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Does taking progesterone (alone or with estrogen) pose an increased risk for breast cancer?

QUESTION

“I am using Prometrium (oral micronized progesterone) 300 mg before bed, as it is the only intervention I have tried (pharmaceutical and naturopathic) that has worked.  I am in perimenopause and have skipped one period but I am very concerned about breast cancer, and can't seem to find any reliable information about how bio identical progesterone would affect risk. If you are able to shed light on this, it is much appreciated.”

ANSWER

Thank you for your excellent question about progesterone and breast cancer

Does taking progesterone pose an increased risk for breast cancer?

The short answer is NO! 

However, we have no randomized controlled trial data documenting that. (Note that some short, exploratory studies are now being done1).  

There has been no risk of breast cancer ever documented from taking progesterone alone(that means only physiological progesterone and not progestins) and without any estrogen. Obviously, the concern is that, at least intermittently now, your perimenopausal system is likely making high levels of estrogen. Soon your estrogen levels are likely to start returning toward normal menstrual cycle levels and then in two or three years will start becoming the low that is normal for menopause (starting one year after the last flow).

There is an important concern about breast cancer risks from progesterone. Why? because estrogen with progestins increase breast cancer risk based on a randomized controlled trial (the Women’s Health Initiative)2 and epidemiology (Million Women Study in Britain3 and the E3N study in France4) data from around the world. Note that both the British and French studies also showed increased breast cancer risk with estrogen alone3-5; we’ll come back to the controversy over that later.

The only large dataset providing answers about estrogen and progesterone and breast cancer risk is from the large (~80,000) French study. This is because oral micronized progesterone was created French scientists and clinicians and became widely used there before it has in the rest of the world. That study was in of women teachers with a particular insurance plan (E3N) who were followed over more than 8 years, were menopausal and whose breast cancers were carefully documented:

We need to answer two important questions:

1. How does progesterone act related to breast cancer risk6?

2. Why would progestins, synthetic “knock-offs” of progesterone, cause breast cancer?

  • Progestins are made from various steroid “base” molecules such as testosterone as well as progesterone itself.
  • To be called a “progestin” a synthetic hormone only has to do two of the many things that progesterone does in our bodies—causes the lining of the uterus to change from proliferative to secretory and preserve an existing pregnancy.
  • Progestins often have effects on the rest of the body’s cell (outside of the uterus) that are different from progesterone, often not known, and it is not possible to predict, without specific research, what these differences are.  
  • One family of progestins (norethisterone, norethisterone acetate and norethindrone) are metabolized into estrogens9
  • Specifically, the progestin in the WHI, medroxyprogesterone, acts in breast cells like a prednisone-type steroid and makes breast cells proliferate10

The controversy about estrogen-alone MHT and breast cancer risk

Most large, long-term studies of breast cancer risk show that estrogen-only MHT (except for only using it in the vagina) is associated with an increased risk for breast cancer 3-5. The single study that did not show that estrogen-alone caused breast cancer was the Women’s Health Initiative randomized controlled trial of conjugated equine estrogen (PremarinÒ) versus placebo11. That study, however, did not enrol enough women to have statistical power to be able to show either a positive or a negative risk12. That is like trying to see something very small and far away with a weak telescope—it is not possible.  The breast cancer risk was recorded as 20% decrease but the variation in risks ranged from decreased by 62% to increased by four percent and it was not statistically significant 13. In addition, the breast tumours were larger and tended to have positive nodes in women on estrogen versus placebo13, and were higher in those with a family history of breast cancer or a combined score for higher breast cancer risks 13. Therefore, I believe that the reasons this controlled did not show an increased risk for breast cancer on estrogen alone was simply that it did not originally have statistical power 12, was stopped at 7 rather than 15 years and by the time it was stopped over half of women had stopped their pills 13.    

In 2020, however, one of the prominent WHI breast cancer experts published a paper saying that 20 years later, that estrogen-alone “was significantly associated with a lower breast cancer incidence” and also a lower breast cancer death rate14. But that is a non-scientific assumption given that the original study was underpowered and could not show either increased or decreased risks! In addition, a well-publicized book is saying the same thing—that estrogen protects against breast cancer15. In my view these are unscientific and dangerous reports that do not fit with the whole of what we know about estrogen’s actions on breast cells10, and MHT with estrogen alone in menopausal women in large, long studies 3-5.

To end on a more personal note—I have a high risk for breast cancer because my mother had it. Yet I needed and took progesterone for 7 years for very difficult night sweats (waking me more than twice a week) and troublesome hot flushes. That is strong evidence I believe that that progesterone is safe related to risks for breast cancer.

 

 

Type: 
Articles
Updated Date: 
March 19, 2021

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