Undoubtedly, the most common question I get about hormone replacement therapy (HRT) for women is some version of: “What about hormones and breast cancer?” It’s a fair question. After all, for the past 20+ years there has been a dogma among physicians and the public alike that HRT causes breast cancer. What I hope to do in this blog is show that this belief is false. I will argue that the combination of bioidentical estrogen and progesterone not only does not increase the risk for breast cancer, but a strong argument can be made that it is actually protective against breast cancer. Now, if you are already well-informed about this subject you know that I am not the only one arguing this. Lots of well-known voices in medicine who are much smarter than me have come to this same conclusion. But despite this, the concern about “hormones and breast cancer” remains deeply embedded not only in the public, but among many health care providers as well.
Breast Cancer and The Women’s Health Initiative
The belief that HRT causes breast cancer stems from the Women’s Health Initiative (WHI), the large NIH-sponsored, randomized controlled trial (RCT) that was first published in 2002. I described the background to the WHI in my last blog about Estrogen and Cardiovascular Disease, but I will briefly review the methodology again here, because understanding the study design is so crucial to understanding the relationship between HRT and breast cancer.
The purpose of the WHI was to formally test whether HRT for postmenopausal women was safe and effective. A number of health outcomes were evaluated, with cardiovascular disease and breast cancer being highest on the list.
The WHI was actually two parallel studies. One study tested the combination of estrogen and progestin compared to placebo, and the second study tested estrogen-alone compared to placebo. The first study with estrogen and progestin was performed in women with an intact uterus (i.e. women who had never had a hysterectomy), and the second study with estrogen-alone was performed in women without a uterus (i.e. those with a history of a hysterectomy). The reason progestin was used in the first study is because when giving estrogen to women with an intact uterus, a form of progesterone must be added to protect against proliferation and cancer of the endometrium. We will see in a moment that the presence of two trials, one involving estrogen and progestin vs. placebo, and one involving estrogen alone vs. placebo, becomes extremely important to the interpretation of the study.
The estrogen used in the WHI was conjugated equine estrogen, or Premarin. Premarin is estrogen derived from female horses. There are similarities between horse and human estrogen (human estrogen is what is known as bioidentical estrogen), which account for why Premarin is effective at providing many of the well-known benefits of HRT to menopausal women. But a number of important differences exist between horse and human estrogen, which account for the adverse effects seen with horse estrogen (such as blood clots) that are not seen with bioidentical estrogen.
The form of progesterone used in the study was progestin. Progestin is a synthetic form of progesterone. This is extremely important to the interpretation of the study as well. Progesterones, broadly speaking, can be categorized as either micronized progesterones or synthetic progestins. Micronized progesterones are bioidentical hormones that have a molecular structure that is identical to human progesterone. Progestins differ from natural progesterone in molecular structure. Progestins are synthesized from various compounds and it is their specific chemical structure that determines their potency and how they interact with the progesterone receptor.
In the 1990’s, when the WHI was designed, the most common form of HRT was Premarin and synthetic progestin, and those are the hormones that were used in the study. Today the most common forms of HRT used are bioidentical estrogen and progesterone (thus the term BHRT: bioidentical hormone replacement therapy).
Women’s Health Initiative: Results
All right, enough background. Let’s review the results of the WHI, specifically how they pertain to breast cancer. The first results of the Premarin/Progestin study (I’ll call this the Prem/Pro study going forward) were published in 2002 and showed a 26% increase in breast cancer, relative to placebo, in women who received Prem/Pro. This received enormous attention at the time, both in medical circles and in the lay media, and understandably so.
The first results of the Premarin alone study were published in 2004. Interestingly, the rate of breast cancer was decreased by 23%, relative to placebo, in the women randomized to Premarin. This decrease in breast cancer was not statistically significant at first, and thus did not receive much attention (actually the increase in breast cancer in the Prem/Pro study was also not initially statistically significant, but this did not stop the media hype).
