The landscape of menopausal hormone therapy (MHT) prescribing is currently undergoing a shift.

Evolving interpretations of safety data from randomized trials and observational studies culminated in the FDA recently deciding to remove the class-wide black box warnings for many systemic estrogen and combined estrogen-progestogen (EPT) products. According to experts, this regulatory change is expected to improve access to MHT but raises questions about balancing symptom relief with long-term safety, particularly breast cancer risk.

JoAnn Manson, MD, MPH, DrPH, professor of medicine at Harvard Medical School, Boston, past president of the Menopause Society, and one of the lead investigators on the Women’s Health Initiative (WHI) trials, supported the removal of the black box warning, stating it “will lead to less fear and alarm about the use of hormone therapy so that women are able to make more informed decisions.” However, she emphasized that “the information about risks and benefits seen in the randomized trials needs to be in the package insert, at least in regular font and regular text,” to ensure transparency without undue alarm.

Why Was the Black Box Warning in the Label?

For decades, MHT has been used to treat menopausal symptoms, including hot flashes, night sweats, and mood changes, as well as to prevent chronic conditions such as coronary heart disease. However, the initial findings of the WHI randomized clinical trials, particularly the estrogen plus progestin trial in 2002, created fears that hormone therapy increases the risk for breast cancer mortality.

In response to the WHI findings, the FDA instituted class-wide labeling changes starting in January 2003, which eventually included boxed warnings for serious risks such as cardiovascular disease, thromboembolism, breast cancer, and probable dementia. These warnings, however, did not stratify risk by age of initiation or formulation type.

According to Stephanie S. Faubion, MD, MBA, director of the Mayo Clinic Center for Women’s Health and medical director for the Menopause Society, the boxed warning “has acted as a deterrent to the use of all hormone therapy,” and the publication of the initial WHI findings resulted in a drastic decrease in MHT use. She explained that before 2002, about 25% of women were receiving systemic hormone therapy; this fell immediately to about 4%-6% and has remained low.

However, Faubion emphasized that the link between MHT and breast cancer is complex and highly dependent on the regimen used, the patient’s characteristics, and the timing of initiation.

What Does the Warning Removal Mean for MHT Use?

The FDA’s proposed label updates signal a move toward individualized care, removing the black box warning for these outcomes — except the one for endometrial cancer with unopposed estrogen in women with a uterus — and removing the recommendation to prescribe at the lowest dose for the shortest duration. Instead, safety information will be revised to reflect risks most relevant to the specific type of MHT product.

She anticipates the removal will “lead to increased rates of clinicians prescribing and women using both systemic and low-dose vaginal therapies,” and it will reduce fears that have prevented millions of women from accessing MHT. Faubion also expects that the removal of the warning will lead to “more informed conversations about the risks and benefits of systemic hormone therapy between patients and their healthcare professionals.” However, she emphasized that it is important to ensure that clinicians have the education necessary to hold these informed conversations, as removing warnings could otherwise lead to “inappropriate prescribing or minimization of real risks.”

Faubion outlined the factors to consider when counseling patients about the risks and benefits of MHT. These include the need for addressing symptoms that warrant MHT, the patient’s age and proximity to menopause onset, and the history of heart attack, stroke, blood clot, estrogen-dependent cancer, or severe active liver disease. She also advocates for the importance of shared decision-making and considering patient preferences, positing that some women may decide MHT is worthwhile for quality-of-life reasons even if they have higher-than-average breast cancer risk.

Laure-Anne Teuwen, MD, PhD, medical oncologist at Antwerp University Hospital, Antwerp, Belgium, said patient counseling must integrate the most robust findings regarding formulations, that is, that there is a lower breast cancer risk with estrogen-only therapy and a higher risk with EPT, and that the risk increases with long-term use. She also advised clinicians to contextualize absolute risks.

Does the Evidence Support a Link Between MHT and Breast Cancer Incidence?

According to Manson, there is evidence from both randomized controlled trials (RCTs), including the WHI trials, and large observational studies to suggest a potential association between the use of MHT and the risk for breast cancer development.

The Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) conducted an individual participant meta-analysis of worldwide epidemiologic evidence, synthesizing data from over 100,000 postmenopausal women who developed breast cancer. The analysis showed that the use of all MHT types except vaginal estrogens was associated with excess breast cancer incidence. The risk for breast cancer development increased with duration of use and was higher for EPT MHT than for estrogen-only MHT. 

