The FDA Has Removed the Black Box Warning From HRT: 9 Things to Know

Since the Food and Drug Administration (FDA) announced last month that it was removing the “black box” warning label from most hormone replacement therapy (HRT) drugs used during menopause, there’s been a lot of talk about the benefits of these medicines. 

A black box label is the strictest safety warning the FDA gives, used to show that a group of medications poses serious health risks. For more than 20 years, the agency warned that all forms of estrogen-containing menopause HRT drugs — also known as menopause hormone therapy, or MHT — raise the risk of health problems, including breast cancer. Recent research has shown that the risks are more nuanced than previously thought and may, for some, be outweighed by the benefits, even with a history of breast cancer.

Major medical groups, including the American College of Obstetrics and Gynecologists (ACOG), applauded the label change for vaginal estrogen, a low-dose HRT. There was some controversy, however, about how the FDA made the changes to labels for systemic HRT (systemic means it travels throughout the body). Usually, removing a black box warning label involves a more extensive and transparent review process. 

Experts spoke about hormone replacement therapy for people with breast cancer during a session at the San Antonio Breast Cancer Symposium last week. They advised that, regardless of the label change, people with a personal or family history of breast cancer should weigh the risks and benefits of menopause hormone therapy with a trusted health care provider. That’s because taking systemic HRT medicines can increase the risk of breast cancer occurring or coming back (recurrence), and that risk varies depending on the type of breast cancer diagnosis.  

Here are nine things to keep in mind about HRT after the FDA label change.

Many people understandably have whiplash when it comes to the recommendations around the safety of  menopause hormone therapy. Lisa Larkin, MD, an internal medicine and women’s health physician from Ohio who spoke at the session, described the shift in messaging as a pendulum swing — from overemphasizing the risks and ignoring the benefits to overemphasizing the benefits and minimizing the risks. “I’m particularly worried,” Larkin said, “about the impact of this messaging when it comes to our breast cancer survivors when the data is unclear.”

Many people with a history of breast cancer can benefit from HRT, but the risks and benefits will be different for each person. The best treatment for you will depend on your symptoms, age, overall health, and cancer history. When it comes to menopause hormone therapy for people at risk of breast cancer and breast cancer survivors, “one size does not fit all,” Tara Sanft, MD, who moderated the session on menopause hormone therapy, told The Breastcancer.org Podcast. Sanft is an associate professor of medicine at the Yale School of Medicine and director of the Yale Survivorship Clinic. 

“It's a very nuanced, personalized decision, so it's very important to have that discussion with your oncologist and gynecologist,” says Parijatham Thomas, MD, who did not present at the session. Thomas is medical director for the cancer prevention center and associate professor of breast medical oncology at the University of Texas MD Anderson Cancer Center.

Vaginal estrogen is a low-dose topical HRT that can be used to help treat vaginal dryness. It can be a topical gel or a ring, cream, or tablet that’s placed in the vagina. When the FDA first applied the box warning to HRT products in 2003, it included topical therapies out of concern that vaginal estrogen could be absorbed into the body. Studies since then show that little to no estrogen enters the bloodstream. Recent studies indicate that vaginal estrogen is generally safe for people who have been diagnosed with breast cancer. 

Systemic HRT — such as pills, skin patches, and shots — raise hormone levels throughout the body.  In women over the age of 50 with no history of breast cancer, research shows that taking combination systemic HRT (which contains both estrogen and progesterone) for five or more years can slightly increase the risk for breast cancer. People who use high-dose systemic HRT may also develop dense breasts, which makes it harder to spot cancer on a mammogram. 

Historically, systemic HRT was not prescribed to people with a breast cancer history because it can increase the risk of recurrence, especially in those with hormone-receptor positive breast cancer. In recent years, however, more experts have begun to acknowledge that, for people with certain diagnoses, the recurrence risk may be lower than thought. For them, the quality-of-life benefits of systemic HRT may outweigh the risk of cancer recurrence if their menopausal symptoms are severe. 

If HRT isn't an option for you, there are a couple of new non-hormonal drugs for menopause symptoms for you to consider. In 2023, the FDA approved Veozah, the first non-hormonal pill to treat moderate to severe hot flashes. And just this fall, the agency greenlit Lynkuet for hot flashes. 

The FDA said it will still warn of the risk of uterine and endometrial cancer associated with estrogen-only HRT. Estrogen-only therapy is typically prescribed to people who have had their uterus removed through a hysterectomy. (Most HRT drugs used for menopausal symptoms contain the hormones progesterone and estrogen.) In women with no history of breast cancer, estrogen-only HRT is not linked to a higher risk of breast cancer. 

If you’re going to take a systemic HRT, studies show that it’s best to start taking it within 10 years of menopause symptoms starting. Also consider your age: The risk for breast cancer increases when people start HRT after the age of 60. Lastly, if you take a systemic HRT, Thomas recommends using the lowest dose for the shortest amount of time possible to minimize your breast cancer risk. 

Findings from the Women’s Health Initiative — the longest and largest study of HRT so far — informed the FDA’s original decision to add a black box warning. Many questions still remain about the effects of menopausal hormone therapy on people with breast cancer, explained Maryam Lustberg, MD, MPH, who presented at the session. Lustberg is the director of the Center for Breast Cancer at Yale. Specifically, she noted that more studies are needed to understand the benefits and risks of menopause hormone therapy for people with metastatic breast cancer, those on ovarian suppression and aromatase inhibitors, and those taking SERDs.

Some HRT options work in different ways, and some may be safer than others for people with certain breast cancer risk or history. “Is it possible to give such agents to our breast cancer survivors and manage certain symptoms without increasing their breast cancer risk?” Thomas said. “That's what we’re still trying to figure out, especially for newer formulations.”