Doctors push back on ‘data-free’ ruling on menopause hormone therapy

Medical experts say the FDA bypassed standard procedures to remove black-box warnings from hormone therapy without adequate scientific evidence.

The US Food and Drug Administration commissioner Marty Makary announced the removal of broad black-box warnings from oestrogen-related menopause medications last week, claiming the treatments could prevent heart disease, osteoporosis, Alzheimer’s disease and death.

Black-box warnings are the strongest safety alerts the FDA requires on medications, highlighting serious or life-threatening risks. The 2003 warnings on hormone therapy cautioned about increased risks of cardiovascular disease, breast cancer and dementia.

Menopause specialists said the decision to remove warnings makes sense for local vaginal oestrogen products but raised concerns about systemic oestrogen treatments and the scientific process behind the ruling.

To make that blanket statement that every woman should take this to prevent heart disease – it’s not true,” said Lauren Streicher, clinical professor of obstetrics and gynaecology and founding medical director of the Center for Sexual Medicine and Menopause at Northwestern University school of medicine.

The FDA used a roundtable panel instead of its typical expert advisory committee process, marking the first time the agency has relied on this format for regulatory decision-making. The panel was not open to public comments in advance.

Makary called hormone therapy a “life-changing, even life-saving treatment” and positioned the announcement as a “medical breakthrough”. Robert F Kennedy Jr, secretary of the US Department of Health and Human Services, claimed hormone therapy was “extending the lives for as much as 10 years”.

“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,” Makary said at the press conference.”

However, researchers said there is no evidence that hormone therapy provides benefits for the wider population of menopausal women beyond those experiencing symptoms such as hot flushes, insomnia and joint pain.

Pauline Maki, professor of psychiatry, psychology and obstetrics and gynaecology at the University of Illinois college of medicine, called the “data-free” decision “harmful” and confusing for women seeking accurate information.

“Women are trying desperately to get the truth, and they’re having a really difficult time,” she said. Regarding hormone therapy for dementia prevention, her area of expertise, “the harm is maybe real, but certainly it’s not showing benefit.”

Streicher, who initially agreed to participate in the July panel, withdrew after preliminary meetings. “It became very clear to me that this was not going to be a scientific panel. This isn’t the scientific approach,” she said. “I said: ‘I’m out. I don’t want any part of this.'”

The evidence on hormone medications is nuanced. Local vaginal oestrogen, typically delivered as creams, tablets, inserts, suppositories or vaginal rings, treats symptoms like dryness, irritation and recurrent urinary tract infections safely. “Those products are really totally safe,” Streicher said, noting they never should have carried the warning.

Systemic oestrogen presents more complexity. Different preparations carry varying risks. Oral oestrogen increases blood clot risk, while transdermal patches do not. Synthetic progesterone carries a small increased breast cancer risk. The medications are unsuitable for people with histories of breast or uterine cancer.

Maki’s research on menopause and dementia illustrates the complexity. She once believed memory issues could be linked to oestrogen loss during menopause. Initial research suggested women using hormone therapy for menopause symptoms saw memory improvements.

However, when Maki conducted a large randomised study among a broader group of menopausal women, not just those with symptoms, results differed significantly. “Far from showing benefit, it actually showed a trend toward harm,” Maki said. Three other large randomised trials produced similar results.

Maki now believes treating menopause symptoms, whether with hormone therapy or other medications, is key to improving memory. Using hormone therapy for dementia prevention more widely is “just not based in science”, she said.

An HHS spokesperson said “randomised 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”. The HHS did not respond to questions about officials’ statements on purported protection against dementia or provide evidence for wider use of the medications.

During the press conference, officials positioned the decision as challenging “medical group think” and “medical dogma”. Kennedy said “the label was designed to frighten women and to silence doctors” and accused the American medical establishment of turning its back on women.

Makary said the decision was “challenging the paternalism of medicine”, but then stated hormone therapy “has saved marriages”, suggesting marital satisfaction as a key outcome of the medication.

“It was not only scientifically wrong, but it was offensive,” Streicher said.”

The FDA opted for the panel format because advisory committee meetings are “bureaucratic, long, often conflicted and very expensive”, Makary said. He indicated more panels with guests who “speak [their] mind passionately” will occur in future.

Typically, expert advisory committees hold public discussions on evidence before making recommendations to the FDA, which subject-matter experts at the agency, rarely the commissioner, may accept or reject. The July panel included researchers who have published on menopause and doctors with large social media followings, but no oncologists.

Makary’s most recent book includes a chapter on hormone replacement therapy arguing that it has been shown to “increase a woman’s longevity by three years”. The more accepted medical term for treatment for women over 40 is menopause hormone therapy.

Streicher expressed concern about precedents set by the decision, noting the agency is also re-examining medications like mifepristone, a safe and effective abortion medication.

“Hormone therapy is safe and effective for those with menopause symptoms,” Streicher concluded. “But do I tell every single woman who goes through menopause that she needs to be on hormone therapy? Absolutely not.”