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Is Estriol Safer Than Estradiol? Answers,
by Dr. Joseph Collins Please Note: In this article I have inserted
direct links to other websites including PubMed. PubMed is the National Library of Medicine's
search service that provides access to over 15 million medical and scientific
citations. I encourage you to use this service for your research. After you
review the abstract you can order the entire article online, or you may go to
your local medical library. Every medical school is associated with a medical
library. The
notation (YMT, pg XXX) refers to my text, in Discover Your
Menopause Type? Question: I
have been told that estriol is a better choice than estradiol because it does
not stimulate cells the same way that estradiol does. Is estriol really
safer, or does it have the same risks as other estrogens. Answer: Short Answer: “Estriol
therapy may have some of the same risks of other estrogen therapies,
specifically if taken in excessive dosages. Like any estrogen therapy, it
should not be used without the guidance of an experienced healthcare
professional.” |
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Long Answer: To
fully understand this we have to first review estrogens, then review estriol
and its metabolite 16-hydroxyestrone. We do know that estriol has
“estrogenic” properties – though considered to be weaker than estradiol.
However the “weakness” is overcome by using higher dosages. The fact that
estriol is metabolized into 16-hydroxyestrone also causes concern. About Estrogens Recall
that estrogen is a generic term for any substance, whether natural or
synthetic, that has the same biological activity as estradiol. Estradiol and
estrone are produced predominantly in the ovaries and adrenal glands, though
fat cells and the liver add to the total amount. Estradiol is the most potent
estrogen that occurs naturally in the human body. Estrone is another estrogen
that occurs naturally in the human body. Estrone & estradiol are the pool
of estrogen production in the human body. Metabolites
of estradiol & estrone include 2-hydroxyestradiol, 2-hydroxyestrone,
16-alpha-hydroxyestradiol, 16-alpha-hydroxyestrone, 2-methoxyhydroxyestrone,
2-methoxyestradiol as well as various glucuronide and sulfate metabolites. |
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As
illustrated, estriol (16-alpha-hydroxyestradiol) is one of many estrogen
metabolites. Of the many metabolites
of estrogens, most research appears to agree that 2-hydroxyestrogens and
2-methoxyestroegns appear to be the most beneficial. Estriol In
normal levels, it is widely held that estriol is not as stimulating as
estradiol to cancer cells (YMT, pg 324-325). This has resulted in the
promotion of estriol as an "anti-cancer" estrogen. However, it has
been known for a while that estriol does in fact bind to some forms of breast
cancer cells (Lippman, 77) as well as uterine,
vaginal and cervical cells (Punnonen, 82). The fact that estriol can be used to decrease symptoms of
estrogen deficiency is because estriol does bind to estrogen receptors. It
is generally accepted as common knowledge that estriol does not bind to cells
as strongly as estradiol does. However, as early as 1977 researchers found
that the binding effect of estriol was capable of partially overcoming the
antiestrogenic effect of Tamoxifen (Lippman, 77). In their abstract they concluded, "We
conclude that estriol can bind to estrogen receptor and stimulate human
breast cancer in tissue culture. Our data do not support an antiestrogenic
role for estriol in human breast cancer." So even before estriol
became popularized there was some disagreement about its ability to decrease
cancer risk. At the very least, if you are on Tamoxifen, be aware that
estriol may overcome the antiestrogenic effect of Tamoxifen. On of the
biggest questions about estriol (a.k.a 16-alpha-hydroxy-estradiol) is the
question “Is the increased cancer risk primarily due to abnormal estrogen
metabolism? This is demonstrated in: “Corresponding
data in patients with breast cancer revealed a significantly greater extent
of 16a-hydroxylation. Because the 16a-hydroxylated compounds (including
estriol {a.k.a 16-alpha-hydroxy-estradiol} ) are themselves potent estrogens,
these changes may have important hyperestrogenic consequences that could have
a bearing on the etiology of the disease.” (Schneider, 82). More
importantly, we need to ask: ”Do these women have inadequate 2-hydroxylation? This
concern about inadequate 2-hydroxylation is supported by the observance of relative increases of
16-alpha-hydroxylation byproducts in women with a history of breast cancer.
The observation is that high 16-alpha-hydroxy-estrone levels, in an environment of low 2-hydroxy-estrone is
associated with increased cancer risk. In
January 2000 an author reports "data suggest that use of oral estriol
may be associated with endometrial hyperplasia and endometrial
carcinoma" (Doren, 2000). If the increased intake
of 16-alpha-hydroxy-estriaol shifted to 2:16 ratio, that shift may be the
contributory cause for increased cancer risk. About 16 a-hydroxy-estrone (16-hydroxyestrone) For
those of us who study the Steroidogenic Pathway as well as
estrogen metabolites, it is understood that 16-hydroxyestrone is a metabolite
of estriol. You may see an example of this pathway on another website: Androgen and Estrogen Metabolism. You
will see the estrogen metabolism is the lower left-hand corner of the page.
