“I am using PrometriumÒ (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.”
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 (the most important kind of scientific study) documenting that. (Note that some short, exploratory studies are now, finally, starting to be done2).
There has been no risk of breast cancer ever documented from taking progesterone alone1. Note—when I write “progesterone,” I mean only the physiological kind of hormone our ovaries make, and notprogestins. I also mean progesterone alone and without any estrogen therapy. One study in France showed that treatment with progestins (usually to treat breast tenderness or heavy flow that are likely from high estrogen levels) in menstruating, midlife women was associated with a small increased breast cancer risk 1. (Taking cyclic or daily progesterone https://www.cemcor.ca/resources/topics/cyclic-progesterone-therapy would be safer and better treatment for breast tenderness or heavy perimenopausal flow [respectively].)
Obviously, you are now in perimenopause when your ovaries are likely, at least part of the time, to be making high estrogen levels3. Because you’ve skipped a period, soon your estrogen levels will be returning toward normal menstrual cycle levels; in two or three years, you will only be making the low estrogen and progesterone levels that are normal for menopause (starting one year after the last flow).
Why the concern that progesterone increases breast cancer?
The confusion originated with the Women’s Health Initiative documentation of increased breast cancer risk in women randomized to take estrogen with progestin versus placebo4. In other words, doctors/scientists/media are mixing up the synthetic progesterone “knock-offs” called “progestins”, with our body’s natural progesterone hormone. Progestins are not progesterone.
Menopausal Hormone Therapy (MHT) is usually combined estrogen and progestin (unless a woman has had a hysterectomy). Several MHT studies have shown estrogen-progestin therapy caused breast cancer: Women’s Health Initiative (WHI) estrogen-progestin trial4 as well as two large observational studies (Million Women Study in Britain5 and the E3N study in France6). Estrogen treatment alone, however, has repeatedly been shown to increase breast cancer risk, including in both the British and French studies5-7. The only estrogen-alone study that did not show increased breast cancer risk was the WHI estrogen-only trial8.
We’ll come back to the controversy over those data later.
The only large dataset providing answers about breast cancer risk from estrogen and progesterone treatment in menopausal women is the large (~80,000 women over eight years) French study6. Oral micronized progesterone was created by French scientists and clinicians; consequently, progesterone became widely used there, years before it became available and/or prescribed in the rest of the world. That French study was in women teachers with a particular insurance plan (E3N), who were menopausal and whose breast cancers were carefully documented:
NOW we need to answer two important questions:
1. How does progesterone act in our breasts related to breast cancer risk9?
- Estrogen causes cells to grow or proliferate10—if that occurs without being limited or slowed, estrogen can promote genetic errors and possibly cancer.
- Progesterone decreases proliferation/cell growth while encouraging cells to become more specialized or mature10—progesterone’s actions decrease cancer risk.
- When progesterone is present, its receptors make the estrogen receptor no longer able to cause breast cells to grow or proliferate11.
2. Why would progestins, synthetic progesterone “knock-offs,” increase breast cancer?
- Progestins are made from various steroid “base” molecules such as estrogen, testosterone, and a few from progesterone itself.
- To be called a “progestin,” the synthetic hormone only has to do two of the many things that progesterone does in our bodies:
1) cause the lining of the uterus to change from proliferative to secretory;
2) preserve an existing pregnancy.
- Progestins often have non-uterus effects on the rest of the body’s cells that are different from progesterone’s actions. These progestin effects are largely unknown, and usually impossible to predict. Few progestins have been carefully studied for all of their effects throughout women’s bodies.
- One family of progestins (norethisterone, norethisterone acetate and norethindrone) are metabolized so they become estrogens12.
- Medroxyprogesterone, the progestin used in the MHT estrogen-progestin WHI randomized controlled trial, acts in breast cells like prednisone (a commonly prescribed “steroid” hormone)—it makes breast cells proliferate13.
The controversy about estrogen-alone MHT and breast cancer risk
Large, long-term studies of breast cancer risk show that estrogen-only MHT is associated with an increased risk for breast cancer5-7(unless it is just applied to the vagina). The single study that did not show that estrogen-alone caused breast cancer was the WHI estrogen-only randomized controlled trial8. That design should make it the strongest evidence since it is a randomized, placebo-controlled trial. However, it did not enrol enough women to have statistical power to be able to show anything about breast cancer risk, either positive or negative14. The estrogen-only trial enrolled fewer than 11,000 women but needed 25,000 to have power to show breast cancer risk. In addition, the statistical power decreased further because the trial was stopped after seven rather than the planned 15 years. Lack of statistical power is like trying to see something like a tennis ball a mile away with a weak set of binoculars—it is not possible.
The breast cancer risk in the estrogen-only WHI trial was not statistically significantly different on estrogen than on placebo15. The result showed a 20% decrease15 but the huge variance—from cancers being decreased by 62% to increased by 4%—indicates lack of statistical power. Also, the breast tumours that occurred in women taking estrogen were larger and tended to have more positive lymph nodes versus cancers in women taking placebo15, supporting that estrogen was likely risky. Women on estrogen alone, as expected, were at greater cancer risk if they had a family history of breast cancer or a higher breast cancer risk score15. Therefore, this controlled trial did not show an increased risk for breast cancer on estrogen-alone simply because it did not have statistical power to show anything about breast cancer14 15.
