Triple estrogen is also considered to be a "natural" estrogen
product. Are they are natural? Does it really matter? The answers depend on how
you define "natural."
Triple estrogen consists of
three separate estrogens. Estriol, Estrone and Estradiol, all of which are derived
from a plant, the wild yam (Diascoreacomposita). How can a hormone that got its
start in a vegetable be considered "natural" in the human body? The
wild yam is rich in "precursor" molecules that can be easily converted
by biochemists into estrogens and other steroid hormones.
molecular structure of these hormones is indistinguishable from that of the "natural"
hormones produced in the human body, and as a result, they function exactly like
those the body produces, especially when used in their natural proportions. Thus,
the crucial variable defining "natural" is not the origin of the hormone
or how it is produced, but whether its chemical structure matches that of the
hormone it is intended to replace.
Premarin is natural for
horses but not for humans!
Premarin is widely considered by physicians
to be a "natural" hormone product, because it is derived from horse
urine and is not synthesized in a laboratory. But is it really natural? Certainly,
it's natural in horses. But when placed in the human body, the hormones in Premarin
are as foreign as any synthetic drug, because the body lacks the enzymes and cofactors
to metabolize them safely.
What about estrogen "patch"
and "cream" products? These are composed of 100% Estradiol, the most
potent and most carcinogenic of all 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% Estradiol, with no Estrone and most importantly, no Estriol, these
products must be considered unnatural once inside the human body.
human physiology is designed to work with three forms of estrogen, Estriol, Estradiol
and Estrone, in a ration of about 90:7:3. Exposing the body to 100% Estradiol
creates an unbalanced, and therefore, unnatural and potentially dangerous situation.
Progesterone protects against cancer, heart disease and osteoporosis
who replace estrogen also need to replace progesterone. This may seem obvious
to anyone who has studied human reproductive physiology, because estrogen and
progesterone are closely linked in the normal menstrual cycle. Each month, as
estrogen levels rise, progesterone levels fall, and vice versa. Unfortunately,
it wasn't always so obvious to physicians and pharmaceutical companies.
the early days of ERT, tens of thousands of women developed endometrial cancer
as a result of taking Premarin in the absence of progesterone. In the absence
of progesterone, the estrogen in Premarin can cause excessive proliferation of
endometrial tissue, which, in an alarming number of instances, can turn malignant.
Progesterone largely prevents this excessive growth. But conventional medicine
being what it is, most physicians do not prescribe natural progesterone for their
menopausal patients. Instead, they prescribe a synthetic progesterone-like drug,
or "progestin," called Provera (medroxyprogesterone), or one of its
Synthetic progestins are not the same thing as progesterone.
Thanks to the pharmaceutical industry's promotional abilities, few physicians
ever make that distinction.
Women who take Provera pay a high
price for the protection it affords against Premarin-induced endometrial cancer.
That price includes an increased risk of cardiovascular disease (CVD), because
progestins strip away most of the protection against CVD that they gain from estrogen
replacement. Since this protection is one of the main reasons they take Premarin
in the first place, and since Provera causes a long list of unpleasant side effects.
Including breast tenderness, weight gain, depression, and breakthrough bleeding,
to name just a few, you have to wonder whether they wouldn't be better off not
Natural progesterone, which comes from the
same source as the natural estrogens in triple estrogen, is a completely different
story. Because it is structurally and functionally identical to the progesterone
the body produces, replacing missing progesterone with natural progesterone puts
back the same hormone the body is accustomed to.
As a result,
when used properly, natural progesterone affords the same protection against endometrial
cancer as synthetic progestins, but does not interfere with estrogen's ability
to protect against CVD. This was most clearly demonstrated in a large scale federal
government sponsored clinical trial, known as PEPI (Postmenopausal Estrogen /
progestin Interventions) (12).