The lines with arrows at both ends means the pathway can go either way. The
numbers in boxes next to the lines are links to the enzymes that cause the
metabolic change. Please
note that estriol is a metabolite of estradiol, which is then converted to
16-hydroxyestrone (bad metabolite). Estradiol may be alternatively
metabolized to the 2 hydroxy-estradiol (good metabolite) or back through
estrone into 16-hydroxyestone (bad metabolite) or on to 2 hydroxy-estrone
(good metabolite). Please note that estriol can be metabolized to
16-hydroxyestrone. I have not found anything that says estriol can be
metabolized backwards to other estrogens. I believe others have noted this as
well and have used this as a point for promoting estriol. I have found no
evidence that estriol is converted to 2-hydroxyestrones. A number of
references point out that estriol is actually as 16-hydroxy metabolite of
estradiol. In 1988, researchers identified increased
levels of 16-hydroxyestrone in women administered oral estriol (van Haaften, 88). At that point in
time the role that 16-hydroxyestrone plays in increasing breast cancer risk
was a new theory, but it caused the researchers to call for more studies. In
1992 researchers demonstrated that 16-hydroxyestrone has a cancer causing
effect that is similar to the mammary carcinogen 7,
12-dimethylbenz[a]anthracene (DMBA), a chemical used to produce cancer in
research settings. They concluded that 16-hydroxyestrone may actually
initiate the formation of cancer cells (Telang, 92). The fact that this study
was done on mice does not take away from the sobering message it delivers;
16-hydroxyestrone can cause cancer. In
1998 it was demonstrated that 16-hydroxyestrone and 16-hydroxyestradiol
stimulate the growth of established human breast cancer cells as much if not
more than estradiol. 2-hydroxyestrone and 2-hydroxyestradiols had a much
weaker effect and even decreased the stimulating effect of estradiol on
cancer cells (Gupta, 98).
Ideally,
estradiol metabolism would result in production of 2 hydroxy-estradiol and 2
hydroxyestrone, both of which inhibit breast cell proliferation. If this
pathway is overwhelmed then 16-hydroxyestone may be produced. Some pesticides
have been shown to cause a shift toward making more of the cancer forming
16-hydroxyestrone (Bradlow, 95). A low fat diet can
result in a significant decrease in both estriol and 16-hydroxyestrone (Longcope, 87). Estriol
As Hormone Replacement
If
estriol is going be considered as an estrogen that can be used for hormone
replacement therapy it is important to recognize that it can stimulate
breast, uterus and other tissues. It's own tissue stimulating effects are
weaker then estradiol, but that may be overcome by increasing the dose of
estriol (WYMT pg 289). Researchers noted that vaginal use of a daily dose of estriol
at 0.5 mg had the same effect as estradiol 0.05 mg daily. They
found that there were no clear differences between vaginal estradiol and
estriol medication in regard to the effects on vaginal and uterine tissues,
similar signs of estrogen stimulation of the endometrium were found following
estradiol and estriol medication (van Haaften, 97). It
should be noted that increasing the dosage of estriol to that it is 10 times
the dosage of what would be used for estradiol (0.05 x 10 = 0.5) will give
the same effects as estradiol. It may appear to be a good idea to take
estriol if it is 10 times weaker than estradiol in its ability to change
tissue. However, when estriol is given in 10 times the dose, the benefit of
its weakness is lost. A
1.25 mg "bi-est" tablet that is 10% estradiol and 90% estriol
(0.125 mg estradiol and 1.125 mg estriol) has the same biological effect as
0.237 mg of estradiol. That means it is as effective, as safe and as risky as
0.237 mg of estradiol. Likewise, a 2.5 mg capsule of pure estriol has the
same biological effect as 0.25 mg of estradiol. A 2.5 mg of
"tri-est" has the same biological effect as 0.65 mg of estradiol. But
there is one considerable difference. Estradiol can be metabolized through
2-hydroxylation, to make the “good metabolites” by using indole-3-carbinol (I3C)and
its derivatives (such as diindolylmethane). Eating cruciferous vegetables
such as broccoli, cauliflower and brussel sprouts provide I3C (WYMT pg
328-329). Though diindolymethane is one of the derivatives from
indole-3-carbinol, other derivatives may also be important, so consider using
indole-3-carbinol with diindolylmethane, or using indole-3-carbinol alone. In
addition to the cruciferous vegetables, isoflavones from soy and kudzu also
promote 2-hydroxylation. The
herb rosemary has also been found to increase 2-16-hydroxyestrone and
decrease 16-hydroxyestrone [Zhu, 98], so using consider this herb,
or using an I3C product that has rosemary in it. Now
go back and look at the Androgen and Estrogen Metabolism
chart again. Estriol is metabolized into 16-hydroxyestrone. The
goal of course is increasing the good estrogen metabolites. The substances indole-3-carbinol and its derivatives
will cause increased production of the healthy 2-hydroxyestrone (WYMT pg
328-329). Talk to your physician, nutritionist or compounding pharmacist
about indole-3-carbinol & rosemary products. Conclusion If
estriol is taken by mouth tissue levels of 16-hydroxylation may rise
considerably (van Haaften, 88). Vaginal estriol may
display similar signs of estrogen stimulation of the endometrium that can be
found following estradiol use (van Haaften, 97). Estradiol
and estrone can both be directed into 2-hydroxyalation by using supplements
and foods that unregulate 2-hydroxylation, such as indole-3-carbinol,
cruciferous vegetables, flax seed, soy, kudzu, rosemary and essential fatty
acids (specifically EPA). What’s The Next Step? First,
we should always be willing to challenge the myth that any hormone is
completely safe. We must realize that estriol has not only the benefits of
other estrogens, but also the risks of other estrogens. Some
women may still consider estriol a choice. For those women we need to provide
clear answers. Testing
the ratio of 16-hydroxyestrone to 2-hydroxyestrone in women on estriol should
be done. We also need to determine if we can shift the metabolism of orally
administered estriol using indole-3-carbinol, cruciferous vegetables, soy,
kudzu or rosemary. Ask
your physician, nutritionist or pharmacist about foods with promote ideal
estrogen metabolism. Consider
having a urine tests that measure 16-hydroxyestrone and 2-hydroxyestrone. Do
not change your hormone replacement without consulting your healthcare
professional. Dr.
Joseph J. Collins |
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Reviewed
& Updated 020205 |
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YourMenopauseType.com,
Inc. |
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