US FDA to lift warnings on menopause hormone therapy

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The Food and Drug Administration will no longer require warnings on hormone replacement therapies that some doctors say has long prevented women from taking medications aimed at treating the symptoms of menopause.

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Since 2003, the drugs for menopausal women have included a black box warning stating that they may increase the risk of heart attacks, strokes, blood clots and certain cancers.

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The impetus for the black box labels, the strongest safety warning the agency can give a medication, came after the early results of a national health study known as the Women’s Health Initiative, funded by the National Institutes of Health. But the scientific evidence behind the warning has shifted over the past two decades.

The FDA is asking drug manufacturers to remove the black box warning, a change that has been a major priority for FDA Commissioner Marty Makary.

“Hormone replacement therapy may improve the health outcomes of women at a population level more than any other intervention arguably with the exception of, say, antibiotics or vaccines,” Makary told reporters Monday.

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Major medical societies – such as the Menopause Society and the American College of Obstetricians and Gynecologists – have long endorsed reevaluating the warning label for low-dose vaginal estrogen products.

More recent research shows that for healthy, newly menopausal women, estrogen therapy is generally safe and effective with individualized patient counseling, but the potential risk differ depending on whether the treatment is taken vaginally or by pills, patches, gels or sprays. Some clinicians associated with ACOG and the Menopause Society say estrogen is the most effective treatment for classic symptoms such as hot flashes and vaginal dryness.

Makary said he believed drugmakers would welcome the shift and change their labels, adding the process probably will take several months. Potential adverse safety events will be included in the regular package insert, Makary said, in favor of a “nuanced discussion” that includes the age of the woman seeking to use the medications.

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Specifically, the FDA is working with companies to update language to remove references to risks of cardiovascular disease, breast cancer and probable dementia, according to the Department of Health and Human Services. The FDA is not seeking to remove the warning for endometrial cancer for systemic estrogen-alone products.

The agency said decisions around hormone replacement therapies should be made between a patient and their doctor, though the recommendation on the product label will be to start the treatment within 10 years of menopause onset or before 60 years of age for systemic therapies such as pills, patches, gels or sprays.

Menopause is a natural physiological process that marks the end of a woman’s reproductive years and takes place, on average, in the early 50s.

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The foundation of hormone replacement therapy is estrogen and progesterone, said Sarah Shealy, a certified nurse-midwife who is also a certified practitioner by the Menopause Society, a nonprofit that aims to help health care professionals, researchers and the public improve health care for middle-aged women.

Estrogen prompts the lining of the uterus to grow. The hormone progesterone keeps that lining, or endometrium, from getting too big, she said, adding the two do “an elegant dance.”

“Anyone who still has their uterus, we also must give progesterone,” said Shealy, who runs a private practice focused on the postpartum period and the menopause transition.

The black box warnings on estrogen products are “really a big deterrent,” said Shealy, who watched part of a July meeting convened by the FDA to discuss the benefits and risks of hormone replacement therapy, sometimes referred to as HRT. She agreed with many of the panelists that the warnings need to be removed.

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Shealy said it was particularly “egregious” that the label is on vaginal estrogen, which she described as a “low cost, low intervention, easy therapeutic treatment” that has the lowest concentration of the hormone.

Hormone replacement therapy had long been thought of as a “panacea for all that ailed midlife and older women,” said a recent JAMA Internal Medicine essay that also said this belief existed without any large-scale randomized studies. The Women’s Health Initiative was supposed to change that.

Researchers specifically set out to “settle the issue of prevention of chronic disease” in women with and without heart disease and tested estrogen derived from the urine of pregnant horses in women 50 to 79 years old to see if it helped, said a statement released by the Women’s Health Initiative after the July meeting. They used progesterone too in women without a hysterectomy.

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But the trials were stopped in 2002 and 2004 when the medication didn’t reduce heart attacks but increased risk of blood clots, stroke and breast cancer while also lowering risk of colon cancer and bone breaks, the statement said.

Practice guidelines stopped recommending hormones to prevent heart disease. The black box label was applied. And hormone use for menopause management plummeted, even though that’s not what the study was evaluating. Two decades ago, about 27 percent of women used hormone replacement therapy compared to about 5 percent in 2020, studies show.

“In short, the pendulum swung from [menopausal hormone therapy] being touted as a panacea to being vilified as a poison,” the JAMA essay said.

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Makary said there’s important nuance that often gets lost in the discussion about HRT – the age at which someone begins the therapy. One of the biggest benefits, he said, is how the therapy protects women’s cardiovascular systems by helping to keep blood vessels soft and dilated, which reduces heart attacks. But this only happens if women start within 10 years of beginning menopause. After that, he said, it’s more likely to cause harm than confer help.

“The lack of specificity, the lack of delineating that nuance, that has many people frustrated,” he said of the WHI’s statement. Menopause health experts say clinicians generally don’t recommend beginning HRT after about age 60.

The statement from WHI researchers said they don’t take a position on whether the FDA should remove or modify the black box warning label. They do, however, encourage the FDA to rethink making a decision based on their findings, which only evaluated estrogen taken by mouth and not the gels, creams and patches which are more commonly used.

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Few people understood those risks were relative to age and health status and not universal, reproductive health experts said. The average age of participants was about 63 years old – more than 10 years beyond the average age of menopause, said Robert Kauffman, an obstetrician-gynecologist and director of reproductive medicine and infertility at Texas Tech University HSC School of Medicine.

“We don’t start women who are 14 years postmenopausal on hormone therapy. They’re started when they’re newly menopausal,” he said. “So, the patients in the original study weren’t representative of the women we actually treat.”

The medical establishment was “so confident” that hormone replacement therapy was good for everything “that we took high-risk women and threw hormones at them,” said Stella Dantas, an obstetrician-gynecologist and immediate past president of American College of Obstetricians and Gynecologists. “Then we found out it was actually detrimental.”

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In a letter after the FDA’s panel, ACOG urged the agency to hold a formal advisory committee meeting aimed at reevaluating the warning labels on low-dose vaginal estrogen therapies and undertake a separate review process for other options. The agency has not convened such a meeting.

Makary, the head of the FDA, published a book last year titled “Blind Spots: When Medicine Gets It Wrong, and What It Means for Our Health.” His critiques center around what he believes to be mistakes in public health, which he refers to as “medical dogma.” The second chapter focuses on the case for using hormone replacement therapies, contending the authors of the Women’s Health Initiative research had misrepresented their findings.

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The FDA’s move comes just over a week after the agency was rocked by tumult. George Tidmarsh, a recently installed top drug regulator, resigned Nov. 2, officials said, amid scrutiny over his comments criticizing a treatment made by Aurinia Pharmaceuticals. The Canadian pharmaceutical company filed a lawsuit that same day accusing him of making false statements and soliciting a bribe because of a “long-standing personal vendetta” against Aurinia’s board chairman. Tidmarsh is listed as an author on a JAMA viewpoint article about the change, which published Monday.

Attendees at the HHS event regarding the move included second lady Usha Vance and Health Secretary Robert F. Kennedy Jr.’s wife, Cheryl Hines.

Some researchers say the decision on whether to use hormone therapies should be approached similarly to that involving any other medication, weighing the benefits against any potential risks.

Still, Kauffman said, “there’s a huge fear among both women and physicians about using estrogen therapy.”

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