Estriol and Breast Cancer

Dr. David Zava Clears Up the Confusion about the Hormone Estriol and its Breast Cancer Risk

Over the past few years controversy has erupted over the risk of developing breast cancer with estriol therapy. A study from Sweden (Rosenberg et al, 2006) suggests that estriol can increase risk of lobular carcinoma when used for five years or less, and decrease the risk when used for more than five years. Unlike estriol however, oral estradiol and synthetic progestins continue to increase risk, even after five years. The results of this study appear confusing because estriol does not continue to increase risk over time. The differences in the way estriol versus other more potent estrogens like estradiol initiate and promote the growth of cancer may help shed light on this confusion.

Estriol is a Bioidentical Hormone

Estriol is a type of estrogen that has been used clinically in many countries, including the U.S., for at least 60 years. I would suggest that physicians who are unsure about estriol go to their local medical library and look at the estriol research. One of the foremost estriol researchers was Dr. Henry Lemon, who spent decades of his career researching this hormone. I was lucky enough to be able to talk with Dr. Lemon shortly before he passed away. In 2001, Dr. John Lee, Virginia Hopkins and I completed the book, What Your Dr May Not Tell You about Breast Cancer: How Hormone Balance May Save Your Life, in which there is a substantial chapter about estriol. A lot of that information was gleaned by going into the library and looking at the research on estriol, and through my talks with Dr. Lemon.

Estriol Hormone Therapy in the Swedish Study

The Swedish study looked at how using different types of hormone replacement therapy affects the risk of ductal, lobular and tubular breast cancers. Ductal carcinomas are much more prevalent than lobular or tubular carcinomas. The longer a woman uses HRT, the higher her risk is for all three types of breast cancer. That’s pretty much what all the studies have shown about the use of estrogens along with a synthetic progestin, including the Women’s Health Initiative and the Million Women Study.

The Swedish study was unusual because it separated estriol therapy out from the other hormone therapies, and it was found that its risk factors are different than other forms of HRT. Overall, with estriol the risk of breast cancer is significantly less than with the estrogen-progestin type HRT. The risk for ductal carcinoma in estriol users goes up slightly for 5 years, and then the risk begins to decrease. The risk for lobular carcinoma is slightly higher, but then also begins to decrease after five years.

What Makes Estriol Different

To understand why estriol behaves differently from other HRT, it’s important to understand the differences between cancer initiation and cancer promotion. There are three basic stages to cancer: initiation, promotion and progression. Initiation of cancer occurs when there is damage to the DNA. The original primordial cell is damaged in some way by estrogen metabolites, ionizing radiation, chemicals or other factors. Once that cell is damaged, in order to turn into a tumor it has to have some growth advantage over the normal cells surrounding it. For breast cancers, it takes from 2 to 4 years for a single cancer cell to go through 10 doublings to make about a thousand cells. That’s still microscopic—you can’t see it with the naked eye. It takes about 20 more doublings before the tumor is million cells, and this is not much bigger than a small grain of rice.     It takes a fast-growing tumor 5 to 7 years and a slow-growing tumor 7 to 10 years before it can be palpated with your hands or visualized by mammography, and by this time the tumor contains hundreds of millions to billions of cells.

One of the things Dr. Lemon discovered in his research is that when you look at the ratio of estradiol and estriol in women, those populations that make more estriol have lower rates of breast cancer. The Japanese population, which has less breast cancer, has more estriol relative to estradiol, and lower overall estradiol levels. Dr. Lemon did experimental work on mammary tumors in rats. He found that rats given estriol prior to being given a carcinogen had a 90 percent reduction in the incidence of mammary cancers. Dr. Lemon concluded that estriol played an important role in allowing the differentiation of the normal stem cells in the breast that are more vulnerable to carcinogenic (cancer causing) insults.  He felt this was a key to breast cancer prevention. One of the hallmarks of a cancer cell is that it loses the ability for its growth to be controlled by its surrounding environment.

It’s not surprising that estriol is protective of the human genome because its level increases a thousand-fold during pregnancy, and is at its highest level just before birth.  I don’t think mother nature would subject the fetus, or the mother, to anything that’s harmful. If estriol is not damaging the fetus during a time when cells are undergoing the most rapid differentiation of that human being’s life, it’s not likely to be harmful later in life when it is used as a form of estrogen replacement therapy. So why the slight increase in lobular breast cancer, as seen in the 2006 Swedish study? An explanation, I believe, lies in how estriol interacts with cellular estrogen receptors in breast cancers that are already present at the time estriol is used as a form of estrogen replacement therapy. To understand this it is important to understand the differences in cancer initiation and cancer promotion.

