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Hormone therapy to treat the symptoms of menopause and perimenopause will no longer carry the strongest safety warning, the head of the Food and Drug Administration (FDA) announced Monday. 

FDA Commissioner Dr. Marty Makary told CBS News’ Norah O’Donnell on Monday morning in advance of the official announcement that the black box warning would be removed from many drugs containing progesterone and estrogen, in both topical and systemic forms. “With the exception of vaccines or antibiotics, there’s no medication that can improve the health of women on a population level more than hormone replacement therapy,” Makary said.

(The Menopause Society notes that the correct term for these medications is “hormone therapy,” not “hormone replacement therapy.)

All menopause treatments containing estrogen — including pills, patches, spray and creams — have since 2003 carried a black box warning, the strongest class of warning issued by the FDA on medication. The announcement from the FDA and the Department of Health and Human Services (HHS) will apply to all hormone therapy medications that currently carry a black box warning. 

However, there are some exceptions. In an email to The 19th, Andrew Nixon, the director of communications for HHS, noted that “the agency is working with companies to update language in product labeling to remove references to risks of cardiovascular disease, breast cancer, and probable dementia. The FDA is not seeking to remove the boxed warning for endometrial cancer for systemic estrogen-alone products. We are hopeful that the companies can make these changes within the next several months.”

In the announcement about hormone therapy labeling, Makary talked about watching the impact that barriers to these treatments had on his own mother, who began perimenopause right around when the original black box warning was implemented over 20 years ago. She was never offered hormone therapy as a result, he said. “She went on to have two different falls recently where she had bone fractures. … And I can’t help but think if her bones had been stronger from hormone replacement therapy, she wouldn’t have gone through that,” Makary said. 

How is estrogen used during menopause treatment?

Two main forms of hormone therapy are prescribed to treat symptoms of perimenopause and menopause. 

First is what’s known as systemic therapy, or the use of hormones absorbed through the bloodstream. These therapies can take the form of combined hormone pills or estrogen patches, sprays or gels. Systemic therapy is often used to treat vasomotor symptoms, like hot flashes and night sweats. 

The second type of hormone therapy is vaginal estrogen, which uses low-dose estrogen administered directly into the vagina through either a cream or suppository. It is often used to help with vaginal dryness, burning, itching and can help reduce recurrent urinary tract infections. 

For years, there has been debate over the black box warning on estrogen, and many experts say that it was never necessary for vaginal estrogen therapy. 

Dr. Monica Christmas, the associate medical director of the Menopause Society, told The 19th that local, vaginal estrogen therapy is safe for the vast majority of people, regardless of other medical conditions, and has minimal systemic absorption. For those drugs, the black box warning “shouldn’t have been there in the first place,” she said.

There are more considerations, though, when it comes to systemic-dose estrogen, she said, such as for people who have had or at risk of  estrogen-receptor cancers (including but not limited to breast cancer), cardiovascular disease, deep vein thrombosis, and a history of embolisms.

When it comes to systemic estrogen, Christmas said “there are good, compelling reasons on both sides” about the black box warning that has existed on those products for the past two decades. “It does give people pause and it makes it so that you do discuss what the potential risks would be. In the vast majority of people close to the onset of menopause, the risks are going to be pretty low, but you want to make sure you’re discussing the pros and cons with people.

That said, she added, “There are lots of medications that have higher associated risks with them that don’t have a black box warning.”

What is a black box warning?

A black box warning is the strongest tool the FDA has to label prescription drugs and medical devices and is done to alert prescribers and patients both of potential life-threatening side effects. This warning is written in a literal black box on the medication’s packaging. 

A black box warning doesn’t mean that a drug is inherently unsafe. It does mean, though, that the FDA has decided that prescribers and patients need to be aware of its potential risks and should have a robust discussion before beginning a course of treatment. 

Why was a black box warning put on estrogen?

The black box warning was first put on estrogen treatments in 2003, following the release of the Women’s Health Initiative study. Its findings suggested that hormone therapy as a menopause treatment increased the risk of breast cancer, stroke and heart disease. 

Currently, the black box warning on estrogen warns of endometrial cancer, cardiovascular disorders, probable dementia and breast cancer. 

What are the arguments for the black box warning?

Dr. Adriane Fugh-Berman is a professor of pharmacology and physiology at Georgetown University Medical Center and has written extensively on hormone therapy. She directs PharmedOut, a research project on the effects of pharmaceutical marketing on prescribing practices. She believes the black box warning should remain as is; research, she said, continues to show health risks associated with estrogen-related therapies. 