In the PEPI trial, 875 postmenopausal
women were randomly placed in one of four treatment groups. (A) Placebo (B) Estrogen
(i.e. Premarin) only (C) Premarin and Provera or (D) Premarin and natural progesterone
(oral). The relevant measure was the level of HDL-cholesterol, which is known
as the "good" cholesterol, since it protects against CVD. The results
clearly demonstrated that when Provera was added to Premarin, HDL levels dropped
to nearly baseline. By contrast, when natural progesterone was added to Premarin,
there was no significant loss of HDL-based CVD protection.
this weren't enough to recommend natural progesterone, there's also the protection
it provides against osteoporosis. This ability has been most clearly been shown
by the work of John R. Lee, MD (13,14).
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 Premarin plus
progesterone (in a cream base) or progesterone alone for a period of at least
3 months. The women also took calcium supplements and maintained a diet and lifestyle
designed to minimize bone loss. He found that natural progesterone replacement
resulted in a remarkable increase in bone mineral density.
of Dr. Lee's patients increased the density of their lumbar vertebrae by 20-25%
in the first year! Over the 3 years of the study, the mean increase in bone mineral
density was 15.4%. According to other studies, including PEPI, a 4-5% 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.
This excellent article has been contributed by Jonathan Wright, MD and John
Morgenthaler and is extracted from their must read book -Natural Hormone Replacement
for Women over 45. It is available from Smart Publications in the USA at a cost
of $9.95 plus $3.95 shipping and handling (US addresses only). California residents
must add 7.5% sales tax, foreign orders call Smart Publications for airmail rates,
Their telephone number in the USA is 707 769 8308 (fax 707 763 3944). Their complete
details are listed under PROFESSIONAL PEOPLE AND ORGANIZATIONS.
with this latest clinical research, IAS can offer a natural triple estrogen cream
of 90% Estriol, 7% Estradiol and 3% Estrone called ESNATRI.
can also offer the natural progesterone listed as progesterone.
is important to stress that your physician must guide a natural hormone replacement
therapy (NRT). DO NOT start any NRT program if you have ever suffered from cancer.
(1). Schliesman B, Robinson L. Serum estrogens, quantitative
analysis of the concentration of Estriol compared to Estradiol and Estrone. Meridian
Valley Laboratories, 1997, Kent WA; Data on file.
(2). Premarin (conjugated
estrogen tablets). Wyeth-Ayerst Company. Physicians' Desk Reference, 52nd edition.
Montvale, NJ; Medical Economics Company 1998: 3111-3113.
(3). Barnes R, Lobo
R, Pharmacology of Estrogens. In: Mishell D, JR, ed. Menopause; Physiology and
Pharmacology, Chicago; Year Book Medical Publishers, Inc. 1987.
G. Estriol in the postmenopausal. Acta Obstet Gynecol Scand. 1987; Suppl 139;1-23.
(5). Lauritzen C. Results of a 5-year prospective study of Estriol succinate treatment
in patients with climacteric complaints. horm metabol res. 1987; 19; 579-584.
(6). Iosif C. Effects of protracted administration of Estriol on the lower genito
urinary tract in postmenopausal women. Arch Gynecol Obstet 1992; 251; 115-120.
(7). Utian W. The place of oestriol therapy after menopause. Acta Endocrinol,
1980; 223 (suppl) 51-56.
(8). Lemon H. Oestriol and prevention of breast cancer.
Lancet 1973; 546-547.
(9). Lemon H, Kumar P, Peterson C, Rodriguez-Sierra
J, Abbo K. Inhibition of radiogenic mammary carcinoma in rats by Estriol or tamoxifen.
(10). Lemon H, Wotiz H, Parsons L, Mozden P. Reduced
Estriol secretion in patients with breast cancer prior to endocrine therapy. JAMA
(11). Follingstad A. Estriol the forgotten hormone? JAMA,
(12). The writing group for the PEPI trial. Effects of estrogen
or estrogen/ progestin regimens on heart disease risk factors in postmenopausal
women. The premenopausal estrogen/ progestin interventions (PEPI) trial. JAMA
(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, 35;316-318.
ALL INFORMATION IS EDUCATIONAL AND PROVIDED UNDER IAS TERMS & CONDITIONS.
IT DOES NOT, AND SHOULD NOT, REPLACE THE ADVICE OF YOUR PHYSICIAN.
Updated: Wednesday, October 30, 2002
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