Hormone therapy may enhance therapeutic benefits of tirzepatide in postmenopausal women

medwireNews: Use of concurrent systemic hormone therapy during tirzepatide treatment is associated with greater weight loss and improved cardiometabolic outcomes than tirzepatide use alone in postmenopausal women with overweight or obesity, US researchers report.

Maria Hurtado Andrade (Mayo Clinic, Jacksonville, Florida) and co-investigators say their findings suggest that “hormone therapy enhances the therapeutic effect of tirzepatide, supporting its potential role as an adjunct to obesity pharmacotherapy in women with excess adiposity who also have a clinical indication for hormone therapy, such as vasomotor symptoms.”

The researchers explain that although “tirzepatide is the most effective obesity medication to date,” there are limited data on the potential modifying effect of hormone therapy in postmenopausal women.

To address this, they reviewed Mayo Clinic Health System data for 120 postmenopausal women (mean age 56 years, 94% White) with overweight (BMI ≥27 kg/m²) and an adiposity-related comorbidity or with obesity (BMI ≥30 kg/m²) irrespective of adiposity-related comorbidity.

All participants had been treated with tirzepatide for at least 12 months; 33.3% were using hormone therapy and 66.6% were not, with the two groups matched by age, BMI, age at and type of menopause, previous obesity medication use, and diabetes status. Transdermal estradiol (0.025–0.1 mg/day) was the most common estrogen delivery method used, followed by oral estrogen (0.5–2.0 mg/day), most often as estradiol. All women in the hormone therapy group who had a uterus also received oral progesterone 100 mg/day.

At baseline, the mean BMI for the entire cohort was 33.6 kg/m² while the mean weight was 90.9 kg.

Hormone therapy users experience greater bodyweight reductions

After a mean 18 months of follow-up, women using hormone therapy had a significantly greater percentage mean reduction in bodyweight than nonusers, at 19.2% versus 14.0%. The greater reduction with hormone therapy was apparent from 3 months but did not reach statistical significance until 15 months, the researchers note.

They also report in The Lancet Obstetrics, Gynaecology, & Women’s Health that a higher proportion of women in the hormone therapy group reached a total percentage bodyweight reduction of at least 20% (45 vs 24%), at least 25% (28 vs 8%), and at least 30% (18 vs 4%).

“The enhanced weight loss response to tirzepatide in people using hormone therapy aligns with our previous findings in postmenopausal women using semaglutide for obesity treatment, whereby those using hormone therapy showed a 32% greater weight loss after 12 months,” Hurtado Andrade et al remark.

Cardiometabolic parameters impacted by hormone therapy use

In addition, the team found that, during the study, women using and not using hormone therapy  had significant improvements in fasting glucose, glycated hemoglobin, systolic blood pressure (BP), and alanine aminotransferase concentration, whereas only women using hormone therapy had significant reductions in diastolic BP, and concentrations of triglycerides and aspartate aminotransferase.

Total cholesterol and low-density lipoprotein cholesterol concentrations remained stable over time among women using hormone therapy but increased, nonsignificantly, in nonusers. High-density lipoprotein cholesterol also remained stable in the hormone therapy users whereas it increased significantly in nonusers.

‘Important clinical implications’

Hurtado Andrade and colleagues conclude: “These findings have important clinical implications, as the menopause transition is associated with increased cardiovascular risk, particularly in women with obesity.”

They add: “The combined use of hormone therapy and tirzepatide might offer substantial benefits in this high-risk population, especially when hormone therapy is indicated for the management of menopausal symptoms.”

However, the authors acknowledge that the study has some limitations including the retrospective design, which limits causal inference, and the fact that there were more women who had undergone hysterectomy than would be expected in the general population, which may limit generalizability.

They therefore say that “[p]rospective, randomised controlled trials with clinical (eg, weight loss) and mechanistic endpoints (eg, measurement of energy balance components) are needed to substantiate these observations, establish causality, and inform clinical decision making.”

In an accompanying comment, Roberto Vettor (University of Padova, Italy) and Mikiko Watanabe (Sapienza University of Rome, Italy) say that the study “highlights an important synergistic effect between hormone therapy and tirzepatide.”

They also believe the work indicates that “innovative obesity drugs,” such as a glucagon-like peptide (GLP)-1–estrogen conjugate or a GLP-1–glucose-dependent insulinotropic polypeptide–estrogen conjugate that delivers estrogen directly via GLP-1 receptors “could be proposed at least in selected life stages such as menopause.”

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Lancet Obstet Gynaecol Womens Health 2026; doi:10.1016/S3050-5038(25)00145-1
Lancet Obstet Gynaecol Womens Health 2026; doi:10.1016/S3050-5038(25)00210-9