Consistent with the findings of the meta-analysis, long-term follow-up data from the WHI randomized trial of conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) suggest that MHT use is associated with increased breast cancer risk. After more than 20 years of median cumulative follow-up, the WHI trial showed that among 16,608 women with a uterus, combined use of CEE plus MPA was associated with a statistically significantly higher breast cancer incidence (584 cases; annualized rate, 0.45%) than placebo (447 cases; annualized rate, 0.36%), yielding a hazard ratio (HR) of 1.28 (95% CI, 1.13-1.45; P < .001).

However, Faubion emphasized that “estrogen alone is not linked with an increased risk of breast cancer, and in a recent meta-analysis of all RCTs on estrogen-alone therapy, it showed a reduced incidence of breast cancer.” Indeed, the use of CEE alone among women with a prior hysterectomy in the WHI CEE trial was associated with a statistically significant lower breast cancer incidence (238 cases; annualized rate, 0.30%) than placebo (296 cases; annualized rate, 0.37%), with an HR of 0.78 (95% CI, 0.65-0.93; P = .005). This protective effect persisted for more than a decade after discontinuing MHT use.

A 2024 meta-analysis of 10 randomized trials supported this negative association between estrogen-alone MHT and breast cancer risk, reporting an overall reduced risk for breast cancer incidence associated with estrogen-alone use (relative risk [RR], 0.77; 95% CI, 0.65-0.91; P = .002).

New findings related to estrogen-progestin use from a matched prospective analysis comparing BRCA carriers who started hormone therapy after menopause (surgical in 95% of cases) with those who did not contrasted with those of other studies of patients using the combination therapy. This research, presented at the San Antonio Breast Cancer Symposium (SABCS) 2025, included patients using any of the following kinds of hormone therapy: estrogen alone, progestin alone, combined estrogen-progestin, tibolone (a synthetic steroid used in some countries), and conjugated estrogen plus the selective estrogen receptor modulator bazedoxifene (Duavee, Duavive).

Over a mean follow-up of 5.6 years from the start of hormone therapy, women who used the therapy had 87 incident breast cancers (12.9%) vs 128 cancers among nonusers (18.9%; P = .002). While that apparent protective effect was limited to women who used estrogen alone, no type of hormone therapy, including estrogen-progestin, was significantly associated with breast cancer risk in either direction, Medscape Medical News reported.

Faubion advises clinicians to look at the evidence from an absolute risk perspective when counseling patients about the potential risk for breast cancer due to MHT use. She used the example from the WHI CEE plus MPA trial, noting the association was about eight to nine extra cases of breast cancer per 10,000 women per year. This translates to “a little less than one extra case of breast cancer per 1000 women per year of use.”

Placing this risk in perspective, Faubion said it is similar in magnitude to many lifestyle factors, such as “one to two glasses of wine per night, as having overweight or obesity, or as being inactive.”

Why Mortality Data Remains Uncertain

The evidence regarding the effect of MHT on breast cancer mortality is conflicting. Early data from WHI analyses (after a total mean follow-up of 11.0 years) demonstrated that deaths directly attributed to breast cancer were greater in the EPT group than in the placebo group (0.03% vs 0.01% annualized mortality rate; HR, 1.96; 95% CI, 1.00-4.04; P = .049).

These findings contrast with more recent WHI analyses, which showed that after long-term follow-up of the WHI CEE plus MPA trial, there was no significant difference in breast cancer mortality, with 71 deaths (annualized mortality rate, 0.045%) vs 53 deaths (annualized mortality rate, 0.035%) and an HR of 1.35 (95% CI, 0.94-1.95; P = .11).

According to Teuwen, the early WHI findings may have been influenced by the shorter follow-up period and fewer events, which may have contributed to discrepancies between the early data and long-term follow-up data.

“Variation in findings across different studies can be explained by differences in study design, population characteristics, MHT regimens, timing and duration of therapy, and confounding factors such as mammography frequency and underlying breast cancer risk,” she said.

Teuwen also addressed the discrepancy between increased incidence and non-increased mortality in the long-term follow-up analysis of WHI, noting that “while [EPT] increases the risk of developing breast cancer, it does not necessarily increase the risk of death from breast cancer.” She explained that this discrepancy may be explained by detection bias and favorable tumor characteristics.