This decrease in breast cancer risk with Premarin, albeit not initially statistically significant, was really remarkable, but it’s even more interesting to see how these results evolved over time. The active phase of these two clinical trials stopped in 2002 and 2004, respectively, but the researchers continued to gather data on the study participants. Long-term data from both trials, after they had followed participants for an average of 20 years, were published in JAMA in 2020. In the Prem/Pro study, there was a statistically significant 28% increase in breast cancer incidence, however there was no significant difference in breast cancer mortality. In the Premarin alone study, there was a 22% decrease in breast cancer incidence, and a 40% decrease in breast cancer mortality, both of which were statistically significant. These are highly meaningful numbers, in particular the decrease in breast cancer mortality. To quote the 2020 JAMA publication: “Prior use of CEE (Premarin) alone is, to our knowledge, the first pharmacologic intervention demonstrated to be associated with a statistically significantly reduction in deaths from breast cancer.”
So here’s the bottom line: Premarin plus Progestin increased the risk of breast cancer. Premarin alone decreased the risk of breast cancer. Not only that, it had an even stronger effect on decreasing breast cancer mortality. We can firmly conclude from this that Premarin protects from developing breast cancer, and it was specifically Progestin, the synthetic form of progesterone, that caused the increase in breast cancer. Today we do not use Progestin in HRT, we use bioidentical micronized progesterone, and there is very good reason to believe that micronized progesterone does not raise breast cancer risk, which we will review below.
These long-term results are really important, but unfortunately are not widely known. To paraphrase Peter Attia, there was an incredible asymmetry between the mega-phone that was used broadcast the initial breast cancer connection with Prem/Pro 20 years ago, and the relative silence in communicating the decrease in breast cancer incidence and mortality seen from Premarin alone. And that is why this breast cancer risk remains entrenched in our minds and remains the primary concern for women considering HRT today.
What Do Other Studies Show About Estrogen Alone?
Is it possible that the WHI was an anomaly? What do other RCTs tell us about the effect of estrogen on developing breast cancer? If anything, they show an even stronger protective effect. It’s important to remember that the WHI is by far the largest RCT that has ever been done looking at HRT and breast cancer or any other outcome. Indeed, when they combine all the other RCTs that have tested estrogen-alone on breast cancer incidence, the cumulative number of participants in all those trials is still less than the number of participants in the WHI. But it is still an interesting exercise, and Chlebowski et al did just that in a study published this year. They found 9 RCTs that included a total of 3,543 participants (the WHI had 10,739 participants). In a meta-analysis of the 9 smaller trials, women randomized to estrogen alone had a 35% decreased risk of subsequent breast cancer compared to those randomized to placebo. When they combined these 9 smaller studies with the WHI, there was a 23% decreased risk of breast cancer relative to placebo (recall the WHI showed a 22% decreased risk…so essentially the same).
Bioidentical Progesterone and Breast Cancer Risk
The WHI clearly showed that Progestin, the synthetic form of progesterone, increased the risk of breast cancer, but what about micronized progesterone, the bioidentical form of progesterone that is more commonly used for HRT today? To my knowledge there has never been an RCT evaluating the effect of micronized progesterone (with or without estrogen) on risk of breast cancer. So here we have to revert to looking at epidemiological data. Such studies are considered to be lower quality than RCTs, but in the absence of RCTs they are still important to review.
The first study I want to look at is called the E3N-EPIC study, which was a large cohort study performed in France. This study assessed the risk of breast cancer in 54,548 postmenopausal women who were using various forms of HRT. For HRT containing synthetic progestins, the breast cancer risk was 40% higher compared to women not using HRT, which was a statistically significant increase. For HRT containing bioidentical micronized progesterone, there was no difference in breast cancer risk compared to women not using HRT (the breast cancer risk was actually decreased by 10% for micronized progesterone, but this was not statistically significant).
A more recent population study was performed in the U.K. and utilized the U.K Clinical Practice Research Datalink. They assessed 431,830 women aged 50 years and older to evaluate whether breast cancer risk was dependent on the type of HRT used. For HRT containing synthetic progestins, there was a 28% higher risk of breast cancer compared to women not using HRT, which was statistically significant. For HRT containing bioidentical micronized progesterone, there was no difference in breast cancer risk compared to women not using HRT (technically it was 1% lower, which was not statistically significant).
