Dr. Marty Makary, the commissioner of the Food and Drug Administration (FDA), said in an interview with CNN last week that changes to the black box warning on hormone therapies for menopause containing estrogen are coming. “We are in serious discussions now about what to do about the black box warning, and I think you’ll hear something on it very soon,” Makary told CNN Chief Medical Correspondent Dr. Sanjay Gupta in the “Chasing Life” podcast.
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.
Experts on menopause care disagree on whether the black box warning should be altered to only apply to certain kinds of treatment or eliminated in full, but all agree it’s a complex matter — and that more research into menopause treatment will help further empower patients and providers.
The 19th broke down what this all means — and what it could mean for your health care.
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.
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.
What are the arguments for keeping 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 is 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 experts believe that this label shouldn’t be applied to all estrogen therapies equally, as early data suggests a significantly lower risk profile for vaginal estrogen, which delivers a lower dose of the hormone.
Dr. Monica Christmas is the associate medical director for The Menopause Society, the nonprofit organization that certifies medical providers seeking to become credentialed in menopause and midlife women’s health. She said the risk for local, low-dose vaginal estrogen therapy is “negligible.” Having the black box warning on all forms of hormone therapy “is confusing to many and can also be a deterrent for women who need a medication that is highly efficacious and extremely safe,” she said.
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.
“For a long time, there has been momentum around wanting the black box warning removed from local, low-dose vaginal estrogen therapy. It seems that people are really listening and understanding what the differences are” between local and systemic estrogen, she said.
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 — 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 has the FDA done about changing 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.
No public comment period has been offered on this topic yet, but the FDA has said one would be opened in the Federal Register after a policy change was announced.
It’s unclear when a decision will be made, though Makary seems committed to leading the FDA to make some kind of change — and soon. “It’s really a tragedy. It’s maybe one of the greatest screw-ups of modern medicine,” Makary told Gupta last week of the current black box warning. “It’s resulted in 50 million women being denied this incredible 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.”