This article was written by Kent Holtorf M.D. and published in the peer-reviewed journal Postgraduate Medicine. It is the most complete review of the subject of hormonal safety. We reproduce this article in its entirety for your review.
In the Headache Clinic, we see approximately seven times the number of women compared to men who are suffering from migraine. Many women begin to have headaches around the time that they begin to have periods (menarche); their headaches are increased during each menses; and often the headaches resolve during the second and third trimesters of pregnancy, when levels of progesterone increase 15 times and levels of protective estriol increase 1000 times (and levels of thyroid hormone increase as well). Headaches often increase during perimenopause and adjustment to menopause, and then afterwards decrease to levels found in childhood prior to the start of menstruation. Clearly, migraine is for many sufferers a hormonal disease.
Migraine is associated with an approximately doubled lifetime risk of stroke. Synthetic estrogens, as well as the natural estrogens estradiol and estrone, and the synthetic progestin Provera, are associated with a small but increased risk of both thrombotic events (clots and strokes) and also an increased risk of cancers, primarily breast and reproductive tumors. The absolute numbers of migraine patients with stroke are small (for example, the statistical finding that migraine doubles your risk for stroke only means that your actual your risk increases from 1 in one thousand to 2 in one thousand). However, it is known that when two or more risks are added together (migraine, stimulative hormones such as estradiol or estrone, and progestins like Provera which have progesterone-blocking effects and thus act like estrogens) the risks are multiplied rather than added. For this reason, I do not follow the common present practice of recommending the addition of estradiol during menses to treat menstrual migraine, or of using PremPro or synthetic HRT during perimenopause.
I believe the use of estriol and progesterone is safe for menstrual migraine, and for perimenopausal migraine, and possibly protective against clotting disorders and certain cancers. The following literature review supports the approach to hormonal migraine at the Headache Clinic.
The Safety and Effectiveness
of Bio-Identical Hormones:
Natural (Bio-Identical) vs.
Kent Holtorf, M.D.
Below is a review of the medical literature demonstrating how natural
hormones are superior to their synthetic counterparts. The conclusion is
clear that bio-identical hormones are a safe alternative to Premarin and
medroxyprogesterone acetate (MPA), marketed as Provera. The natural
bio-identical 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 HRT with bio-identical hormones
are safer1-79 and far superior to Premarin and Provera with better
outcomes and fewer risks and side effects1-79.
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, 49-51, 53, 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, 76, 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, 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 4 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
progesterone, results in an increased risk of heart attack and stroke with
MPA use but not with natural progesterone use.
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 10 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 MPA, increases blood flow to the heart and
decreases the risk of heart attack and stroke.
In a series of studies, Adams,51, 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 itself76, 77 or in combination with estrogen51, 61, 15 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.51, 15, 53, 54
This anti-athrogenic (inhibits plaque formation) effect of progesterone is
directly opposite to the effects of synthetic progestins, which is
pro-athrogenic (promotes plaque formation). In addition, MPA is unique in
that it is shown to increase the amount of collagen in vascular plaques,
which promotes thrombus (clot) formation.54, 15 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, while the latter
increases the risk of heart disease, heart attack and stroke.
A review paper by Clarkson, published in the Journal of Reproductive
Medicine and entitled Progestogens [term for all progesterone like
compounds including progesterone and progestins] and Cardiovascular
Disease-A Critical Review, the negative effects of MPA in comparison to
progesterone were discussed. The authors summarize, “Of particular
interest is the attenuating effect medroxyprogesterone acetate (MPA) has
on the cardiovascular benefits of postmenopausal estrogen treatment. MPA
reduces the dilatory effect of estrogens on coronary arteries, increases the
progression of coronary artery arteriosclerosis, accelerates low-density
lipoprotein uptake in plaque, increases the thrombogenic potential of
atherosclerotic plaques and promotes insulin resistance and its consequent
hyperglycemia. These effects may be largely limited to MPA and not shared
with other progestogens.” 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 together,
provide 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 risk of coronary and cerebral vascular events.
Estrogen and progesterone are superior to estrogen and Provera in the
effects on HDL cholesterol. In the large 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 Provera. HDL (good
cholesterol) was increased by 9% when estrogen and natural progesterone
were used versus just a 3-4% increase with estrogen and Provera. The
investigators were surprised by the superiority of natural 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
wanted to take micronized [natural] progesterone. I was quite impressed
with the better effect.12”
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 this
cardiovascular risk factor have previously, however, been clearly shown,
with MPA and other synthetic progestins negating the positive effects of
estrogen on lipids63-65, 70, 72 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 on lipids 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
double52, 73, 49, 75 the amount of insulin resistance (Type II diabetes)
when compared to estrogen alone or estrogen and progesterone.52, 62,
73, 49 Thus, synthetic progestins are expected to promote vascular disease
and increase the risk of heart attack and stroke while natural progesterone
does not possess this detrimental effect.
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 inhibited this protein, but medroxyprogetreone acetate (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 on vascular walls.
The contrasting effects of progesterone and MPA seem clinically important,
inasmuch as MPA is a widely used progestin in the regimen of hormone
replacement 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 Journal, Clinical
Therapeutics. He writes, “The 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
A review of progesterone verses synthetic progestins was done by
Fitzpatrick from the department of Internal Medicine at the Mayo Clinic. In
this review, entitled "Micronized Progesterone: Clinical Indications and
Comparison with Current Treatments," published inFertility 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 4 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
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
A large study compared the risk of breast cancer in 1,897 women on
combined estrogen and progestin versus 1,637 controls that had never used
any HRT. It was found that the use of progestin increased the risk of breast
cancer by 38%. 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. 4-hydroxyequilenin, a component of Premarin, 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.23-26, 39 Estriol is shown to decrease the
incidence and inhibit breast cancer in rats,24, 39, 26 while the levels of
estriol in a women are inversely 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 6 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 in the Journal of the American Medical
Association, titled "Estriol, the forgotten estrogen?" He reviewed a study in
which estriol was given to postmenopausal women with 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 “The
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 likely play a major role in the
incidence of breast cancer.40-48 In a study by Kabat et al, entitled "Urinary
Estrogen Metabolites and Breast Cancer: A Case Controlled Study," it was
found that 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, 33, 79, 19, 81 making it
pro-carcinogenic and increases the risk of breast cancer.6, 78, 9, 10, 55, 19
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 with medroxyprogesterone use. Natural progesterone,
as opposed to medroxyprogsterone, has a strong anti-proliferate effect on
breast tissue.1, 8, 81 This is the opposite effect of Provera and results in a
strong anti-breast cancer effect of natural progesterone,30, 31, 1, 8 again
opposite of 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 10-13 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 opposite of that of synthetic progestins, which
increase proliferation and increase the risk of breast cancer.4, 5, 7, 9, 33,
78, 79, 19
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, 1,083 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 more important
parameter. Additionally, women in the low progesterone group experienced
10 times more deaths from neoplasm (cancer) when compared to those
with normal progesterone.30
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 (anti-cancer effect).32
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 do 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, it is clear that the negative
outcome of the WHI study with the use of MPA is certainly of no surprise,
given its 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
the 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
[Hormone Replacement Therapy] should not be abandoned based on the
results of a known toxic drug combination. It is the utmost importance for
women to understand that they have alternatives to Premarin and Provera
that are scientifically shown to be safer and healthier.
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estradiol and progesterone on human breast epithelial cell cycle in vivo.
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