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The history of hormone replacement therapy (HRT)* has been marked by pendulum swings. During much of the 20th century, it was considered the treatment of choice for menopausal symptoms, ranging from hot flashes to night sweats, depression, weight gain and vaginal dryness. It was also used to prevent heart disease, osteoporosis and other chronic health problems.
Then, a large 2002 clinical trial called the Women’s Health Initiative (WHI) called out HRT’s risks to women’s health. Based on science that’s now considered outdated, WHI found a strong association between HRT use and a heightened risk of breast cancer, heart disease and stroke among the study’s participants. That led to the black box warning label that the FDA is in the process of removing from all products containing estrogen or progesterone only, or a combination of the two hormones.
*Recently renamed menopausal hormone therapy (MHT); HRT will be referred to as MHT for the rest of this article.
A black box warning is the strongest warning the FDA can issue, based on evidence of a drug or product’s potentially serious health risks. In the case of MHT, these included what was believed to be an increased risk of breast cancer, heart disease and stroke.
These presumed risks were exaggerated, according to the FDA’s current leadership, thus obscuring the benefits of MHT and discouraging women from using it.
The black box warning led to a precipitous drop in hormone therapy use, from 27 percent in 1999 to just 5 percent in 2020.
That trend is about to change.
There were two major flaws in the study’s approach. First, the average age of the participants was 63, well past the menopausal transition that typically occurs between ages 45 and 55, with an average age of 51.5. These post-menopausal women may have already had cardiovascular issues that got worse with MHT use. Additionally, the study tested the impact of synthetic hormones that are not often in use today.
Taken together, these two problematic features may have skewed the WHI’s findings toward higher risk, prompting the FDA to add its black box warning to all MHT products and formulations.
While many women welcome the FDA’s recent decision, clinicians and scientists tend to favor a more nuanced approach. With the removal of the black box warning, the pendulum may have swung too far, says Dr. Susan Loeb-Zeitlin, an assistant professor of clinical obstetrics and gynecology, assistant attending obstetrician and gynecologist and Director of the Women’s Midlife Center at Weill Cornell Medicine.
Keep reading to see what she has to say about the FDA’s latest move, along with her best advice on whether and how to use MHT.
MHT is composed of medications that replenish the ovarian hormones—estrogen and progesterone—that decline during menopause. It’s administered to alleviate menopausal symptoms. MHT comes in a variety of local and systemic forms, including creams, gels, patches and pills.
The safest formulation is vaginal estrogen. It’s risk-free for most women at any age.
Systemic MHT, usually taken in the form of a patch, may come with health risks for some women. “The use of vaginal estrogen has an excellent safety profile, and the benefits for alleviating vaginal discomfort, sexual function and urinary tract symptoms can be significant,” Dr. Loeb-Zeitlin says.
She and her colleagues are delighted that the black box warning is being removed from vaginal estrogen products. However, systemic hormonal formulations require a more nuanced approach, she says. While appropriate and beneficial for some women, they’re not for everyone.
“We were expecting the FDA to remove its black box warning from vaginal estrogen,” she adds, “but not from every type of MHT formulation. Systemic MHT shouldn’t be used by all menopausal women.
“By removing the label on all forms of MHT, the FDA may be making all menopausal women feel they should be using it,” she continues. “Currently, the FDA approves MHT for specific indications, including severe and bothersome hot flashes and night sweats and for the prevention of osteoporosis for women at risk. For other indications, there is a lack of conclusive evidence about the benefits.”
Let’s go back to that swinging pendulum. After the WHI’s findings, MHT went from being perceived as beneficial to potentially dangerous. Usage dropped from 27 percent of menopausal women in 1999 to 5 percent in 2020.
That number has already begun to tick up again. Says Dr. Loeb-Zeitlin, MHT can indeed be a boon to women’s health. It should be initiated when women are within the first 10 years of menopause and before the age of 60.
However, it is not recommended for women with a history of breast cancer. MHT can increase the risk of a recurrence, especially in the case of hormone-sensitive breast cancer—the most common subtype.
The same holds true for women with a history of heart disease.
Thankfully, there are non-hormonal alternatives for symptom relief.
For women who aren’t appropriate candidates for MHT, and for those who’d prefer not to use it, non-hormonal options are available, Dr. Loeb-Zeitlin says. The following prescription drugs are FDA-approved for symptom alleviation:
paroxetine hydrochloride (Paxil), an SSRI that is FDA-approved for hot flashes and night sweats, as well as mood and sleep issues
fezolinetant, a novel treatment that blocks the activity of a protein implicated in a woman’s temperature control system, thus easing hot flashes and night sweats
elinzanetant, another novel treatment—recently approved by the FDA—with a similar mechanism of action that works to ease these same symptoms.
One additional prescription drug is often used off-label (for a purpose that isn’t FDA-approved): gabapentin, an anti-convulsive medication that slows and calms nerve impulses.
Menopausal symptoms can also be eased via cognitive behavioral therapy and even hypnosis.
Dr. Loeb-Zeitlin makes an under-recognized point around the importance of managing hot flashes: “Hot flashes are actually an independent risk factor for heart disease, so one way or the other, I’d advise all menopausal women to seek treatment for that troubling, potentially problematic symptom.”
“MHT should be prescribed for symptom relief,” Dr. Loeb-Zeitlin says, “not for the prevention of heart disease, blood clots, stroke or dementia. That’s because the research isn’t all the way ‘there’ yet.”
A growing body of research attests to the likely benefits of MHT for a woman’s heart health, including its positive effect on insulin resistance—a precursor to diabetes. However, more research will be needed to determine the following:
These unknowns also explain why most doctors would have preferred a more nuanced approach on the part of the FDA. “Its blanket removal of the black box warning should have been more selective,” says Dr. Loeb-Zeitlin and her fellow members of the American College of Obstetricians and Gynecologists, including its president, and of the Menopause Society.
Luckily for women in midlife, a lot of attention is being paid to menopause these days, particularly in the form of advocacy. But there’s a lot of misinformation on social media around the mistaken notion that everyone needs estrogen. MHT can be beneficial, but not always and not for everyone.
The best way to see whether you’re a good candidate for MHT is in consultation with your gynecologist or a menopause specialist. An open and thorough conversation will clarify any sources of confusion and help you find your way to the optimal approach to symptom relief, be it hormonal, non-hormonal or psychotherapeutic.
Learn more about The Women's Midlife Center here. Make an appointment with a gynecologist at Weill Cornell Medicine here.
