While ob/gyns were generally pleased with FDA’s decision to remove the black box warning on menopausal hormone therapy products, many were wary of how it was done, and how potential benefits were overstated by federal health regulators.
At an HHS press conference, Secretary Robert F. Kennedy Jr. and FDA commissioner Marty Makary, MD, MPH mischaracterized the findings of the pivotal Women’s Health Initiative (WHI) study, which was stopped early due to concerns of increased breast cancer risk among those on hormone therapy, experts said.
Makary said the study “was misrepresented and created a fear machine that lingers to this day.”
But Rachel Weinerman, MD, an ob/gyn and reproductive endocrinologist at Case Western Reserve University in Cleveland, told MedPage Today that the results were important in the context of their time. When the WHI was conducted in the 1990s and early 2000s, some evidence had suggested hormone therapy’s health benefits may extend beyond menopausal symptom relief.
Indeed, the expectation was that the WHI would find cardiovascular benefits. But that’s not what happened.
“Before that study came out, there was an assumption that a woman should be on hormone replacement therapy, unless contraindicated,” Weinerman told MedPage Today. “After the study came out, that changed, and the assumption was that a woman shouldn’t be on hormone replacement therapy unless absolutely needed.”
Essentially, the WHI showed a 26% increased risk of breast cancer, a 29% increased risk of coronary heart disease, a a 41% increased risk of stroke, and a twofold increased risk of pulmonary embolism with hormone therapy.
Since then, science has made a lot of progress in understanding why the WHI found what it did. For starters, the mean age of women in WHI was 63.
“WHI specifically enrolled older women and women who had been in menopause longer, thinking that those women would benefit the most from the cardiovascular protection offered by estrogen,” Weinerman explained. “What we’ve learned is that estrogen does provide cardiac protection … but in a very specific way. It has to start within the very first few years of menopause in order to have a benefit, and if you wait too long before you start it, then it can actually be problematic and not provide that same benefit to women.”
Care has evolved too, she noted. The WHI used conjugated equine estrogen (Premarin), which has been dropped in favor of hormones that are naturally produced by the ovaries, such as estradiol, Weinerman said.
JoAnn E. Manson, MD, MPH, DrPH, chief of preventive medicine at Brigham and Women’s Hospital in Boston and a long-time WHI principal investigator, said that the study’s main conclusion that “hormone therapy should not be started for the express purpose of trying to prevent heart disease, stroke, or cognitive decline” has not really changed.
Manson co-authored a secondary analysis of the WHI that was published in JAMA Internal Medicine earlier this year. It concluded that menopausal hormone therapy reduced vasomotor symptoms without significantly affecting atherosclerotic cardiovascular disease risk in younger women — but it did raise heart risk in women older than 70.
“Hormone therapy is a complex treatment,” Manson told MedPage Today. “It has a complex pattern of benefits and risks and personalized decision making is tremendously important.”
A 2022 position statement from The Menopause Society (TMS) states that the benefit-risk ratio of hormone therapy is good for women age 60 and under who are within 10 years of menopause and have no contraindications. However, it becomes less favorable for women who start therapy after age 60, and who are more than 10 years out from menopause onset.
After the HHS briefing, TMS issued a statement saying it agrees with the decision since the “boxed warning may have been a deterrent to the use of low-dose vaginal estrogen, which is a safe and effective therapy.”
“However, systemic estrogen still comes with potential risks that should be reviewed in detail with women initiating therapy,” TMS stated.
This nuanced take on menopausal hormone therapy is a far cry from the figures cited by Kennedy and Makary at the press conference.
Kennedy said hormone therapy could “reduce the risks of cardiovascular disease and mortality by as much as 50%, Alzheimer’s disease by 35%, and bone fractures by 50% to 60%, as well as reducing cognitive decline and all-cause mortality — in other words, extending the lives for as much as 10 years.”
But in an accompanying HHS press release, studies supporting those figures were old and small, including a New England Journal of Medicine study from 1980 and a JAMA study from 1991.
Jen Gunter, MD, an ob/gyn and pain medicine physician, said the press conference was “a fire hose of misinformation” in a video reaction posted on her Substack newsletter, The Vajenda.
“It’s all based on shitty observational and old data. It’s really embarrassing,” Gunter said, noting that there aren’t good data to support the claims about cardiovascular disease, cognitive decline, or longevity.
Experts also took issue with the fact that the changes weren’t made using traditional FDA methods. Instead of a typical advisory committee meeting, the FDA convened an expert panel on menopausal hormone therapy earlier this year, where participants urged the removal of the black box warning.
Ob/gyns say it would be a mistake to make women think menopausal hormone therapy is a cure-all that will improve their health, and return them to the pre-WHI days.
“The hormone therapy story is … a very complicated story with changing perspectives based on changing science,” Weinerman said. “And I think that we have to be humble enough to understand that our knowledge progresses.”