“Breast cancers diagnosed in MHT users tend to be detected at an earlier stage, partly due to increased mammography screening,” she said. She added that the majority of MHT-associated breast cancers are hormone receptor-positive, which generally have a more favorable prognosis.

Does the Type of Therapy Influence the Link Between MHT and Breast Cancer?

According to Manson, the type of MHT used — estrogen alone vs EPT — is “perhaps the most significant determinant of breast cancer risk.”

In the CGHFBC meta-analysis of prospective studies, the excess breast cancer risk increased steadily with duration of use for both EPT combinations and estrogen-only therapy, but the risks were nearly twice as high for EPT compared with estrogen-only therapy during 5-14 years of use (RR, 2.08 with EPT vs 1.33 with estrogen-only therapy).

Manson noted that the type of progestogen in EPT may influence the relationship between MHT use and breast cancer risk. She explained that MPA has been the MHT that is “most strongly linked to breast cancer in the randomized trials, including the WHI, and the observational studies.” She also said that MPA appeared to be “most relevant in increasing the risk of breast cancer” in the WHI combination trial because CEE alone was linked to a reduced risk for breast cancer.

Manson said that newer progestogen formulations, such as micronized progesterone, have been “less well studied for breast cancer,” but it is “possible, based on observational studies, that they pose less of a risk of breast cancer than the MPA.” Teuwen reiterated that current research gaps include “insufficient randomized controlled trial data on newer MHT regimens” and “limited evidence on the comparative risks of different progestogens, especially natural progesterone and dydrogesterone, versus synthetic progestins.”

Does Timing and Duration of MHT Use Correlate With Increased Breast Cancer Risk?

Current evidence suggests that breast cancer risk increases with the duration of MHT use, particularly for EPT. In the Million Women Study (MWS), the relative risk for breast cancer for current MHT users at baseline increased with increasing total duration of use of MHT. For current users of EPT combinations, the relative risk was substantially increased across duration categories, culminating in a highly significant risk increase after 5 years or more of MHT use.

For women who begin EPT at age 50, 5 years of EPT use is estimated to result in six additional breast cancers among 1000 users by age 65, and 10 years of EPT use is estimated to result in 19 additional cancers among 1000 users by age 65.

Manson cautioned, however, that WHI data suggest that “the risk stayed relatively constant even in long-term cumulative follow-up with the women off of hormone therapy for many years, so there is probably a residual increase in risks that lasts many years.”

Updated FDA guidance is expected to include information recommending initiating MHT in women younger than 60 years or within 10 years of menopause onset to optimize the benefit-risk balance. However, Teuwen noted that the evidence supporting a protective effect of early initiation regarding breast cancer is “not very reliable,” citing the MWS finding that risk is higher when treatment is started at or soon after menopause (less than 5 years).

What Research Gaps Remain Concerning MHT Safety?

Despite evidence from the WHI and large cohort studies such as MWS and E3N, research gaps persist regarding the safety profile of MHT, said Teuwen. She explained that there are insufficient RCT data on newer formulations, specifically transdermal estradiol and micronized progesterone. She added that limited definitive evidence exists regarding the comparative risks across different progestogens, particularly natural progesterone and dydrogesterone vs synthetic progestins, despite observational data suggesting lower risk for the former. Manson echoed this sentiment, calling for “more research on the other types of progestogens, including micronized progesterone and bioidentical formulations.”

Teuwen and Faubion also highlighted that there is a lack of information on dose-response relationships and the impact of lower-dose or intermittent regimens that are currently used.

“We need to better understand the safety profile of the commonly used hormone therapy regimens we have today and how they differ from what was used previously,” Faubion said.

When asked about the ideal study design to obtain more definitive answers regarding MHT and breast cancer risk, Teuwen emphasized the need for large, multicenter RCTs directly comparing contemporary MHT formulations to placebo. She added that trials should include stratification by baseline breast cancer risk and use standardized mammography protocols to minimize detection bias. In addition, trials should enroll women at the typical age of MHT initiation (eg, aged 50-54 years) and include long-term follow-up of at least 10-20 years to capture both incidence and mortality outcomes, along with detailed collection of tumor subtype and receptor status.

Faubion, Manson, and Teuwen reported having no relevant financial relationships or conflicts of interest.

Christos Evangelou, PhD, is a freelance medical writer and science communications consultant.