Hormones and Breast Cancer: Why the Confusion Won’t Go Away!

For decades, women have been caught in the middle of one of medicine’s most contentious debates. The question seems simple enough on the surface: does hormone replacement therapy (HRT) increase the risk of breast cancer? Yet after more than 80 years of experience with estrogen products, billions of prescriptions and many scientific studies, the answer about hormones and breast cancer remains surprisingly complicated.

The Premarin Paradox

The FDA first approved Premarin to treat menopausal symptoms in May, 1942. The conjugated estrogens in Premarin were made from pregnant mares’ urine. We suspect that is the origin of the brand name.

Few drugs have lasted as long or seen such extreme swings in popularity. Scientists refer to the formulation as conjugated equine estrogen (CEE).

Premarin grew in popularity from the post-war years through the 1960s (when Feminine Forever was a best-selling book) and the 1970s. By the 1990s, when the baby boomers began to hit menopause, doctors prescribed Premarin more often than any other drug in America. Women took it expecting not only to alleviate menopausal symptoms but also to improve their cardiovascular health and ward off osteoporosis.

But problems with the estrogen story started appearing early. In 1946 doctors published a case in which a woman on prolonged estrogen therapy developed endometrial cancer (JAMA, July 6, 1946).  The authors argued that estrogen was responsible for this cancer of the uterine lining.

It took decades for doctors to fully grasp the seriousness of this problem. In the mid 1970s Premarin was peaking in popularity. But major studies convinced many doctors that uterine cancer was too big a risk to ignore. Prescriptions plummeted!

Then physicians discovered that adding progesterone could protect the uterus from cancer. Sales soared once again. The makers of Premarin added progestin (medroxyprogesterone acetate or MPA) to the pill to create the brand Prempro.

The Women’s Health Initiative: Hormones and Breast Cancer

In the early 1990s the National Institutes of Health initiated the Women’s Health Initiative (WHI). The scientists wanted to know if hormone replacement therapy would reduce the risk of cancers, cardiovascular disease and bone fractures, as well as prolong life. It was the largest and most comprehensive study of hormone therapy ever conducted.

Because of the concerns about uterine cancer, many women received Prempro (estrogen plus progestin). Women who had had hysterectomies, however, received only estrogen (Premarin).

In 2002, the Women’s Health Initiative, was stopped early. Investigators had detected more strokes, cardiovascular events and cases of breast cancer among women on Prempro than among those on placebo (JAMA, July 17, 2002).

The WHI Turned Medicine Upside Down

Before the results of the Women’s Health Initiative were published in 2002, we would frequently hear from women who were worried that the use of HRT might be linked to breast cancer. In many cases, their physicians reassured them that there was no connection between hormones and breast cancer. They claimed that HRT was not only safe but essential for bone strength and heart health.

Here is a letter we published in our newspaper column on October 26, 1998, years before the WHI data were released:

Q. I am debating hormone replacement therapy. My doctor is very enthusiastic about Prempro, and says it will prevent osteoporosis and heart disease. My grandmother was crippled by spinal fractures so this is of concern.

I do worry about side effects such as breast cancer. My doctor downplays the danger but I would like to know as much as possible about all my options, including herbs, diet and exercise.

Then there was this from an irate husband:

“My wife is so angry at her physician that she can barely bring herself to schedule a visit. For years she was told to take Premarin and Provera. When reports surfaced that there might be a problem with breast cancer, she asked her doctor about this risk. He repeatedly reassured her that there was nothing to worry about. Hormones were so safe, he claimed, that his own wife was taking them.”

As mentioned above, The Women’s Health Initiative was stopped prematurely in 2002. Initially, the medical community greeted this news with a great deal of skepticism. Here is an example of what some women faced:

Doctor Fires Patient Over HRT

“I have been on hormone replacement therapy for ten years, and my doctor has always been a strong proponent of HRT. I have been uncomfortable taking this and have asked about its safety in the past. He maintained that the news media only picks out the negative results of studies and ignores the positives, and he has always convinced me to continue taking HRT.

“I called my doctor’s office to discuss the recent warnings and learned that he has not changed his position concerning the benefits of HRT. I informed the nurse that I was uncomfortable taking the hormones and was going to discontinue taking them. I was then shocked to receive a letter from my doctor saying he can no longer treat me since I don’t agree with his philosophy on these drugs.

