As a friend of mine used to say, "If things don't make
sense, follow the money trail." Because the sale of non-bioidentical
estrogen and progesterone makes so much money for drug companies, I
suspect that those companies find their profits very threatened by
the use of safer or bioidentical hormones. As has frequently been the
case when natural products threaten pharmaceutical sales, there appears
to be a major public relations misinformation campaign. Although I
am not privy to what goes on in the pharmaceutical "back rooms," my
impression is that they feel that if consumers can be confused and
frightened enough by misinformation, profits can be protected. My impression
(as a physician without a financial stake in either side) is that bioidentical
hormones are far safer and effective than synthetic progesterone and
pregnant horse urine (Premarin). Historically, unfortunately, when
there is big money to be made, there has been no problem getting big-name
doctors to tout the health benefits of infant formula over breast milk
and even of smoking! It's sad when information put out by actresses,
like Suzanne Somers in her recent book Ageless (on bioidentical hormones),
is more accurate than information put out by prominent physicians!
But this is what happens when money talks.
To help supply more accurate information on the subject, I'd
like to offer readers an excellent review article by Dr. Kent Holtorf.
Kent is a superb
physician and a friend of mine whom I greatly respect. I think that after reading
this article, it will be clear to you that bioidentical hormones are the way
Natural (Bioidentical) vs. Synthetic Hormone Replacement Therapy
by Kent Holtorf, MD
Below is a review of the medical literature demonstrating how natural
hormones are superior to their synthetic counterparts. The conclusion
is clear that bioidentical hormones are a safe alternative to Premarin
and medroxyprogesterone acetate (MPA), marketed as Provera. The natural
bioidentical hormones are very different from their synthetic versions,
often having completely opposite physical and cellular effects. Thus,
it is critical that women be given the information that these natural
hormones do not have the negative side effects of the synthetic hormones
and in no way pertain to the conclusions reached by the Women's
Health Initiative (WHI) study. Natural hormones are a safe and more
conservative approach to hormone replacement therapy that does not
carry the risks associated with Premarin and Provera.
I have found that patients feel great on the natural hormones, but when they
are on synthetic hormones, they often do not fully respond or have considerable
side effects. Medical studies confirm that women report improved satisfaction
when they are changed from MPA (synthetic progesterone) to natural progesterone
and have an improved quality of life.2,50 The medical studies also show that
hormone replacement therapy (HRT) with bioidentical hormones are safer and
far superior to Premarin and Provera with better outcomes and fewer risks and
The WHI study demonstrated that when MPA was added to Premarin, there was a
substantial increase in the risk of heart attack and stroke. This was an expected
outcome with MPA, as it has clearly been shown to not only negate any cardioprotective
effects of estrogen, but also to actually promote cardiovascular disease and
increase the risk of heart attack and stroke.12-17,34-36,49-54,65,70-73
Natural estrogen and progesterone, on the other hand, have an opposite effect.
They maintain and augment the cardioprotective effects of estrogen and decrease
the risk of heart attack and stroke.49,50,61,67,70-72,26,77
A number of other medical studies have shown that coronary artery spasm, which
increases the risk of heart attack and stroke, can be reduced with estrogen
and progesterone,13-15,68,69 but the addition of MPA to estrogen has the opposite
effect and results in vasoconstriction,13-15,68,69 increasing the risk of heart
attack and stroke in postmenopausal women. In a study where 18 monkeys had
their ovaries removed to simulate menopause, they were then put on estradiol
plus either Provera or natural progesterone. After four weeks, the researchers
injected a substance that causes the coronary arteries to constrict, cutting
off the flow of blood to the heart muscle. The researchers reported that the
animals receiving Provera would have died within minutes had they not received
protective drug treatment. Those on the natural progesterone required no such
treatment. The researchers summarized, "We conclude that medroxyprogesterone
(Provera) in contrast to progesterone increases the risk of coronary vasospasm."13
This coronary spasm induced by MPA acetate, but not by progesterone, results
in an increased risk of heart attack and stroke with MPA use but not with natural
Researchers compared the effects of (natural) estrogen and progesterone with
estrogen and medroxyprogesterone on exercise-induced myocardial ischemia (lowered
blood flow) in postmenopausal women with coronary artery disease. This was
a blinded, randomized, crossover study. Women were placed on natural estradiol
for four weeks. They were then randomized to receive either natural progesterone
or Provera along with the estradiol. After ten days on the combined treatment,
the patients then underwent a treadmill test. The patients then crossed over
to the opposite treatment and repeated the treadmill test. It was found that
exercise time to myocardial ischemia was increased with natural progesterone
(decreased risk of heart attack) vs. Provera. They state, "These results
imply that the choice of progestin in women at higher cardiovascular risk requires
careful consideration." Provera is expected to increase the risk of heart
attack and stroke while progesterone is not."14 This coronary dilatation,
produced by natural progesterone, but not by MPA, increases blood flow to the
heart and decreases the risk of heart attack and stroke.
