11/18/2025
What's Behind the Estrogen Black Box Warning Removal?
Just last week, the FDA made a major announcement regarding a black box warning on estrogen products. The black box warning has to do with increased risk of breast cancer for anyone using these products. This warning dates back about 20 years, and the FDA, with RFK Jr. in support, has retracted the alleged increase in breast cancer risk.
I thought it would be worthwhile to review the data which dates back over decades. It can be overwhelming, and a brief article perhaps won't do justice to the entire subject. But hopefully, I can capsulize some salient points for you.
I will start with the take home points:
This announcement is most helpful for women who have had a hysterectomy and have no history of breast cancer. This group should consider taking an estrogen supplement beginning with onset of menopausal symptoms, without fear of increasing their risk for breast cancer.
If you have a history of breast cancer, estrogen usage still comes with some risk, so still best to avoid, except for vaginal estrogen products for treatment of vaginal dryness and related symptoms.
If you have an intact uterus, there’s not too much in this news for you. If you have menopausal symptoms, you can take estrogen with progesterone, but there is a slight increase in breast cancer risk.
Brief History of Estrogen Supplements
Estrogen was first isolated in the 1920s and then was able to be extracted from the urine of horses for commercial production of estrogen as replacement therapy. It was first used for treatment of menopausal symptoms in the 1930s. Conjugated estrogens were sold as Premarin in the 1940s (and is still widely prescribed) and enjoyed widespread use in the 1950s. It was often prescribed indefinitely following menopause, with the presumption that it would extend youthfulness and femininity.
It was not until the 1970s that it became apparent that use of estrogen over time increased the risk for developing endometrial cancer. This risk, of course, was not an issue in women who had undergone a hysterectomy. For those with an intact uterus, it was reported that adding a small dose of progesterone to the estrogen eliminated the risk. And still today, if estrogen is used for menopausal symptoms in a woman with an intact uterus, the recommendation is to take estrogen with added progesterone. This is an important point that seems to have been lost in the publicity surrounding this recent announcement. Women with an intact uterus should not be taking estrogen by itself, rather estrogen combined with progesterone.
Estrogen enjoyed a very good reputation for all sorts of benefits through the 1970s and 1980s: for the relief of menopausal symptoms (most notably hot flashes and night sweats, vaginal dryness, and mood swings); the maintenance of bone density to prevent osteoporosis; and presumed improvement in cardiovascular risks. However, in parallel with the findings of increased risk for endometrial cancer, some early studies raised concerns about increased breast cancer risk as well.
Data Leading to Black Box Warning
These concerns led to several very large studies (the Nurses' Health Study, the Women’s Health Initiative Study (WHI), and the Million Women Study), designed to prove, if possible, one way or the other, whether hormone replacement therapy increased the risk of breast cancer and whether it decreased the risk for cardiovascular disease. Results reported at about the 5-year mark showed an increased risk for the development of breast cancer in women who were on estrogen, and in women who were taking combined estrogen and progesterone. Furthermore, there was reported an increase in cardiovascular risk as well. These landmark studies were the premise for adding the black box warning regarding increased breast cancer risk to virtually all estrogen products in the early 2000s.
Over the past twenty years, longer-term follow-up has found that what appeared to be an increased risk for breast cancer early on goes away if you follow these women over a longer time frame, and importantly, there appears to be no increased risk for dying of breast cancer. But it is important to be aware that taking both estrogen and progesterone, particularly over prolonged periods (e.g., ten years or more), definitely has an associated increased risk for breast cancer. Also, regarding cardiovascular risks, though more “events” might occur early on, there is no increased risk for death from cardiovascular disease.
As is often the case, published studies often have conflicting or nuanced results, and one really must dig into the data to come to trustworthy conclusions. I will try to summarize the conclusions I have come to in my review.
Summary Points
1) Estrogen comes in a wide variety of formulations and of varying compounds, and one cannot attribute the same risks and benefits to each one. The safest product is vaginal estrogen applied specifically for symptoms of vaginal dryness and dyspareunia (painful in*******se). There is no increased risk for breast or other cancer with these products. Its use is still not recommended in women who have a history of breast cancer, although it may be safe in those women as well.
2) The purported increased breast cancer risk attributed to estrogen was clearly overblown with the black box warnings added to all products 25 years ago. Estrogen by itself for menopausal symptoms appears to be safe. Furthermore, more recent reports have even found a decreased breast cancer risk with unopposed estrogen. For women who have had a hysterectomy and no history of breast cancer, I think there is compelling data to take estrogen, especially if menopausal symptoms are present. Benefits appear to far outweigh any risks in most women.
3) For women with an intact uterus, taking estrogen by itself is not an option due to the increased risk for endometrial cancer. For the general population, annual incidence of endometrial cancer is 28 per 100,000 women per year. Use of unopposed estrogen appears to double the incidence. This would mean that instead of 280 cases of endometrial cancer per 100,000 women over 10 years, there would be 560 cases. That added risk is just too high to consider this option.
4) For women taking estrogen with progesterone, the estimated increased incidence of breast cancer is between 8 and 18 cases per 100,000 women over 10 years. The general population has a breast cancer incidence of ~280 cases per 100,000 women over 10 years. So for women taking estrogen with progesterone, which is the only option for women with an intact uterus, the number of women with breast cancer would increase from ~280 to ~ 292 per 100,000 women over 10 years. I think most women and physicians would consider this an acceptable risk if there was strong enough reason to prescribe it, ie, significant menopausal symptoms.