FDA Announces Removal of ‘Black Box’ Safety Warning From Hormone Therapy for Menopause

As reported on by Contemporary OB/GYN, the US Department of Health and Human Services (HHS) and the FDA announced actions to revise safety labeling for menopausal hormone therapy (MHT), also known as hormone replacement therapy (HRT). The FDA informed application holders that updated labeling will more clearly describe benefit and risk considerations for systemic and local vaginal hormone products.

MHT is approved to treat vasomotor symptoms (VMS), symptoms related to vulvovaginal atrophy or genitourinary syndrome of menopause (GSM), and, for some products, prevention of osteoporosis. According to the FDA, the requested labeling changes follow a comprehensive review of scientific literature, updated drug utilization data, public input and the July 2025 FDA Expert Panel meeting.

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The agency reviewed data published since the original Women’s Health Initiative (WHI) trials, which began in the 1990s. WHI investigated estrogen plus progestin therapy in women with a uterus and estrogen-alone therapy in women without a uterus. Both trials were stopped early in the 2000s because of reported increases in breast cancer, stroke and lack of evidence of coronary artery disease prevention. Separate WHI studies in older women reported an increased risk of probable dementia.

Class-wide boxed warnings were added beginning in 2003. In subsequent years, clinicians and patient groups questioned the applicability of WHI findings to younger menopausal women for whom MHT is indicated. FDA drug utilization data indicate that MHT may be underused: in 2020, approximately 2 million women aged 46 to 65 years received prescriptions for systemic therapy, although the prevalence of moderate to severe VMS is estimated at about 34% among women aged 45 to 65 years.

The FDA noted that WHI participants had a mean age of 63 years, which differs from the typical age of menopause onset in the United States (51 years). The agency stated that many women start MHT between ages 45 and 55 years for symptom relief, whereas WHI enrolled an older population with higher baseline risks. The probable dementia findings were also based on women aged 65 to 79 years, older than the population initiating MHT for VMS.

“The WHI studies evaluated the safety of oral conjugated equine estrogens + medroxyprogesterone acetate,” said Lora Lansen, MD, chief medical officer at Elektra Health, and a board and Menopause Society-certified family physician. “That was the most popular and widely accessible version of hormone therapy at the time. Newer therapies include transdermal estradiol—which significantly diminishes the risk of VTE by avoiding first-pass hepatic metabolism—and oral micronized progesterone, which, unlike synthetic progestogens, has a seemingly neutral effect on breast tissue. It’s important to note that we need more data to make up for the dearth of research in this domain and until we better understand the full impact of MHT on breast cancer risk, women with a personal history of breast cancer remain ineligible for MHT.

Lansen added, “In reevaluating WHI data, we’ve also learned that timing matters. The risk of MHT-associated adverse outcomes is still considered relatively high for women who start MHT over 60 years of age and/or 10-plus years after their final menstrual period. More data is needed to determine whether MHT can be safely administered in this patient population. For now, it is recommended that MHT start <60 years old and <10 years after the final menstrual period. It can be continued for as long as there is perceived benefit.

Based on its assessment, the FDA requested several key labeling changes:

For all MHT products (systemic and local vaginal):

• Remove language in the boxed warning related to cardiovascular disease, breast cancer and probable dementia.
• Remove language related to endometrial cancer except for systemic estrogen-alone products.
• Remove the recommendation to use the lowest effective dose for the shortest duration.
• Remove the probable dementia warning throughout labeling.

For systemic products:

• Add consideration of starting therapy for moderate to severe VMS in women younger than 60 years or within 10 years of menopause onset.
• Add WHI data for women aged 50 to 59 years.
• Retain the boxed warning regarding endometrial cancer for estrogen-alone products.
• Retain information on cardiovascular disease and breast cancer in labeling outside the boxed warning.

For local vaginal estrogen products:

• Condense safety information and prioritize content most relevant to local use.

At an HHS press conference announcing the broader policy shift, Health and Human Services Secretary Robert F. Kennedy Jr. stated, “Today, we are standing up for every woman who has symptoms of menopause and is looking to know her options and receive potentially life-changing treatment.” He added, “We are returning to evidence-based medicine and giving women control over their health again.”

FDA Commissioner Marty Makary, MD, MPH, said, “Women and their physicians should make decisions based on data, not fear.”

As estrogen and progesterone decline during menopause, hormone therapy can relieve symptoms such as VMS, sleep disturbances and bone loss. Alicia Jackson, PhD, director of the Advanced Research Projects Agency for Health, said, “Estrogen is a key hormone for women’s health. Every single part of a woman’s body depends on estrogen to operate at its best.”

The FDA also noted that randomized studies show reductions in all-cause mortality and fractures among women who initiate systemic hormone therapy within 10 years of menopause or before age 60 years. Updated labeling is expected to reflect these considerations.

In addition to labeling changes, the FDA approved 2 new therapies: a generic version of conjugated estrogens and a non-hormonal treatment for moderate to severe VMS. The agency stated that the generic conjugated estrogen product is expected to improve affordability and access.