In a series of studies, Adams51,61 studied the cardioprotective effects of
estrogen and progesterone verses estrogen and MPA. The estrogen and progesterone
combination resulted in a 50% reduction in athrosclerotic plaque in the coronary
arteries.61 This effect was independent of changes in lipid concentrations.
However, when MPA was combined with estrogen, almost all of the cardioprotective
effect (athrosclerotic plaque reduction) was reversed and negated.51 MPA was
also shown to increase insulin and glucose levels, further increasing the risk
of heart disease, heart attack, and stroke.51 A number of additional studies
have also shown that progesterone by itself 76,77 or in combination with estrogen15,51,61
will inhibit athrosclerotic plaque formation. Synthetic progestins, on the
other hand, have a completely opposite effect. They promote athrosclerotic
plaque formation and inhibit any plaque-inhibiting action of estrogen.15,51,53,54
This anti-athrogenic ( plaque-formation inhibiting) effect of progesterone
is directly opposite to the effects of synthetic progestins, which is pro-athrogenic
(plaque-formation promoting). In addition, MPA is unique in that it is shown
to increase the amount of collagen in vascular plaques, which promotes thrombus
(clot) formation.15,54 This increases the risk of heart attack, stroke, and
blood clots. Again, there are significant differences in natural progesterone
and synthetic progestins, with the former reducing the risk of heart disease,
heart attacks, and strokes, and the latter increasing the risk of heart disease,
heart attack, and stroke.
A review paper, Progestogens [term for all progesterone-like compounds including
progesterone and progestins] and Cardiovascular Disease – A Critical
Review, by Clarkson, published in the Journal of Reproductive
the negative effects of MPA in comparison to progesterone. The authors summarize:
particular interest is the attenuating effect medroxyprogesterone
acetate (MPA) has on the cardiovascular benefits of post-
menopausal estrogen treatment. MPA reduces the dilatory effect of
estrogens on coronary arteries, increases the progression of coronary
artery arteriosclerosis, accelerates low-density lipoprotein uptake
plaque, increases the thrombogenic potential of atherosclerotic plaques,
and promotes insulin resistance and its consequent hyperglycemia.
effects may be largely limited to MPA and not shared with other
They boldly display in the middle of the
page a summary stating, "The data strongly suggests caution in the
use of MPA…"
and list as their summary of findings that "These studies, taken
a basis for concern, not about all progestogens, but specifically about MPA."15
Again, after a review of the literature, it is of no surprise, rather it
was expected that the MPA arm of the WHI study would show an increased
coronary and cerebral vascular events.
Estrogen and progesterone are superior to estrogen and Provera in the effects
on HDL cholesterol. In the large Postmenopausal Estrogen/Progestin Interventions
(PEPI) trial,11 875 postmenopausal women were randomized to receive placebo,
Premarin, Premarin, and Provera, or Premarin and natural progesterone.