It has become popular to claim estrogen does not increase breast cancer
In 2018 a well-publicized book co-written by a psychologist and doctor asserted that estrogen therapy protects against breast cancer17.
In 2020, 20 years after the WHI estrogen-only trial began, a prominent breast cancer researcher published a paper saying that estrogen-alone “was significantly associated with a lower breast cancer incidence”16. It also claims that estrogen-randomized women with breast cancer had a lower breast cancer-related death rate than those on placebo16. Those conclusions are not scientific. Given that the original trial was underpowered to test for breast cancer risk, follow-up studies could not show that estrogen treatment either increased or decreased breast cancer.
The 2018 book and the 2020 WHI follow-up paper do not mention the well-documented power issue14 nor integrate all we know about estrogen’s actions on breast cells13, and about the breast cancer risk in hundreds of thousands of women who have taken estrogen-alone MHT in large and long studies5-7.
In summary, multiple evidence shows that one of progesterone’s “jobs” is to decrease the risk for breast cancer. It does that by decreasing the proliferation/ overgrowth-promoting actions caused by estrogen9, and by transforming estrogen’s actions in breast cells to decreased proliferation11. Scientific evidence says that women should never take estrogen therapy without progesterone (the uterus is only one part of women’s body that needs balanced estrogen and progesterone). A woman who has had a hysterectomy and lacks a uterus still has a brain, breasts and bones that need progesterone. Furthermore, balanced actions of progesterone and estradiol (ideally delivered through the skin rather than by mouth to decrease blood clots) are needed following the pattern of the normally ovulatory menstrual cycle9.
Estrogen causes an increased risk for breast cancer.
Estrogen with progesterone decreases or prevents breast cancer.
Progesterone alone does not cause breast cancer.
1. Fabre A, Fournier A, Mesrine S, et al. Progestagens use before menopause and breast cancer risk according to histology and hormone receptors. Cancer EpidemiolBiomarkers Prev 2008;17(10):2723-28.
2. Carson E, Segara D, Parker A, et al. The WinPro study: A window of opportunity study of endocrine therapy with and without prometrium in postmenopausal women with early stage hormone receptor-positive breast cancer. Cancer Res 2019;79((4 Supll)) doi: 10.1158/1538-7445.SABCS18-OT1-01-03
3. Prior JC. Perimenopause: The complex endocrinology of the menopausal transition. Endocrine Reviews 1998;19:397-428.
4. Writing Group for the Women's Health Initiative I. Risks and benefits of estrogen plus progestin in health postmenopausal women: prinicpal results from the Women's Health Initiative Randomized Control trial. JAMA 2002;288:321-33.
5. Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2003;362(9382):419-27.
6. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107(1):103-11. doi:
7. Beral V, Banks E, Reeves G, et al. The effect of hormone replacement therapy on breast and other cancers. In: Critchley H, Beral V, Gebbie A, eds. Menopause and hormone replacement. London: RCOG Press 2004:136-50.
8. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA 2004;291(14):1701-12.
9. Prior JC. Women’s Reproductive System as Balanced Estradiol and Progesterone Actions—a revolutionary, paradigm-shifting concept in women’s health. Drug Discovery Today: Disease Models 2020:31-40.
10. Clarke CL, Sutherland RL. Progestin regulation of cellular proliferation. Endocrine Reviews 1990;11:266-301.
11. Mohammed H, Russell IA, Stark R, et al. Progesterone receptor modulates ERalpha action in breast cancer. Nature 2015;523(7560):313-17.
12. Pasapera AM, Gutierrez-Sagal R, Herrera J, et al. Norethisterone is bioconverted to oestrogenic compounds that activate both the oestrogen receptor alpha and oestrogen receptor beta in vitro. EurJ Pharmacol 2002;452(3):347-55.
13. Courtin A, Communal L, Vilasco M, et al. Glucocorticoid receptor activity discriminates between progesterone and medroxyprogesterone acetate effects in breast cells. Breast Cancer ResTreat 2012;131(1):49-63.
14. Anderson G, Cummings S, Freedman LS, et al. Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. Control Clin Trials 1998;19(1):61-109.
15. Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295(14):1647-57.
16. Chlebowski RT, Anderson GL, Aragaki AK, et al. Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials. JAMA 2020;324(4):369-80. doi: 10.1001/jama.2020.9482 [published Online First: 2020/07/29]
17. Bluming A, Tavris C. Estogen matters. Why taking hormones in menopause can improve women's well-being and lengthen their lives - without raising the risk of breast cancer. New York: Little, Brown Spark 2018:1-302.
May 10, 2021—CeMCOR appreciates the excellent feedback on this article provided by Lara Briden ND, and Laura Wershler.