Menopausal hormone therapy may boost weight loss seen with Zepbound

Key takeaways:

• Postmenopausal women prescribed tirzepatide had 35% greater weight loss when taking concurrent hormone therapy.
• Estrogen may have a synergistic effect with GLP-1 therapies.

SAN FRANCISCO — Concurrent use of menopausal hormone therapy may augment the weight loss benefits of tirzepatide for postmenopausal women with overweight or obesity, researchers reported at ENDO 2025.

“We found an association between hormone therapy use and greater weight loss in postmenopausal women,” Regina Castaneda Hernandez, MD, a research fellow in the division of women’s health at Mayo Clinic, told Healio. “This was a retrospective study, so further research is needed to confirm these findings. We cannot overlook preclinical data showing that there is a potential synergistic effect between estrogen and GLP-1 signaling; however, we need to further explore the underlying mechanisms. Postmenopausal women represent a unique group due to their distinct hormonal and metabolic profiles, which contribute to the increased cardiovascular risk observed in this population; yet, they remain underrepresented in pivotal obesity pharmacotherapy trials.”

Tirzepatide (Zepbound, Eli Lilly), a dual GLP-1/GIP receptor agonist, has demonstrated robust efficacy in mixed-sex trial populations; however, its effects for postmenopausal women — and how any effects might be modified by hormone therapy — have not been widely explored, Castaneda Hernandez said.

For the retrospective, real-world study, researchers analyzed electronic health records data from 120 postmenopausal women prescribed tirzepatide for overweight or obesity for at least 1 year; one-third were taking menopausal HT and the rest were not. Menopausal HT formulations included transdermal or oral estrogen, with or without progesterone. Researchers used propensity score matching based on BMI, age at menopause, menopause type and diabetes status, matching each participant prescribed menopausal HT with two participants not taking menopausal HT. The primary endpoints were total body weight loss percentage at 3, 6, 9, 12 and 15 months and again at last follow-up. Median follow-up was 18 months.

At last follow-up, the menopausal HT group experienced greater total body weight loss compared to controls (19.18% vs. 13.96%; P = .002). By the last follow-up, a higher proportion of women in the HT group achieved at least 20% total body weight loss (45% vs. 23.8%; P = .02), at least 25% total body weight loss (27.5% vs. 7.5%; P = .005) and at least 30% total body weight loss (17.5% vs. 3.8%; P = .015) compared with those not taking HT.

“When menopause hormone therapy is appropriate, combining it with obesity pharmacotherapy may offer synergistic benefits by addressing both the hormonal changes of menopause and the biological drivers of excess adiposity,” Maria Daniela Hurtado Andrade, MD, PhD, an assistant professor of medicine in the division of endocrinology, diabetes and metabolism at Mayo Clinic, told Healio in an email.

The researchers said the data should not imply that all postmenopausal women with overweight or obesity receive both treatments. Additionally, healthy user bias and the alleviation of menopause-related symptoms with HT could have contributed to the greater weight loss among women taking HT.

“Menopausal HT should be prescribed based on individualized clinical indications, typically for the management of vasomotor symptoms and after a careful assessment of risk factors such as age, time since menopause, and personal or family history of breast cancer or thromboembolism,” Andrade told Healio in an email.

Andrade said the findings contribute to a growing body of evidence supporting tailored treatment approaches that address both hormonal and metabolic drivers of disease.

“As we move toward more personalized obesity care, it is essential to recognize how biological sex and menopausal status shape treatment response,” Andrade told Healio in an email. “This approach will not only improve individual outcomes but also advance equity in obesity research and care delivery.”

For more information:

Regina Castaneda Hernandez, MD, can be reached at castaneda.regina@mayo.edu.

Maria Daniela Hurtado Andrade, MD, PhD, can be reached at hurtado.mariadaniela@mayo.edu.