This study demonstrates the superior effect of natural progesterone over
HDL (good cholesterol was increased by nine percent when estrogen and natural
progesterone were used versus just a three to four percent increase with
estrogen and Provera). The investigators were surprised by the superiority
progesterone over synthetic Provera34 with Dr. Healy, a PEPI trial investigator,
stating, "I think the biggest surprise certainly was the HDL effect of
micronized progesterone. And I quite agree with Dr. Barrett-Connor that
any ongoing trial now, whether they be the National Heart, Lung Blood Institute
study on estrogen in women who have known coronary disease or the Women's
Health Initiative, should relook at the regimens being offered." Elizabeth
Connor, cardiologist and PEPI investigator, stated, "If I were treating
a women primarily because she was worried about heart disease or because
she has dyslipidemia and low HDL cholesterol, I would probably see if she
to take micronized (natural) progesterone. I was quite impressed with the
Many experts were surprised when the PEPI trial demonstrated that MPA,
but not progesterone, significantly attenuated (blocked) the positive effects
of estrogen on lipids. The opposing effects of MPA and progesterone on
risk factor have previously, however, been clearly shown, with MPA and
other synthetic progestins negating the positive effects of estrogen on
while progesterone either maintains or augments estrogen's positive effects
on lipids.66,67,70-72 Thus, based on their effects on lipids, progesterone
would be expected to decrease the risk of heart disease and stroke, while
synthetic progestins such as Provera would be expected to increase the
risk of heart
attack and stroke.
Based on the results from the PEPI Trial and other studies,11,74 the President
of the American Heart Association stated that, just based on this difference
in the effects on HDL, a women who changes her medication from MPA to natural
progesterone would significantly lower her risk for heart disease.35 The
differing effects of progestins (synthetic progesterones) and progesterone
is another risk factor that results in an increased risk for heart disease,
heart attack, and stroke when the synthetic is used but not natural progesterone.
MPA and synthetic progestins are also shown to significantly increase,
even double49,52,73,75 the amount of insulin resistance (type
2 diabetes) when
compared to estrogen alone or estrogen and progesterone.49,52,62,73 Thus,
progestins are expected to promote vascular disease and increase the risk
of heart attack and stroke, while natural progesterone does not possess
Progesterone was compared to Provera for its ability to decrease the formation
of a protein that initiates athrogenic plaques (coronary artery disease),
vascular cell adhesion molecule-1. It was shown that progesterone clearly
this protein, but MPA (Provera) did not. The authors write, "Because
the expression of VCAM-1 is one of the earliest events that occur in the
atherogenic process, this adhesion molecule might be the target of progesterone
walls. The contrasting effects of progesterone and MPA seem clinically
important, inasmuch as MPA is a widely used progestin in the regimen of
therapy."32 This is another process in which MPA promotes heart disease
and the risk of heart attack and stroke, while progesterone reduces heart
disease and the risk of heart attack and stroke.
Doctor Lignieres, from, the Necker Hospital Department of Endocrinology
and Reproductive Medicine in Paris, France, reviewed the scientific literature
that compared natural, oral micronized progesterone and commonly used progestins
and published his findings in a 1999 issue of the journal Clinical
He writes, "…most commonly used synthetic progestins, norethisterone,
and medroxyprogesterone acetate, have been associated with metabolic and vascular
side effects (e.g., suppression of the vasodilating effect of estrogens) in
both experimental and human-controlled studies. All comparative studies to
date conclude that the side effects of synthetic progestins can be minimized
or eliminated through the use of natural progesterone..."49
A review of progesterone verses synthetic progestins was done by Fitzpatrick
from the department of Internal Medicine at the Mayo Clinic. In this review,
"Micronized Progesterone: Clinical Indications and Comparison with Current
in Fertility and Sterility, the author
summarizes the study's findings:
A large body of evidence, including the
Postmenopausal Estrogen/Progestin Interventions study, suggests that
the use of combination estrogen and oral micronized progesterone
is optimal for long-term hormone replacement therapy…However,
use of progesterone-like hormones (progestins) is associated with
a number of potential
adverse reactions, including bleeding, amenorrhea, and, at higher
doses, somnolence. There is also evidence that synthetic progestins
have a teratogenic (birth defect) effect when administered during
