Menopausal Hormone Therapy May Boost GLP-1 Weight Loss

— Effect was sustained with one agent, but didn't last with another

Menopausal women taking hormone therapy in addition to a GLP-1 medication may see greater and sustained weight loss, a retrospective cohort study suggested.

Women taking semaglutide (Wegovy) and menopausal hormone therapy had significantly greater total body weight loss starting at 9 months compared to their counterparts taking semaglutide alone (-9.8% vs -8.2%, P<0.001), reported Regina Castaneda, MD, a postdoctoral research fellow at the Mayo Clinic in Jacksonville, Florida.

These differences persisted at 12 months (-11.0% vs -9.5%, P=0.001) and 15 months (-11.6% vs -9.7%, P<0.001), she noted in a presentation at the Menopause Societyopens in a new tab or window annual meeting.

On the other hand, for those taking tirzepatide (Zepbound), concurrent menopausal hormone therapy use was associated with modestly greater weight loss at 3 months (-6.6% vs -5.9%, P=0.031), but there were no significant differences at later timepoints.

Castaneda told MedPage Today that the difference between the two agents is noteworthy. She suggested this divergence could be a ceiling effect since tirzepatide produces greater weight lossopens in a new tab or window on its own "and may overcome many of the metabolic disadvantages associated with menopause, leaving less opportunity for hormone therapy to provide an additional measurable benefit." It also could be mechanistic, since the two agents work through different pathways, she said.

Overall, Castaneda said this study "adds to a growing body of evidence suggesting that sex, reproductive stage, and hormonal status may influence how patients respond to obesity treatments." Nonetheless, she stressed that "weight management is not an indication for menopause hormone therapy," which should only be prescribed for established indications.

Previous small, retrospective studiesopens in a new tab or window have suggested that women taking menopause hormone therapy in addition to GLP-1 agents may have more weight loss benefitsopens in a new tab or window. Some studies have looked at the effect of GLP-1 medications on midlife women but did not explore the role of hormone therapy or did not break analysis down by agent.

"This real-world cohort of midlife women adds to growing evidence that estrogen and hormone therapy may modulate weight loss on GLP-1s," JoAnn E. Manson, MD, MPH, DrPH, of Harvard Medical School in Boston and past president of the Menopause Society, told MedPage Today.

Manson, who was not involved in the research, added that while the observational study needs to be confirmed by larger prospective trials, "these findings could inform more personalized and effective treatment strategies for GLP-1s in postmenopausal women."

This retrospective study looked at multisite EHR data from nSights from 2017 through December 2025. Participants were age 45 years or older with a body mass index (BMI) of ≥27 kg/m² and using either semaglutide or tirzepatide for 12 months or longer. Those with a history of bariatric surgery, active malignancy, concurrent use of other obesity medications, or pregnancy were excluded.

There were 2,379 women in the semaglutide cohort (793 semaglutide alone, 1,586 with concurrent hormone therapy). The tirzepatide group included 1,476 women (984 tirzepatide alone, 492 with concurrent hormone therapy). Baseline characteristics and adiposity-related comorbidities were balanced between groups.

Women taking semaglutide and concurrent menopausal hormone therapy were significantly more likely to achieve certain percentages of body weight loss: ≥10% (55% vs 51%, P=0.045), ≥20% (22% vs 18%, P=0.037), ≥25% (13% vs 10%, P=0.008), and ≥30% (6% vs 4%, P=0.015).

For the tirzepatide group, concomitant menopausal hormone therapy was associated with a higher proportion achieving ≥5% total body weight loss (88% vs 84%, P=0.04), but there were no significant differences at higher weight-loss thresholds.

Castaneda emphasized that since the current evidence is limited to observational studies, a causal relationship has not yet been proven; prospective studies are needed to confirm the findings and shape treatment strategies.

Research looking at differences by hormone therapy formulation, route of administration, timing relative to menopause, and individual biological factors, as well as using endpoints beyond BMI, such as body composition, visceral adiposity, preservation of lean mass, bone health, and broader cardiometabolic outcomes, also is needed, she said.

She also pointed out that women who use menopausal hormone therapy may be different from nonusers in terms of health behaviors, healthcare engagement, socioeconomic factors, and medication adherence. While the authors used propensity-score matching, residual confounding remains possible, Castaneda said.