“I’ve gone to this doctor for years, and he initially prescribed HRT for me ten years ago. I didn’t realize that if I opted to stop, he would refuse to treat me. I am in excellent health and have no medical reason to take hormones other than menopause. Is it acceptable for a doctor to respond in this manner, by ‘dumping’ a patient? I thought it was the patient’s choice whether or not to take HRT.”

Although initially many HRT proponents tried hard to poke holes in the data, most physicians eventually accepted that there was indeed an increased risk of cancer as well as cardiovascular disease associated with estrogen and progestin therapy.

But over the years the doubters began to gain ground. Some researchers described HRT concerns as “mass fear” and “hysteria.” These experts maintained that the benefits of hormone replacement therapy far outweighed the risks. If there was an increased risk of breast cancer, they claimed, it was extremely small and may have only represented an earlier diagnosis rather than a true cancer increase. They also suggested that if HRT were linked to breast cancer, any tumors would be easier to treat and less dangerous than “normal” breast cancer.

Fast Forward 20 Years: Hormones and Breast Cancer? More Complicated Than Ever

The Food and Drug Administration recently decided to remove longstanding warnings from official prescribing information for HRT.

Here is what the old “BOXED WARNING” used to say for Prempro:

“The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported an increased risk of deep vein thrombosis (DVT), pulmonary embolism, stroke and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogen (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo [see Warnings and Precautions (5.1), and Clinical Studies (14.6)].

“The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), and Clinical Studies (14.7)].

Breast Cancer

“The WHI estrogen plus progestin substudy demonstrated an increased risk of invasive breast cancer [see Warnings and Precautions (5.2), and Clinical Studies (14.6)].

“In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA and other combinations and dosage forms of estrogens and progestins.

“Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.”

On February 12, 2026 the FDA described its:

“Labeling Changes to Menopausal Hormone Therapy Products”

“The U.S. Food and Drug Administration has approved drug labeling changes to six menopausal hormone therapy products, also known as hormone replacement therapy (HRT), to clarify risk considerations for these drugs. Specifically, risk statements related to cardiovascular disease, breast cancer and probable dementia were removed from the ‘boxed warning,’ the agency’s most prominent safety-related warning.“

What Does the Research Tell Us About Hormones and Breast Cancer?

Here is where it gets incredibly confusing. Please remember that there were two key arms of the Women’s Health Initiative study. Women who no longer had a uterus because of hysterectomy only got estrogen in the form of conjugated equine estrogen (CEE). In other words, Premarin.

Women who still had a uterus received CEE plus progestin (medroxyprogesterone acetate or MPA). In other words, Prempro. The researchers analyzed both groups for a risk of breast cancer.

An analysis of the data from the Women’s Health Initiative was published on March 29, 2013 in the Journal of the National Cancer Institute. It established that HRT (with estrogen and progestin) increased the risk of breast cancer. The authors concluded:

“In summary, estrogen plus progestin use is associated with increased breast cancer incidence, especially when its use is initiated close to menopause.”

What About Estrogen by Itself?

A study published in JAMA (July 28, 2020) reported on the “Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women’s Health Initiative…”

The authors asked this important question:

“What is the association of estrogen plus progestin or estrogen alone with breast cancer incidence and breast cancer mortality?”

Conclusions:

“CEE [Premarin] alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases and was associated with statistically significantly lower breast cancer mortality with 30 deaths vs 46 deaths. In contrast, CEE plus MPA [Prempro] compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases vs 447 cases and no significant difference in breast cancer mortality with 71 deaths vs 53 deaths.”

In other words, estrogen alone (abbreviated CEE, aka Premarin) was associated with a lower risk of breast cancer. These were women who were not at risk of endometrial cancer because they no longer had uterine tissue.

Women who did have a uterus needed protection from uterine cancer and took Prempro (estrogen in the form of conjugated equine estrogen [CEE] plus MPA, aka medroxyprogesterone acetate). This group did have a higher risk of breast cancer.

A Recent Overview from Europe About Hormones and Breast Cancer

The “European Code Against Cancer, 5th edition” was published in the journal Molecular Oncology, (Jan. 2026).

The authors conclude:

“The updated report from the Collaborative Group on Hormonal Factors in Breast Cancer showed that every HRT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with the duration of use and these risks were greater for oestrogen–progestagen than oestrogen‐only preparations. Among current users, these excess risks were observed even during Years 1–4 of use (oestrogen–progestagen RR 1.60; oestrogen‐only RR 1.17) and were twice as great during Years 5–14.

“The updated 20‐year breast cancer mortality data from the Million Women study showed that current users as well as past users who used HRT for more than 5 years were at an increased risk of breast cancer death.