the first four months of pregnancy. Treatment with combined estrogen
and progestin medication impairs glucose tolerance in some patients.62
The synthetic progestins also may attenuate the beneficial lipid
and cardioprotective effects of concomitantly administered estrogen.63,64
Because of the potential adverse reactions, careful medical oversight
is required if the synthetic progestins are to be used during
the first trimester of pregnancy or by patients with diabetes,
hyperlipidemia, or hypertension. For indications in which oral
delivery of synthetic progestins currently are used, the theoretic
benefits of oral delivery of the natural form of the hormone
are obvious. In addition to the decreased potential for adverse
effects, there are clear advantages in convenience, cost, compliance,
and quality of life.50
Premarin, being an oral estrogen,
will increase clotting factors and inflammatory proteins, increasing
the risk of thromboembolism,
stroke, and heart attack.16,18 This does not occur with transdermal
estrogens.18 In fact, it can be considered malpractice to give oral
contraceptives or oral HRT to smokers because of the increased risk
of stroke, but non-smokers are at increased risk, as well. When oral
Premarin is taken with Provera, the risk of thromboembolism, stroke,
and heart attack increase in a synergistic manner. Ninety percent
of my patients are on transdermal natural estrogens for this reason.18
The Nurses Health Study followed 58,000 postmenopausal women for
16 years (725,000 person-years). The study found that, compared with
women who never used hormones,
use of unopposed postmenopausal estrogen from ages 50 to 60 years increased
the risk of breast cancer to age 70 by 23%. The addition of a progestin to
the estrogen replacement resulted in a tripling of the risk of breast cancer
to a 67% increase in the risk of breast cancer.9,78
A large study compared the risk of breast cancer in 1897 women on combined
estrogen and progestin vs. 1637 controls that had never used any HRT. It
was found that the use of progestin increased the risk of breast cancer by
The authors conclude, "This study provides strong evidence that the addition
of a progestin to HRT enhances markedly the risk of breast cancer relative
to estrogen use alone."10 Again, natural progesterone is documented to
reduce the risk of breast cancer.
Premarin is made from pregnant horses' urine, hence its name: Pre (pregnant)-mar
(horse)- in (urine). It consists of a combination of conjugated equine (horse)
estrogens that are more potent and more carcinogenic than other natural estrogens
such as estradiol and especially estriol. A component of Premarin, 4-hydroxyequilenin,
is especially potent – 100 times the potency of natural estrogen – and
carcinogenic.20-22,80 One author summarizes, "These results suggest that
4-hydroxyequilenin has the potential to be a potent carcinogen through the
formation of variety of DNA lesions in vivo."22 Natural estrogens have
no such carcinogenic metabolites.
The natural estrogen, estriol, is shown to cause much less breast cell proliferation
and is felt to be a much safer form of estrogen than even estradiol and especially
Premarin.23-27,39 Estriol is shown to decrease the incidence and inhibit
breast cancer in rats,24,26,39 while the levels of estriol in a women are
correlated with the risk of breast cancer, with low levels being associated
with cancer while high levels are protective.25,26,56,57,59,60 An analysis
of six epidemiologic studies of estrogen levels in women found that there
are higher estriol levels in populations with lower risks for breast cancer.26
Dr. Follingstad published an article, "Estriol, the Forgotten Estrogen?" in
the Journal of the American Medical Association
in which he reviewed a study in which estriol was given to postmenopausal
breast cancer. Thirty-seven percent
of the patients demonstrated remission or arrest of the disease. He concluded
that estriol should be given to all women who need estrogen replacement therapy
but are at risk for breast cancer. A case can be made that all women are
at risk and estriol should be part of all HRT regimens. He writes, "Enough
presumptive and scientific evidence has been accumulated that we may say
that orally administered estriol is safer than estrone or estradiol…let
us have the estrogen that causes the least risk."27
In a large study that looked at the effect of estrogens on breast cancer
in rats, it was shown that estriol was protective. The authors felt that "[t]he
superior protective action of estriol may be partly related to its greater
solubility in plasma and decreased binding to plasma-albumin, compared to oestrone
[estrone] or 17B-oestradiol [estradiol]."58 Premarin on the contrary
increases the risk of breast cancer.20-22,80
There has been considerable research in estrogen metabolism and its relation
to breast cancer. Estradiol can be metabolized to either a potent carcinogenic
compound, 16-hydroxyestrone, or to a noncarcinogenic compound, 2-hydroxyestrone.
