Postmenopausal women taking the obesity medication tirzepatide (Zepbound) experienced greater weight loss when also using menopause hormone therapy, according to a new retrospective cohort study. The combination was also associated with additional improvements in cardiometabolic health.
The study, led by Dr. Maria Daniela Hurtado Andrade of the Mayo Clinic in Jacksonville, Florida, examined 120 postmenopausal women with overweight or obesity who were treated with tirzepatide for at least 12 months. Women using hormone therapy lost an average of 19.2% of their body weight, compared to 14% in those not using hormone therapy—a difference that represents a 35% greater weight reduction (P=0.0023).
“Women in the hormone therapy group not only lost more weight but also showed notable improvements in key cardiometabolic parameters, supporting a potential enhancing effect of hormone therapy on tirzepatide’s therapeutic impact,” the researchers wrote in Lancet Obstetrics, Gynaecology, & Women’s Health.
Both groups demonstrated improvements in fasting glucose, HbA1c, HDL cholesterol, alanine aminotransferase, and systolic blood pressure. However, hormone therapy users also showed significant reductions in diastolic blood pressure, triglycerides, and aspartate aminotransferase. Total cholesterol and LDL cholesterol remained stable in hormone therapy users but slightly increased in nonusers.
The researchers suggested that these additional benefits may result not only from greater weight loss but also from estrogen’s known effects on glucose and lipid metabolism, liver function, vascular health, and reduction of visceral fat.
“These findings will next be tested in a randomized clinical trial to determine whether benefits extend beyond weight loss—specifically, whether hormone therapy enhances the cardiometabolic effects of tirzepatide,” Dr. Hurtado Andrade said. “If confirmed, this could accelerate the development of evidence-based strategies to improve health outcomes for millions of postmenopausal women.”
Menopause represents a critical period during which cardiovascular disease risk increases, particularly in women with obesity. The study emphasizes the need for personalized obesity management strategies that account for menopausal status.
Commentary accompanying the study by Drs. Roberto Vettor of the University of Padova and Mikiko Watanabe of the University of Rome noted that while women generally respond better to GLP-1 receptor agonists, older postmenopausal women often have blunted responses, highlighting the potential role of sex hormones like estrogen. They called for stratification of randomized trials by sex and menopausal stage to better understand these effects.
The study cohort had an average age of 56.4 years, with 94% identifying as white and 77% classified as having obesity. Many participants had comorbidities, including dyslipidemia (75%), hypertension (63%), and type 2 diabetes (53%). Among hormone therapy users, 68% received transdermal estradiol and 33% an oral formulation.
By month 15, hormone therapy users were more likely to achieve weight loss milestones of 20% (45% vs. 24%, P=0.022), 25% (28% vs. 8%, P=0.005), and 30% (18% vs. 4%, P=0.015). Overall, 40% of women reported side effects, with gastrointestinal issues being the most common (30% in hormone therapy users vs. 43% in nonusers).