Cancer Initiation vs. Cancer Promotion

As we detailed in the chapter “The Estrogens: Angels of Life, Angels of Death, in What Your Doctor May Not Tell You about Breast Cancer,” estrogen can be dangerous when it is metabolized down the wrong pathways. There are a lot of things that can drive estrogen down the wrong metabolic path, such as having too much of it without adequate progesterone, exposure to excessive levels of petrochemical products, eating trans-fats, and not getting adequate vitamins such as B6 and B12, which help to detoxify the bad estrogens. The most interesting thing about the differences in the three primary estrogens made in your body, estradiol, estrone, and estriol, is that only the first two, and not estriol, are capable of being converted by enzymes into what we call the bad estrogen metabolites that damage DNA. Estriol cannot be converted to a bad estrogen by these same enzymes, which may be why mother nature makes so much of it during pregnancy—to protect the fetus’ genome.

Estriol is a much safer form of estrogen because it isn’t metabolized into other hormones; it’s a one-way street. It never loses its unique identity. Estriol does not have the potential to damage DNA and initiate cancer like its sister estrogens, estradiol and estrone.

Estriol and Cancer Promotion

While estriol is not capable of initiating cancer, it can stimulate the growth of a preexisting cancer if the estriol concentration is high enough. Whether or not estriol stimulates breast cancer cell growth depends on the dose, the timing and the delivery system. When we’ve looked at studies of oral vs vaginal delivery of estriol, it’s pretty clear that when you drive the estriol concentration up high enough, you can get stimulation of the endometrial (uterus) lining and breast tissue.

Some excellent work came out of Dr. Isaac Schiff’s laboratory in Boston in the 1970s looking at the vaginal delivery of estriol. (Dr. Schiff is now Chief editor of the Menopause journal.) What Dr. Schiff’s laboratory found is that when estriol is delivered vaginally vs. orally you get a much greater increase in serum levels, which is why it takes less estriol with vaginal delivery to get the desired clinical response.

With the lower dosing of estriol recommended in most Western European countries and Japan, which is to use 0.5 mg vaginally every other day, the levels in the bloodstream remain quite low and have less growth-promoting effects on the uterine lining and breast cells. It is fascinating that estriol has a more potent estrogenic effect on the lower reproductive tract, especially the vaginal tissue, than it does on the uterine lining or breast cells. Researchers have found that the estrogen receptors in the lower reproductive tract have a higher affinity for estriol than they do for estradiol, and the reverse is true for the uterine lining and breast cells. This is why the lower vaginal dosing has been reported to help with vaginal dryness and atrophy (better and more potent response to estriol) without stimulating growth of the uterine lining or breast cells. However, I always remember the words of Dr. Lemon echoing in my ears, “If you give enough estriol it will act just like estradiol to stimulate the growth of the breast and uterine cells.” He emphasized that the trick to getting estriol to work successfully as a form of ERT that does not stimulate the breast cells, is to use it at the proper dosing.

Back to the 2006 estriol study on breast cancer, and how it relates to cancer initiation and promotion. There is little doubt that estriol does not convert to bad estrogens and initiate cancer. It is only those cancers that are already present in women after growing for many years (probably 5 to 7 years), whose growth is stimulated by estrogens, that makes them show up clinically a little faster. Estriol, like any other estrogen, was likely stimulating the growth of preexisting breast cancers in these women, which would explain why the study showed estriol is associated with a slight increased breast cancer risk.

What is different about estriol and the other estrogens, however, is that estriol did not continue to increase risk, and actually decreased it beyond 5 years. This is likely because, beyond 5 years of estriol therapy, there are no more tumors forming due to estriol’s protective actions on cancer initiation. This is a hypothesis, but it fits what we know about cancer initiation with estrogens and the growth rate of breast cancer.

Just imagine if we had a hormone therapy that helped prevent breast cancer initiation, like estriol, combined with a hormone that helped prevent cancer promotion caused by excessive estrogens (estriol included). This magic hormone already exists, and it’s called progesterone.

It’s ironic and sad that the two hormones that have the greatest potential to prevent breast cancer are now being maligned by our medical establishments as “potentially” having the same risks as more potent estrogens and synthetic progestins. Science says this just isn’t true. If one looks deep into the true motives of those worried about the risks of estriol and progesterone, it is easy to understand their position.


Rosenberg LU, Magnusson C, Lindström1 E et al, “Menopausal hormone therapy and other breast cancer risk factors in relation to the risk of different histological subtypes of breast cancer: a case-control study,” Breast Cancer Research 2006, 8: 18 Jan 2006.

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