FDA ending ‘black box’ warning for hormone replacement therapy for women

The U.S. Food and Drug Administration (FDA) will no longer require “black box” warnings against hormone replacement therapy (HRT) for treating menopause in women.

Health and Human Services Secretary Robert F. Kennedy, FDA Commissioner Marty Makary, MD, MPH, agency leaders and physicians announced the change to counteract “more than two decades of fear and misinformation” about HRT, which is an FDA-approved treatment for women.

“Tragically, tens of millions of women have been denied the life-changing and long-term health benefits of hormone replacement therapy because of a medical dogma rooted in a distortion of risk,” Makary said in a news release. “For too long, issues of women’s health have been underrecognized. Women and their physicians should make decisions based on data, not fear.”

The state of medicine

“Women have used HRT products for decades to relieve menopausal symptoms,” HHS’ official announcement said. “However, their use plummeted in the early 2000s when the FDA applied boxed warnings following a Women’s Health Initiative (WHI) study that found a statistically non-significant increase in the risk of breast cancer diagnosis.”

In the news conference, Makary described the $1 billion WHI study as the largest in U.S. history. The headline that HRT causes breast cancer was released to news media, with scientific data published a week later. Physicians saw results showing no statistical significance in the increase in breast cancer, he said.

“If we don’t have statistics, then we don’t have science,” Makary said. “All of a sudden, snake oil cures diseases and science goes … out the window.”

He also described a hotel room meeting of researchers who argued about creating baseless fear by connecting HRT with something so sensitive as breast cancer. That’s exactly what happened, Makary said, and “the fear machine took on a life of its own,” leading to “medical groupthink” that was “perfectly backwards.”

Since then, up to 50 million women have missed out on potentially beneficial HRT, Makary said, citing their experience and that of his own mother.

Follow the science

In the WHI study, the average age of women in the study was 63 years — over a decade past the average age of a woman experiencing menopause — and study participants were given a hormone formulation no longer in common use, according to the HHS announcement.

Since then, randomized studies show that women who initiate HRT within 10 years of the onset of menopause, generally before age 60, have a reduction in all-cause mortality and fractures. Women may also reduce their risk of cardiovascular diseases by as much as 50%, Alzheimer’s disease by 35%, and bone fractures by 50% to 60%. Though the starting time of HRT and duration of use are decisions made between the prescriber and the individual patient, the FDA’s labeled recommendation will be to start HRT within 10 years of menopause onset or before 60 years of age for systemic HRT.

It's also become clear that serious symptoms are widespread — present in up to 80% of women — last up to eight years, and can be debilitating. Mood swings, night sweats, weight gain and more have led to the breakup of families, and there are long-term ramifications for heart and brain health, Makary said.

“What are we doing, not offering women this potentially powerful treatment?” Makary said. “With few exceptions, there may be no other medication in the modern era that can improve the health outcomes of women on a population level than hormone replacement therapy.”

A new start of medicine for women

American Medicine is at the starting line, not the finish line, examining women’s health, said FDA Principal Deputy Commissioner Sarah Brenner, MD, MPH.

“For decades in medicine, understanding and addressing the differences between women's and men's bodies has been deprioritized,” she said. “The unique physiological changes and needs of women have either been steamrolled or ignored.”

The previous warning about HRT shaped family decisions and FDA policy. Realigning beliefs with new science takes time, effort and courage, but is worth it, Brenner said.

Why not prescribe it?

The news conference included appearances by urologist Rachel Rubin, MD, and urologic surgeon Kelly Casperson, MD.

An entire generation of physicians and other clinicians did not learn important details about HRT and the symptoms of genitourinary syndrome of menopause, Rubin said. When women’s hormone levels decrease, effects can include recurrent urinary tract infections that are at least uncomfortable for patients, can have serious health consequences, and cost billions for health care, Rubin said. Vaginal hormones are safe and can help, she said.

“So why aren't more doctors prescribing this life saving medication? Because until today, the warning label on the box falsely says that vaginal estrogen causes cancer, stroke, blood clots, heart attacks and probable dementia, yet not a single scientific study shows this,” Rubin said.

A monumental shift

Casperson called it a monumental shift in women’s health to correct decades of misleading guidance. As a resident physician, Casperson recalled being told “women were too complex, as if their health needs were unknowable.” She described a later meeting with a tearful bladder cancer survivor who was in pain.

“She wasn't complicated. She was in pain, and no one had treated it,” Casperson said. “That moment shifted everything. I started asking, who is taking care of the people who are supposed to be partnered with the people that urologists like me are giving testosterone and Viagra to? Because here's the truth, women's care has been an afterthought. He gets treated, she gets dismissed. Families fracture. It doesn't have to be this way.”

Casperson predicted the change will have worldwide repercussions. Worldwide, women spend more years in ill health than men, but a safe, effective treatment has been held back by fear. “What happens here will be followed in other countries too,” she said.

Helping patients find relief

American College of Obstetricians & Gynecologists President Steven J. Fleischman, MD, MBA, FACOG, issued a statement supporting the FDA change and commending Kennedy and his aides.

The change removes a barrier in the shared decision-making process that physicians and patients use to determine treatment of menopausal symptoms, he said. That is important because systemic estrogen products, such as oral estrogen, transdermal patches, gels and sprays, have different safety profiles than low-dose vaginal estrogen, and are not without risk, Fleischman added.

“ACOG has long advocated for removal of the ‘black box warning’ on low-dose vaginal estrogen because the warning has posed a barrier for people who suffer from vaginal and urinary symptoms of menopause and could find needed relief with vaginal estrogen,” his statement said. “By discouraging clinicians from prescribing low-dose vaginal estrogen, the current warning label harms patients by making inaccessible an effective treatment for symptoms that can significantly decrease health-related quality of life. We hope that this regulatory step forward will improve access to this important treatment option.”