Women who metabolize estradiol to 16-hydroxyestrone have a significantly
increased risk for breast cancer, and it is being realized that these metabolites
play a major role in the incidence of breast cancer.40-48 In a study by Kabat
et al., "Urinary Estrogen Metabolites and Breast Cancer: A Case Controlled
Study," postmenopausal women with the highest levels of 16-hydroxyestrone
compared to 2-hydroxyestrone were shown to have a risk factor for breast cancer
that was 32 times that of controls. I routinely check these levels in women
and determine the ratios, because they have a profound effect on breast cancer
risk. Interestingly, women with family histories of breast cancer will usually
have elevated 16-hydroxyestrone. If an increased level of the carcinogenic
estrone is present, measures are taken to reverse this metabolization pattern
and then the levels are re-checked. Estriol, however, does not convert to the
carcinogenic 2-hydroxyestrone, making it a much a safer form of estrogen. Estriol
also improves multiple sclerosis while other estrogens make it worse – another
indication of its profoundly different effects.28,29
A number of studies demonstrate that synthetic progestins, such as Provera,
increase breast cell proliferation,4,5,7,9,19,33,79,81 making it pro-carcinogenic,
and increase the risk of breast cancer.6,78,9,10,19,55 This cell proliferation
with Provera has been shown to be particularly bad.7 This increased cell
proliferation, as expected, translates into an increased risk of breast cancer
use. Natural progesterone, as opposed to medroxyprogesterone, has a strong
anti-proliferate effect on breast tissue.1,8,81 This is in complete contrast
to Provera's effect and results in a strong anti-breast cancer effect
of natural progesterone,1,8,30,31 again in direct contrast to Provera.
A double-blind, placebo-controlled study looked at the effects of estrogen
and progesterone on women prior to breast surgery. Patients were given a
placebo, estrogen, or estrogen and progesterone for ten to 13 days prior
to breast surgery.
Estradiol increased cell proliferation rates by 230%, but progesterone decreased
cell proliferation rates by 400%. The progesterone, when given with estradiol,
inhibited and prevented any breast proliferation (cancer preventive).1 Progestins
do not have this beneficial effect.
In a double-blind, randomized study, Foidart et al. also showed that progesterone
eliminated estrogen-produced breast cell proliferation,8 demonstrating the
strong anti-proliferative and anti-cancer effect of natural progesterone.
This effect is that opposite of that produced by synthetic progestins, which
proliferation and increase the risk of breast cancer.4,5,7,9,19,33,78,79
A prospective epidemiological study conducted at Johns Hopkins demonstrated
the profound anti-breast cancer action and protective role of natural progesterone
against breast cancer. In that study, 1083 women who had been evaluated and
treated for infertility were followed for 13 to 33 years. The results showed
that the risk of breast cancer was 5.4 times in subjects who had a low progesterone
level when compared to those with a normal level. This was particularly striking
because the result was so significant despite the fact that the high progesterone
group actually had significantly more risk factors for breast cancer than
the low progesterone group, indicating that the progesterone level is a far
important parameter. Additionally, women in the low progesterone group experienced
ten times more deaths from neoplasm (cancer) when compared to those with
In another study, the protective effect of progesterone or Tamoxifen, a potent
estrogen antagonist, was investigated in estrogen-induced breast cancer in
rats. Results of the study indicated that the induction rate, multiplicity,
and size of estrogen-induced mammary tumors were reduced by simultaneous
administration of either Tamoxifen or progesterone.31 Natural progesterone
is also shown to
reduce the number of estrogen receptors in breast tissue (anticancer effect).3
These studies indicate that, with respect to the risk of breast cancer, heart
disease, heart attacks, and stroke, natural hormones offer a safe and more
conservative approach to HRT. A large amount of scientific evidence overwhelmingly
demonstrates that natural hormones are safer than the study drugs of the
WHI, Premarin, and Provera. Unfortunately, the overwhelming majority of women
not know that there are safe alternatives to their current HRT or to the
one they stopped after the results of the WHI were released. As you can see,
is clear that the negative outcome of the WHI study with the use of MPA is
certainly no surprise, given MPA's clear history of having a negative
impact on almost every risk factor for heart disease. Natural progesterone
has just an opposite effect of MPA on almost every cardiac risk factor, with
MPA increasing the risk of heart attack and stroke, while progesterone decreases
the risk. If progesterone was used in the trial, the results would assuredly
have been different, and their results in no way pertain to natural hormones,
which are a safe choice with significantly less risk.
