Clinicians Call for Easing FDA Warnings on Low-Dose Estrogen

Charles Powell, MD, said he sometimes has a hard time persuading patients to start on low-dose vaginal estrogen, which can help prevent urinary tract infections and ease other symptoms of menopause.

Charles Powell, MD

Many women fear taking these vaginal products due to what Powell considers excessively strong warnings about the risk for cancer and cardiovascular disease linked to daily estrogen pills that were issued in the early 2000s.

He is advocating for the US Food and Drug Administration (FDA) to remove the black box warning on low-dose estrogen. His efforts are separate from his roles as an associate professor of urology at the Indiana University School of Medicine, Indiana, and as a member of the American Urological Association (AUA), Powell said.

In his quest to find out how to change labeling, Powell has gained a quick education about drug regulation. He has enlisted Representative Jim Baird (R-IN) and Senator Mike Braun (R-IN) to contact the FDA on his behalf, while congressional staff guided him through the hurdles of getting the warning label changed. For instance, a manufacturer of low-dose estrogen may need to become involved.

“You don’t learn this in med school,” Powell told Medscape Medical News in a recent interview.

With this work, Powell is wading into a long-standing argument between the FDA and some clinicians and researchers about the potential harms of low-dose estrogen.

He is doing so at a time of increased interest in understanding genitourinary syndrome of menopause (GSM), a term coined a decade ago by the International Society for the Study of Women’s Sexual Health and the North American Menopause Society to cover “a constellation of conditions” related to urogenital atrophy.

Symptoms of GSM include vaginal dryness and burning and recurrent urinary tract infections.

The federal government in 2022 began a project budgeted with nearly $1 million to review evidence on treatments, including vaginal and low-dose estrogen. The aim is to eventually help the AUA develop clinical guidelines for addressing GSM.

In addition, a bipartisan Senate bill introduced in May calls for authorizing $125 million over 5 years for the National Institutes of Health (NIH) to fund research on menopause. Senator Patty Murray (D-WA), the lead sponsor of the bill, is a longtime advocate for women’s health and serves as chairwoman for the Senate Appropriations Committee, which largely sets the NIH budget.

“The bottom line is, for too long, menopause has been overlooked, underinvested in and left behind,” Murray said during a May 2 press conference. “It is well past time to stop treating menopause like some kind of secret and start treating it like the major mainstream public health issue it is.”

Evidence Demands

Increased federal funding for menopause research could help efforts to change the warning label on low-dose estrogen, according to JoAnn Manson, MD, chief of preventive medicine at Brigham and Women’s Hospital in Boston.

photo of Jo Ann Manson
JoAnn Manson, MD

Manson was a leader of the Women’s Health Initiative (WHI), a major federally funded research project launched in 1991 to investigate if hormone therapy and diet could protect older women from chronic diseases related to aging.

Before the WHI, clinicians prescribed hormones to prevent cardiovascular disease, based on evidence from earlier research.

But in 2002, a WHI trial that compared estrogen-progestin tablets with placebo was halted early due to disturbing findings, including an association with higher risk for breast cancer and cardiovascular disease.

As compared with placebo, for every 10,000 women taking estrogen plus progestin annually, incidences of cardiovascular disease, stroke, pulmonary embolism, and invasive breast cancer were seven to eight times higher.

In January 2003, the FDA announced it would put a black box warning about cardiovascular risk and cancer risk on estrogen products, reflecting the WHI finding.

The agency at the time said clinicians should work with patients to assess risks and benefits of these products to manage the effects of menopause.

But more news on the potential harms of estrogen followed in 2004: A WHI study comparing estrogen-only pills with placebo produced signals of a small increased risk for stroke, although it also indicated no excess risk for breast cancer for at least 6.8 years of use.

Manson and the North American Menopause Society in 2016 filed a petition with the FDA to remove the black box warning that appears on the front of low-dose estrogen products. The group wanted the information on risks moved to the usual warning section of the label.

Two years later, the FDA rejected the petition, citing the absence of “well-controlled studies,” to prove low-dose topical estrogen poses less risk to women than the high-dose pills studied in the WHI.

The FDA told Medscape Medical News that it stands by the decisions in its rejection of the petition.

Persuading the FDA to revise the labels on low-dose estrogen products likely will require evidence from randomized, large-scale studies, Manson said. The agency has not been satisfied to date with findings from other kinds of studies, including observational research.

“Once that evidence is available that the benefit-risk profile is different for different formulations and the evidence is compelling and definitive, that warning should change,” Manson told Medscape Medical News.

But the warning continues to have a chilling effect on patient willingness to use low-dose vaginal estrogen, even with the FDA’s continued endorsement of estrogen for menopause symptoms, clinicians told Medscape Medical News.

Risa Kagan, MD, a gynecologist at Sutter Health in Berkeley, California, said in many cases her patients’ partners also need to be reassured. Kagan said she still sees women who have had to discontinue sexual intercourse due to pain. In some cases, the patient will bring the medicine home only to find that the warnings frighten their spouse.

“The spouse says, ‘Oh my God, I don’t want you to get dementia, to get breast cancer, it’s not worth it, so let’s keep doing doing outercourse’,” meaning sexual relations without penetration, Kagan said.

Difficult Messaging

From the initial unveiling of disappointing WHI results, clinicians and researchers have stressed that women could continue using estrogen products for managing symptoms of menopause, even while advising strongly against their continued use with the intention of preventing heart disease.

Newly published findings from follow-ups of WHI participants may give clinicians and patients even more confidence for the use of estrogen products in early menopause.

According to the study, which Manson co-authored, younger women have a low risk for cardiovascular disease and other associated conditions when taking hormone therapy. Risks attributed to these drugs were less than one additional adverse event per 1000 women annually. This population may also derive significant quality-of-life benefits for symptom relief.

Manson told Medscape Medical News that estrogen in lower doses and delivered through the skin as a patch or gel may further reduce risks.

“The WHI findings should never be used as a reason to deny hormone therapy to women in early menopause with bothersome menopausal symptoms,” Manson said. “Many women are good candidates for treatment and, in shared decision-making with their clinicians, should be able to receive appropriate and personalized healthcare for their needs.”

But the current FDA warning label makes it difficult to help women understand the risk and benefits of low-dose estrogen, according to Stephanie Faubion, MD, MBA, the medical director at the North American Menopause Society and the director of Mayo Clinic’s Center for Women’s Health in Jacksonville, Florida.

photo of Stephanie Faubion
Stephanie Faubion, MD, MBA

Clinicians now must set aside time to explain the warnings to women when they prescribe low-dose estrogen, Faubion said.

“The package insert is going to look scary: I prepare women for that because otherwise they often won’t even fill it or use it.”

Kerry Dooley Young is a freelance journalist based in Washington, DC.

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