The GLP-1/GIP dual-receptor agonist tirzepatide led to at least 15% loss of total body fat in premenopausal, perimenopausal, and postmenopausal women, but postmenopausal women taking menopausal hormone therapy had the greatest weight loss, according to research presented at The Menopause Society 2025 Annual Meeting in Orlando, Florida. 

Midlife weight gain has been associated with cardiovascular risk, and tirzepatide is currently the most effective weight-management medication available, Regina Castaneda, MD, postdoctoral research fellow at the Mayo Clinic in Jacksonville, Florida, told attendees. 

“Understanding the influence of the reproductive stage and the potential impact of menopausal hormone therapy on treatment outcomes is essential” in considering tirzepatide effectiveness in women with midlife weight gain, Castaneda said.

Starting from a population of 521 women, the researchers were able to match 160 women, an average 50 years old, into four groups of 40 women each. The women were matched based on diabetes status, prior use of weight loss medications, and baseline BMI. 

The average age was 37 years for the group of premenopausal women, 49 years for the group comprising perimenopausal women, 59 years for the group of postmenopausal women not taking hormone therapy, and 56 years for the group of postmenopausal women taking oral or transdermal hormone therapy. 

At baseline, there were no significant differences among the groups in terms of cardiometabolic comorbidities, and all groups experienced significant weight loss with tirzepatide over a mean duration of 18 months. 

The premenopausal women experienced a significant 18.7% loss of total body fat and the perimenopausal women had a significant 18.6% loss of total body fat, neither of which differed significantly from the 19.9% total body fat loss seen in the postmenopausal women taking hormone therapy. The postmenopausal women not taking hormone therapy had significantly less weight loss, ie, 15.6% of total body fat (P = .02). 

Karen Adams, MD, clinical professor of ob/gyn and director of the Program in Menopause and Healthy Aging at Stanford Medicine in Palo Alto, California, was not involved with the research and told Medscape Medical News the results were surprising. 

“We know that tirzepatide causes weight loss, but this study shows that tirzepatide-associated weight loss is significantly less in postmenopausal women not on hormones than in postmenopausal women on hormones,” Adams said. “This gives us yet another data point to factor into the risk-benefit calculation of menopausal hormone therapy for postmenopausal women.”

Castaneda proposed several possible hypotheses for the weight loss differences in postmenopausal women taking and not taking hormone therapy. One potential reason could relate to “healthy user bias,” she said, wherein women on hormone therapy happen to be engaging in healthier lifestyles more broadly, possibly because the hormone therapy is helping to manage their vasomotor symptoms, for example, making it easier for them to exercise more often. 

In addition, Castaneda noted preclinical evidence in mice that has suggested a synergistic interaction between estrogen and GLP-1 signaling, with estrogen providing an additive effect to the impact of GLP-1 drugs on women’s appetite suppression.

Emphasizing that the study results show only association, not causation, Castaneda said that menopausal hormone therapy is not indicated for weight loss and that the use of hormone therapy and weight loss medications must be individualized for each patient.

“Obviously, improved response to GLP-1s is not a reason to start women on hormones in the absence of other indications,” Adams said. “But weight gain in midlife is a real problem, and it’s encouraging to know that when women are on menopausal hormone therapy, they are more likely to see improved weight loss on tirzepatide than if they were not.” Adams said it will be important to investigate whether there are differences in outcomes among women taking tirzepatide based on the different forms of hormone therapy they are taking.

The research was funded by the National Institutes of Health and the Mayo Clinic. Castaneda reported having no disclosures. Adams reported receiving speaker honoraria from Continuing Education Company, Inc. 

Tara Haelle is a science/health journalist based in Dallas.