The same is true of the increased incidence of breast cancer demonstrated
in the study with the use of Premarin and MPA. This in no way pertains to
use of the natural hormones, estriol and progesterone, which both decrease
the risk of breast cancer. The public, and also doctors, need to be told
that there is a safer alternative to Premarin and Provera and that HRT should
be abandoned based on the results of a known toxic drug combination. It is
of the utmost importance for women to understand that they have alternatives
to Premarin and Provera that are scientifically shown to be safer and healthier.
23456 Hawthorne Blvd, Suite 160
Torrance, CA 90505
310-375-2705; Fax: 310-375-2701
Dr. Holtorf is the Medical Director of the Holtorf Medical Group,
Inc, Center for Hormone Imbalance and Fatiguing Conditions in Los Angeles,
specializing in chronic fatigue syndrome, fibromyalgia, hypothyroidism,
chronic illness, and the treatment of complex endocrine dysfunction.
He is board certified and is a Board Examiner for the American Academy
of Anti-Aging Medicine. He is also chief of the Medical Advisory Board
for the Fibromyalgia and Fatigue Centers, Inc.
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of estradiol and progesterone on human breast epithelial cell cycle
in vivo. Fertil Steril. 1995;63:785-791.
2. Fitzpatrick LA, et al. Comparison of regimens containing oral micronized
progesterone of medroxyprogesterone acetate on quality of life in postmenopausal
women: a cross-sectional survey. J Womens
Health Gen Based Med. 2000
3. Gompel, et al. Antiestrogen action of progesterone in breast tissue.
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4.Van der Burg, et al. Effects of progestins on the proliferation of
estrogen-dependent human breast cancer cells under growth factor-defined
conditions. J Steroid Biochem Mol Biol. 1992 Jun;42(5):457-65.
5. Mol JA, van Garderen E, Rutteman GR, Rijnberk A. New insights in
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6. Hulka BS. Links between hormone replacement therapy and neoplasia.
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8. Foidart JM, Colin C, Denoo X, Desreux J, Beliard A, Fournier S,
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JL. The major metabolite of equilin, 4-hydroxyequilin, autoxidizes
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22. Zhang F, Swanson SM, van Breemen RB, Liu X, Yang Y, Gu C, Bolton
JL. Equine estrogen metabolite 4-hydroxyequilenin induces DNA damage
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of mammary carcinoma. Acta Endocrinol Suppl. 1980; 233:17-27.
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29. Bansil S, Lee HJ, Jindal S, Holtz CR, Cook SD. Correlation between
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30. Cowan LD, Gordis L, Tonascia JA, Jones GS. Breast cancer incidence
in women with a history of progesterone deficiency. Am
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32. Otsuki M, Saito H, Xu X, Sumitani S, Kouhara H, Kishimoto T, Kasayama
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36. Hargrove JT, et al. menopausal hormone replacement therapy with
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37. Hargrove, Osteen KG. An alternative method of hormone replacement
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38. Hargrove JT, Eisenberg E. Menopause. Med.
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