November 26, 2025
On November 10, 2025, the U.S. Food and Drug Administration announced it was removing the long-standing “black box” warning from many menopausal hormone replacement therapy (HRT) labels. For many women, that warning created fear and confusion about whether hormones are “too risky,” even when facing unmanageable symptoms.Menopausal HRT involves taking estrogen, with or without a progestogen, to ease symptoms that appear as hormone levels fall around menopause. Hot flashes, night sweats, poor sleep, mood changes, vaginal dryness, brain fog, body aches, and bone loss can all be part of that picture [1].
In 2002, the Women’s Health Initiative (WHI) reported on a study that examined a single combined HRT regimen using oral conjugated equine estrogens with a synthetic progestogen, medroxyprogesterone acetate (MPA), in postmenopausal women [1]. The average age of participants was 63, and many were more than a decade into menopause. The study was stopped early due to an increased hazard ratio for breast cancer and cardiovascular disease, stating that the “health risks exceeded health benefits” [2]. Critics argued that the data did not reach statistical significance, and measures of symptom relief and quality of life were not included [3]. Additionally, there were no statistically significant differences in death rate from either cancer or cardiovascular disease between HRT and placebo groups [2]. Never-the-less, the study did report that the “relative risk” for breast cancer doubled; however, the absolute risk was actually quite small (about 8 cases per 10,000 women per year on combined HRT versus 3–4 per 10,000 on placebo, which works out to roughly one extra case per 1,000 women per year).
Soon after the WHI published its results, the U.S. Preventive Services Task Force advised against systemic HRT to prevent chronic conditions in people who had gone through menopause, though notably excluding treatment of menopausal symptoms and bone loss from this recommendation [4]. Health Canada and Canadian professional groups followed suit, adopting a similarly cautious approach, subsequently updating product monographs to emphasize potential risks with warnings that remain in package inserts to this day. Unfortunately, sensationalized press coverage of the increased relative risks were communicated without adequate context, creating a wave of disproportionate fear that deterred an entire generation of women from accessing and benefiting from HRT.
Despite these cautionary policies and visible risk warnings, it is important to distinguish the use of systemic HRT for disease prevention from its established role in the management of menopausal symptoms. In clinical practice (and supported by current medical guidelines) systemic HRT remains the most effective treatment for bothersome hot flashes and night sweats, and in appropriate candidates, can improve sleep, mood, brain fog, body aches, sexual function, and overall daily functioning [5]. Systemic HRT can also slow early postmenopausal bone loss and reduce fracture risk for selected women [6].
The research to date has highlighted 3 critical factors that substantially influence HRT safety profiles: timing of initiation, route of administration, and progestogen formulation. However, it is important to note that long-term safety data, particularly beyond 10–15 years of continuous use, remains limited, which necessitates individualized risk-benefit assessment.
Starting HRT before age 60 or within ten years of menopause is associated with a lower risk of all-cause mortality and cardiovascular events compared with initiating therapy later [10,11]. The ELITE trial further demonstrated the importance of early initiation, showing that women who began transdermal estradiol within six years of menopause had slower carotid artery wall thickening than those who started later [9]. This timing advantage suggests a critical window during which HRT may confer metabolic and vascular benefits; however, the current body of evidence does not yet support using HRT as a primary strategy to prevent heart disease [10].
The route of estrogen delivery significantly impacts specific health risks. Oral estrogen increases the risk of venous thromboembolism (blood clots that can travel from the leg to the lungs), whereas standard-dose transdermal estradiol does not carry this elevated risk [11]. Additionally, oral estrogen is associated with a higher rate of gallbladder disease compared to transdermal therapy, a consideration that should be factored into route selection [12].
Distinct from systemic HRT, local vaginal estrogen treats genitourinary syndrome of menopause (GSM), which can include dryness, pain with intercourse, urinary discomfort, and recurrent infections [13]. Low-dose vaginal estrogen works mainly in the vaginal and urinary tissues, so it does not require a progestogen for uterine protection. Because only a tiny amount reaches the bloodstream, large cohort results from the Nurses’ Health Study have found that vaginal estrogen does not increase risks for cancer or cardiovascular disease [14].
Women with an intact uterus require a progestogen alongside systemic estrogen to protect the endometrium and reduce endometrial cancer risk. Progestogen regimens include oral or vaginal progesterone or synthetic progestins, or a levonorgestrel intrauterine system. Critically, progestogen type influences breast cancer risk: combined estrogen–progestogen therapy raises breast cancer risk more than estrogen-alone, with synthetic progestins conferring a higher risk than micronized progesterone [15]. Emerging alternatives such as oral estrogen conjugated with bazedoxifene (a selective estrogen receptor modulator, or SERM) eliminate the need for a progestogen, with early studies indicating this SERM reduces breast tissue proliferation (reducing the risk of cancer) [16-18]. On the estrogen front, conjugated equine estrogens have a different risk/safety profile than 17ϐ estradiol [19, 20].
The FDA recently decided to remove the boxed warning from both systemic and local estrogen products while keeping detailed risk language, in an effort to align labels with current evidence.
Some menopause specialists expressed concern about the rationale for removing the black box warning from systemic estrogen. OB-GYN Dr. Jen Gunter supports lifting the warning for vaginal estrogen but cautions that the FDA relied heavily on older observational data while giving less weight to stronger, more recent evidence on systemic HRT. She also warns against public messaging that overstates the benefits of systemic HRT, particularly claims about reduced mortality, cardiovascular protection, or dementia prevention, which are not supported by high-quality randomized trials. Dr. Gunter emphasizes that HRT remains an effective option for symptom relief and quality-of-life improvements, including sleep, cognition, vasomotor symptoms, and pain, but it should be prescribed based on individual risk assessments, not promoted as a universal cure-all or a chronic disease prevention strategy.
In Canada, the science remains unchanged despite U.S. label revisions. Health Canada has not removed its own “serious warnings and precautions” box for menopausal hormone therapy, so Canadian product monographs still include WHI-era warnings about breast cancer, cardiovascular disease, stroke, and dementia. The Canadian Menopause Society has endorsed the FDA’s decision, arguing that outdated boxed warnings perpetuate stigma and contribute to the underuse of safe, effective therapy in appropriately selected women. They urge Canada to modernize labeling to reflect current evidence.
Ontario Health’s Menopause Quality Standard continues to support HRT as first-line treatment for bothersome vasomotor symptoms and calls for shared decision-making, structured follow up, and attention to equity in access. Similarly, the Society of Obstetricians and Gynaecologists of Canada (SOGC) guidelines on managing menopause outline a range of hormonal and nonhormonal options for treating vasomotor symptoms, mood, cognitive concerns, and sexual health. More recently, Canada’s Drug Agency (CDA-AMC) reviewed transdermal and oral menopausal hormone therapies, and highlighted the importance of counselling on route of administration, particularly for women at higher risk of venous thromboembolism. Collectively, these organizations are signaling that Canadian counseling should focus more on individual risk, symptom relief, and patient values rather than on historic U.S. black‑box language.
The removal of the black box warning has sparked both optimism and confusion, underscoring the need for clear, evidence-based guidance. As research continues to refine our understanding of hormone therapy, the goal remains the same: to help women make informed, individualized decisions grounded in science rather than headlines. HRT is a highly effective option for symptom relief, especially when started early, but it is not a universal solution for chronic disease. Ongoing conversations with knowledgeable clinicians, paired with a solid understanding of systemic and local options, will ensure women can navigate menopause with confidence and clarity.
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