The point with both these population studies is that there was a clear difference between the increased risk seen with synthetic progestin (the 40% and 28% increase in risk were both very much in line with what the WHI showed in the Prem/Pro study) compared to the absence of increased risk seen with bioidentical progesterone.
HRT In Breast Cancer Survivors
There is one final issue I would like to address: the use of HRT in women who have a history of breast cancer. Just as there has been a dogma in medicine that HRT causes breast cancer, there has also been a dogma that women diagnosed with breast cancer should not use HRT. This belief is also not supported by the medical literature. If you are interested in reading about his issue further, there is a wonderful book published in 2018 called Estrogen Matters written by Avrum Bluming, MD and Carol Tavris, PhD. In addition, Dr. Bluming has written a number of peer-reviewed research publications on this subject, including one titled “Hormone Replacement Therapy After Breast Cancer; It Is Time” which was published in The Cancer Journal in 2022. This is a great article that is worth your read, and I wanted to briefly summarize it here.
Bluming reports there were 25 studies published between 1980 and 2013 that evaluated the use of HRT in breast cancer survivors (5 of these were RCTs, the rest were cohort studies). Of the 25 studies, 5 reported fewer breast cancer events among those receiving HRT, and 4 reported reduced mortality from breast cancer. Four out of 5 of the RCTs reported no increase in breast cancer events among survivors randomized to HRT. One RCT, however, reported an increase in breast cancer recurrence (15% vs. 5%) among those randomized to HRT compared to placebo. The increase in breast cancer was seen only as local recurrences or contralateral tumors, and there was no increase in the development of distant metastases, nor was there an increase in the risk of death.
Therefore, only 1 out of 25 studies published over a 33 year time period found an increased risk of breast cancer recurrence, and in that one study the risk was local only, with no increased risk of systemic recurrence or mortality. Furthermore, these studies were published during the time period in which those using HRT would have mostly used progestin (synthetic progesterone) as the source of progesterone. Because we have already seen from the WHI and other studies that progestin does slightly increase the risk for breast cancer, it makes this finding even more remarkable. The use of bioidentical estradiol and micronized progesterone, with all of their associated benefits, should not be denied to survivors of breast cancer because 1 study out of 25 showed an increase in (local only) breast cancer recurrence and in that one study progestin was the progesterone agent used.
Conclusion
Bioidentical hormone replacement therapy has tremendous potential benefits for menopausal women, both in the short-term improvement of quality of life, and in the long-term prevention of chronic disease. Potential benefits range from treatment of menopausal symptoms (hot flashes, night sweats, disrupted sleep, fatigue, joint pain, mood swings, and more), to improved bone strength and reduced risk of osteoporosis, to prevention and treatment of genitourinary syndrome of menopause (vaginal atrophy, urinary leakage, risk for UTI), and to reduced risk of cardiovascular disease. For the past 20 years many women have been discouraged from using BHRT due to a perceived association with breast cancer. Based on the most up-to-date view of the medical literature, women may freely pursue the benefits of BHRT without being worried that it will increase their risk of breast cancer.
References
Rossouw et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33. PMID: 12117397.
Women's Health Initiative Steering Committee. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004 Apr 14;291(14):1701-12. PMID: 15082697.
Chlebowski 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 Jul 28;324(4):369-380. PMID: 32721007.
Chlebowski et al. Randomized trials of estrogen-alone and breast cancer incidence: a meta-analysis. Breast Cancer Res Treat. 2024 Jul;206(1):177-184. Epub 2024 Apr 23. PMID: 38653905.
Fournier et al. Breast cancer risk in relation to different types of hormone replacement therapy in the E3N-EPIC cohort. Int J Cancer. 2005 Apr 10;114(3):448-54. PMID: 15551359.
Abenhaim et al. Menopausal Hormone Therapy Formulation and Breast Cancer Risk. Obstet Gynecol. 2022 Jun 1;139(6):1103-1110. Epub 2022 May 3. PMID: 35675607.
Bluming AZ. Hormone Replacement Therapy After Breast Cancer: It Is Time. Cancer J. 2022 May-Jun 01;28(3):183-190. PMID: 35594465.