“Estrogen is a known risk factor for endometrial cancer. The first hormone therapies that came out were estrogen only — and women had a seven to 14 times increased risk of endometrial, uterine cancer,” Fugh-Berman said. “This is not arguable. Estrogen increases endometrial cancer.”

Fugh-Berman noted, though, that we don’t know as much about the long-term effects of vaginal estrogen and that the warning could be changed to note that — though she would like to see more research on these treatments long-term, too. Studies show that the level of estrogen in the blood from vaginal estrogen is far lower than in those who have taken estrogen orally or transdermally.

She also said that until the Women’s Health Initiative study, the numerous observational studies that showed that women who took hormones had fewer heart attacks, less dementia and fewer strokes also found that the women taking hormone therapies were of higher socioeconomic status: They exercised more, they had lower blood pressure to begin with, and they smoked less. “Women were taking hormones as part of a healthy lifestyle they could afford, so the hormone use was a marker for healthy behavior.”

What was the argument for removing the black box warning?

Many believe that removing the label is a critical step in helping more people manage menopause better — while also helping guard against adverse health outcomes and helping patients better understand the uses for different forms of hormone therapy. 

Many of the proponents of removing the black box warning note that the average age of participants in the Women’s Health Initiative Study was 63, or firmly postmenopausal. That made it less relevant for those in the immediate phase of menopause. (Menopause is defined as the final menstrual period, which can be confirmed after a consecutive 12 months without menstruation. The average age of menopause in the United States is 51.)

Last year, researchers published an analysis of the original Women’s Health Initiative data in the Journal of the American Medical Association and found that combined hormone therapy — or using both estrogen and progestin —  is safe and effective for treating vasomotor symptoms if started before the age of 60 or within 10 years of starting menopause if the patient does not have certain other conditions, such as a history of certain forms of cancer. 

Christmas said the push to remove the warning from all forms of hormone therapy speaks to the fear people may have about these medications even after counseling with their health care professionals. 

“The scare that everybody had after the Women’s Health Initiative in the early 2000s — we’ve now been able to go back and look at that data and — not saying that it was bad data, not saying that it was faulty data — but recognizing that it’s nuanced,” Christmas said. “For younger people at the onset of menopause, those risks are lower. For older people, they are higher. So, there could be some caveats around the warning and how the risk is described, so that people have a better understanding and aren’t forgoing treatment if they are highly symptomatic.”

What does hormone therapy do — and not do?

Christmas also said that she thinks there is a current misperception about what hormone therapy can and cannot do. 

“There’s this belief out there right now that there are some magical properties of hormone therapy, that it’s anti-aging, that it’s going to make you skinny, that it’s going to make your hair stop thinning, that you’re going to feel more energetic. There are all these mystical properties ascribed to it that actually aren’t true,” Christmas said. 

There are benefits, though, especially since it can help alleviate symptoms like night sweats. 

“If you’re not sleeping well, you are going to feel more lethargic or tired the next day and may even have more mood swings and more brain fog. And if someone gives you something, whether it be hormone therapy or one of the other non-hormonal options, to manage your night sweats and you sleep better, then there are going to be all these other downstream benefits,” she said. “You may feel better, but we shouldn’t talk about this like it’s a vitamin, something everyone should be on.”

What steps did the FDA take to change the warning?

In July, Makary convened an FDA Expert Panel on Menopause and Hormone Replacement Therapy for Women. A dozen doctors chosen by the FDA spoke about why they believe the black box warning should be removed, saying it can deter both patients and prescribers alike from utilizing hormone therapy during menopause. The experts’ focus was largely on low-dose estrogen treatments, such as vaginal estrogen. It remains to be seen whether any changes the FDA makes would affect just this form of hormone therapy.

What would the implications be for patients?

Recent observational studies have suggested that hormone therapy, timed correctly, can help reduce the risk of cardiovascular disease in post-menopausal people, could reduce the risk of breast cancer in certain populations and could help with certain forms of memory function after menopause.  

But Christmas advises some caution in hearing news of this research too. 

“There’s a difference between observational trials and good clinical trials — randomized, controlled trials are the gold standard — or even looking at meta analysis or systemic reviews. The observational trials have shown some potential benefits with hormone therapy for preventative measures,” she said, though clinical trials have not yet shown these benefits. 

“Telling someone that there is a definite benefit for cognitive or cardiovascular health hasn’t really been proven,” she said.  

When it comes to all hormone therapy, what is warranted is “a very thoughtful conversation with a health care professional and the patient to understand whether or not they’re a good candidate for it, because everybody won’t be,” Christmas said. “I think there’s a fear that if you remove that warning, that doing so won’t give people pause to do that counseling and make sure that the patient they’re putting on hormone therapy is an appropriate candidate.”