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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?


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.



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.”


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.


Estrogen Metabolism


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.


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.


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



Reviewed & Updated 020205




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