The authors also discuss the difference in data between “observational” studies and the randomized controlled trials of the Women’s Health Initiative:

“The evidence of association between oestrogen‐only HRT and breast cancer risk is not consistent across the study types. The observational studies consistently report increased breast cancer risk with the use of oestrogen‐only HRT, whereas the WHI trial suggests protective effects of oestrogen‐only HRT. This discrepancy may be explained by time to HRT initiation from the menopause and the interaction between oestrogen‐only HRT and adiposity”

“The evidence consistently points to vaginal oestrogen‐only HRT as not being associated with an increased risk of breast cancer.”

The updated recommendation on HRT from  the European Code Against Cancer, 5th edition:

“If you decide to use hormone replacement therapy for menopausal symptoms, after a thorough discussion with your healthcare professional, limit its use to the shortest duration possible.”

Another consideration is the risk of ovarian cancer. Twenty years after the Women’s Health Initiative, data show that unopposed conjugated estrogens doubled the risk for this rare but deadly cancer (Journal of Clinical Oncology, Oct. 20, 2024).  Combination therapy did not.

What About Bio-Identical Hormones?

We know that millions of women (and their healthcare providers) believe that “natural” or “bio-identical” hormones pose no risk of cancer or cardiovascular disease. We wish we had data like the Women’s Health Initiative to support that belief. There has never been a study comparable to the WHI for natural estrogens and progesterone. Consequently, we can draw no conclusions one way or the other.

Susan Love, MD, one of this country’s greatest breast cancer physicians, told us candidly that she did not think there was any significant difference between natural and synthetic hormones regarding cancer risk. She pointed out that women who have naturally high levels of hormones are at greater risk for breast cancer. You can’t get any more “bio-identical” than your own hormones.

Dr. Love commented that very little research has been done on such formulations, and there is no evidence that they are safer than other types of estrogen and progesterone. We only wish there were large, well-conducted randomized controlled trials to answer this important question.

A Doctor’s Dilemma

One physician summarized the dilemma like this:

Q. I am a family physician. Back when we were prescribing hormone replacement therapy (HRT) regularly, I used to offer women the option of plant-based estrogens instead of synthetic hormones. Since we learned the results of the Women’s Health Initiative (WHI), though, I’ve viewed all estrogens as carrying similar risk until proven otherwise.

There are practitioners who are saying that bio-identical hormones are safer. They encourage women to use them as an alternative for menopausal symptoms. Is there any research that shows that the risks are lower for plant-based HRT than for synthetic?

A. There is no comparable study of plant-based estrogens, and there is not likely to be one. The Women’s Health Initiative was a very large, expensive study, funded by the National Institutes of Health. Women’s health expert, Susan Love, MD, responded to a question like yours: “I think that it is very unlikely that bio-identical hormones, as they’re called, will be any safer than Prempro.”

Final Words

This is a large and complex topic. People have very strong feelings about hormone therapy. We encourage everyone to discuss the most recent data with their healthcare providers.

We are disappointed that the granddaughters and great-granddaughters of the first women who took hormone replacement therapy are still confronted with so many unanswered questions about this treatment.

Here is a quick overview of what has been presented above:

• Estrogen alone increases the risk of endometrial cancer (uterine cancer) in women who have an intact uterus.
• When estrogen, in the form of conjugated equine estrogen (CEE) and medroxyprogesterone acetate or MPA are combined, the risk of endometrial cancer is mitigated.
• When estrogen, in the form of conjugated equine estrogen (CEE) and medroxyprogesterone acetate or MPA are combined, the risk of breast cancer is increased.
• The longer a woman takes combined HRT, the greater the risk.
• Vaginal estrogen does not appear to increase the risk for breast cancer. (The European Code Against Cancer, 5th edition states: “The evidence consistently points to vaginal oestrogen‐only HRT as not being associated with an increased risk of breast cancer).
• There have been no long-term, large-scale randomized controlled clinical trials of bio-identical hormones comparable to the WHI study. We cannot draw any conclusions regarding safety without such a study.

We welcome your thoughts and experiences regarding hormone replacement therapy. We know that there are many women who have been incapacitated by menopausal symptoms. For them, HRT may be absolutely essential for well-being. For others, though, the connection between hormones and breast cancer may be too worrisome, especially if there is a family history of cancer.

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We have summarized information on estrogen and natural treatments for hot flashes and other symptoms in our Guide to Menopause.