The US Food and Drug Administration says plans are imminent to tweak the lengthy “black box” warning on many hormone replacement products for women with menopause symptoms, which some experts say is long overdue, and has denied millions of women this life-changing therapy, reports CNN.
The warning is the strongest type of alert the FDA puts on a drug label. Since 2003, labels of menopause treatments that contain oestrogen – including pills, patches, sprays and creams – have warned that their use can increase the risk of uterine and breast cancers, as well as strokes and blood clots.
The labels also warn about an increased risk of dementia for women over 65.
The caution was added after a large government-funded study found that women taking oestrogen pills after menopause had higher risks for some kinds of cancers, heart disease and stroke compared with women who took a placebo.
The study participants had an average age of 63, so many were past menopause when they started the therapy.
However, after the study and the label change, prescriptions for HRT drugs for women dropped by more than 70%, and doctors became reluctant to prescribe them.
“It’s really a tragedy. It’s maybe one of the greatest screw-ups of modern medicine,” said FDA Commissioner Dr Martin Makary. “It’s resulted in 50m women being denied this incredible therapy.”
The result has been under-treatment of symptoms that can be debilitating for women in midlife. In the late 1990s, more than one in four postmenopausal women were taking hormones to manage symptoms, but by 2020, that number had dropped to about one in 25, one study found.
Newer analyses of the original study, called the Women’s Health Initiative, have since found that hormone therapy started in women under 60, or within 10 years of starting menopause, may safely help manage menopausal symptoms like hot flushes and poor sleep as long as the women don’t have specific contraindications, such as a history of hormone-sensitive breast or uterine cancer.
Makary also said HRT may also have important benefits like reducing bone loss, heart disease risk and memory loss.
“Women live longer and feel better on hormone replacement therapy when started before 60,” he said.
The potential change comes after a July meeting of experts, convened by the FDA, to discuss the benefits and risks of HRT for women. The panellists urged the agency to remove the warning label.
“I am begging the FDA, and all of us are begging, please remove the box label,” said Dr JoAnn Pinkerton, a Professor of Obstetrics and Gynaecology at the University of Virginia School of Medicine. “And please stop harming women.”
Some women’s health experts say the FDA overstepped when it applied the boxed warning to all forms of oestrogen replacement.
“That is a real mistake,” said Dr JoAnn Manson, a Professor at Harvard Medical School and one of the principal investigators of the Women’s Health Initiative study.
Some forms don’t raise oestrogen levels in the blood, so they aren’t likely to raise a woman’s cancer risk. For example, studies have found that low doses of oestrogen delivered by tablets, creams or rings in the vagina can safely treat symptoms of dryness, painful sex and urinary tract infections in postmenopausal women, Manson said.
The black box warning, though, may stop women from using them.
“It scares them away. And even after they purchase the product, they just don’t take it,” she said.
“This is really where women are being tremendously under-treated and are suffering unnecessarily due to a boxed warning that is just class labelling,” said Manson, who is chief of the Division of Preventive Medicine at Brigham and Women’s Hospital.
She added that it would also be reasonable for the FDA to consider removing the warnings on oestrogen-containing therapies that are delivered through the skin in patches, sprays or creams to relieve the symptoms of menopause like hot flushes and night sweats.
Those deliver hormones into the bloodstream, but observational studies suggest that they have a more favourable balance of risks and benefits than pills, she said.
Manson feels less certain about removing the boxed warning from oestrogen-containing pills that are taken by mouth, however.
“I think that’s where it’s evidence-based and justified,” she said.
A 2022 review by the US Preventive Services Task Force concluded that, in women who are past menopause, there was no net benefit to taking either oestrogen alone – prescribed for women who’ve had their uterus removed – or a combination of oestrogen and progestin, which is typically prescribed for women who still have their uterus, to prevent chronic health conditions like heart disease and dementia.
What’s less clear is whether a woman who starts hormone therapies in perimenopause need to stay on them long-term to get memory, heart and bone benefits.
“It’s a very good question,” said Dr Roberta Diaz Brinton, a neuroscientist who studies oestrogen’s effects on the brain at the University of Arizona. “We need to answer that.”
Other experts say there’s not enough scientific evidence to support long-term use of hormones to prevent heart disease, Alzheimer’s disease or osteoporosis.
Four medical societies – the American College of Obstetricians and Gynaecologists, the Menopause Society, the Endocrine Society, and the American Association of Clinical Endocrinology – support the use of hormones to alleviate menopausal symptoms, but they don’t recommend continued use for preventing chronic conditions like heart disease.
Dr Leslie Cho, who runs Cleveland Clinic’s Women’s Cardiovascular Centre, said she’s supportive of the idea of lifting the warning from vaginal oestrogen cream. “It’s never made sense on the cream,” she said.
But she’s worried that some of the benefits being discussed are drawn from after-the-fact analyses of studies that weren’t designed to look at those outcomes in the first place.
“I’m so glad to hear the FDA chair talk about this, because then, if that’s the case, they should do a study. They should fund a study,” she said.
In a world where people can get hormones prescribed over the internet, Cho said she worries too many women could start taking hormones when they have risks like high blood pressure, obesity or high cholesterol that could overshadow the benefits. Even in younger women, studies show hormones may increase the risk of dangerous blood clots, she said.
“Women have to talk to their physicians about HRT before they believe in all the hype that’s currently ongoing, because so much of it is hype,” she said.
See more from MedicalBrief archives:
FDA panel urges removal of warnings on menopause meds
Early menopause may raise dementia risk later – UK study of 150,000 women
HRT not linked to increased risk of dementia — Largest study yet
Hormones safe for menopause – US study dispels old flawed findings