After two decades of black box warnings that scared doctors away from prescribing hormone replacement therapy, the FDA is reversing course, removing those labels from six hormone replacement products on Feb. 12.

The shift could restore treatment options for menopausal women who were discouraged from using hormone replacement therapy, even when they might benefit.

“It should have been done a long time ago,” said Dr. Brian Egan, chair of the OB/GYN department at Prime Healthcare’s Saint Joseph Medical Center in Joliet.

The categories are systemic combination therapy (estrogen and progestogen), systemic estrogen-alone therapy, systemic progestogen-alone therapy for women with a uterus using systemic estrogen and topical vaginal estrogen therapy.

The American College of Obstetricians & Gynecologists also approved the labeling change, which has “long advised clinicians to counsel patients based on an individual’s unique risk factors and treatment goals,” Dr. Steven J. Fleischman, president of the American College of Obstetricians & Gynecologists, said in a written statement.

Hormone replacement therapies are used to control menopausal symptoms. The American Society of Health-System Pharmacists recently reported a shortage of estrogen patches.

The FDA’s black box warning alerts health care providers and patients about potentially serious or life-threatening risks.

For years, doctors were “nervous” about prescribing any form of hormone replacement therapy for any woman, said Dr. Gamilah Pierre, a board-certified obstetrician-gynecologist, a longtime staff member of Silver Cross Hospital in New Lenox.

“Yes, some people really should not be on hormone replacement therapy,” Pierre said. “However, that black box warning probably took the option away for more people than it should have.”

The FDA asked, “drug sponsors of all HRT products that contain estrogen or progestogen and in all dose forms to remove language about the risk of cardiovascular disease, breast cancer and probable dementia from the boxed warning, as well as make other safety-related labeling changes,” according to the FDA.

However, the FDA did not ask drug sponsors to remove risks of cardiovascular disease and breast cancer from the labels “Warnings and Precautions.”

Nor is the FDA requesting drug sponsors remove the boxed warning for endometrial cancer for systemic estrogen-alone products, according to the FDA.

Dr. Kalish Hill, chief medical officer of St. Mary’s Hospital in Kankakee, said the labeling change helped eliminate a “blanket warning” and reduce the “angst” people might experience when taking hormone replacement products, especially patients likely to benefit with minimal risk.

But hormone replacement therapies still need appropriate management.

“We don’t know who will be prescribing these,” Hill said. “And we really want to make sure it’s someone experienced in prescribing hormonal therapies.”

Hormone replacement therapy ‘used to be good until it wasn’t’

Menopause is the permanent cessation of menstrual periods, typically diagnosed when a woman experiences no period for 12 months, according to Mayo Clinic.

In the U.S., the average menopause age is 51.

Symptoms may include hot flashes, night sweats, sleep disruption, mood changes and brain fog.

Using hormone replacement products to treat menopausal symptoms began in 1942 when the FDA approved Premarin, an oral estrogen therapy derived from pregnant mares, for hot flashes, Egan said.

In 2002, the federally funded Women’s Health Initiative halted a major hormone therapy trial after researchers found increased risks of breast cancer, heart disease, stroke and blood clots among participants. The findings led to widespread concern about hormone therapy and ultimately prompted the FDA to add its black box warnings in 2003.

Pierre said this “knee-jerk” reaction stemmed from fear that anyone taking any hormone replacement products would have a stroke or breast cancer.

“So they slapped on the black box warning and people stopped talking about it,” Pierre said.

‘Data has caught up with the science’

Egan said when researchers later dissected the data, they learned the women having problems with heart disease, blood clots and strokes tended to be more than 10 years past menopause and over the age of 60.

“But women who started [hormone replacement therapy] sooner – at the onset of symptoms – they actually lived longer and had less heart disease and strokes,” Egan said.

Current research suggests women who begin hormone replacement therapy before age 60 or within 10 years of menopause’s onset may reduce cardiovascular diseases up to 50%, Alzheimer’s disease up to 35%, and bone fractures up to 60%.

But Hill said, given the risks of hormone replacement therapy, asymptomatic women should consider non-medical interventions for bone health: weight-bearing exercises, resistance training, calcium and vitamin D.

“And by all means, not smoking,” Hill said.

Ultimately, “hormone replacement therapy got a bad reputation for the wrong reason,” Pierre said. But now, the “data has caught up with the science,” Egan said.

The labeling change now helps doctors individualize care and lets patients participate in that care, Pierre said.

“It allows a conversation to happen,” Pierre said. “That doesn’t mean there’s no risk. And it doesn’t imply – because there’s no black box warning – everybody can just pick it up at the supermarket.”

What this means for post-menopausal women

Hill said providers need to consider quality of life and each woman’s risk-benefit ratio.

“The greatest risk comes from over-prescribing in patients that are asymptomatic,” Hill said, “and the greatest benefit is for women who are menopausal with symptoms inhibiting function.”

That said, doctors should start with the lowest possible dose and discuss risks and benefits so patients can make informed decisions.

“And that’s where medicine has been going for years now,” Hill said. “We wanted targeted medicines for patients and individualized treatment plans, not one-size-fits-all.”

Dr. Annevay D. Conlee, a board-certified family medicine doctor who specializes in obstetrics and gynecology with OSF HealthCare in Illinois, said research should continue to determine “which women are truly best-suited for this therapy” and then create evidence-based guidelines.

“I do think we have to be cautious about swinging too far the other way,” Conlee said. “We [women] all go through menopause; it’s a natural phase of our life.”

Conlee said some women move gently through menopause, which allows their bodies to adapt to the hormonal changes. Others struggle with intense symptoms that need treatment, especially if their ovaries fail rapidly, she said.

What about women who can’t take hormone replacement products? Egan said non-hormonal medications can still treat symptoms.

For instance, venlafaxine, a serotonin-norepinephrine reuptake inhibitor, and gabapentin, an anticonvulsive medication, are both used off-label to control hot flashes, he said.

Still, even “patients in the strictest category” can often use topical vaginal estrogen therapy to treat genitourinary symptoms, since little estrogen is absorbed systemically, Pierre said.

In fact, the American College of Obstetricians & Gynecologists, has “long advocated for removal of the ‘black box warning’ on low-dose vaginal estrogen,” Fleischman said in the statement.

Pierre hopes the labeling shift also leads to a language shift. Menopause isn’t a disease that needs fixing, she said. It’s a transition that needs support.

“Hormone replacement therapy is a tool to support the transition,” Pierre said.