Tirzepatide Plus Hormone Therapy Boosts Weight Loss in Menopause: Regina Castaneda, MD

Midlife weight gain is a persistent challenge for many women, but emerging research suggests hormone therapy may enhance response to glucagon-like peptide-1 (GLP-1)–based treatments.

In a recent analysis, women taking tirzepatide alongside menopause hormone therapy achieved greater total body weight loss than those who did not use hormone therapy. In an interview with The American Journal of Managed Care^® (AJMC^®), Regina Castaneda, MD, postdoctoral research fellow at Mayo Clinic, discussed how reproductive stage influences weight loss outcomes and why the combination may have synergistic effects according to rodent studies. Speaking at The Menopause Society 2025 Annual Meeting, she emphasized the need for more studies to confirm these findings and better understand the mechanisms behind this.

This transcript has been lightly edited; captions were auto-generated.

Transcript

Can you explain why combining tirzepatide with hormone therapy led to greater weight loss in postmenopausal women?

We conducted a retrospective observational study evaluating the impact of reproductive state and weight loss outcomes with tirzepatide, and tirzepatide is currently the most effective weight loss medication. We know it's a dual GLP-1/GIP receptor agonist, and we know that estrogen has a lot of effects beyond reproduction. The menopause transition is associated with changes in body composition, energy expenditure, so we wanted to know what is the role of reproductive stage.

This question is very important. Millions of women struggle with weight gain during midlife, and the reality is that we don't know what the answer is. We don't know why we're observing these superior weight loss outcomes in women using tirzepatide in addition to hormone therapy.

We have several hypotheses. First of all, we are potentially seeing the effect of the healthy user effect, whereby hormone therapy users are perhaps more likely to engage in healthier lifestyles. Also, the mitigation of vasomotor symptoms is potentially contributing to adherence to lifestyle interventions. Now, it's perhaps more feasible to do the 150 minutes of exercise per week, or it's easier to engage with their diet.

But last but not least, we have some preclinical data from rodents showing a potential synergistic interaction between estrogen and GLP-1 signaling, where estrogen amplifies the appetite-suppressing effects of GLP-1. The reality is that we need more studies to identify what are the underlying mechanisms behind this, and I'm actually very excited that our data is paving the way for more controlled studies in the future.

How does reproductive stage appear to influence response to tirzepatide?

In our study, the premenopausal and perimenopausal women achieved nearly 20% total body weight loss after 18 months of treatment, and this is consistent with trials from the SURMOUNT program. However, postmenopausal women who had never been exposed to hormone therapy lost nearly 15% total body weight. When we compared this to postmenopausal women who were using hormone therapy, that group achieved nearly 20% total body weight loss, so outcomes closely resembled those in the pre- and perimenopausal groups.

This association really demands more studies. This could be perhaps a direct effect of hormone therapy, or potentially we're seeing the effect of the healthy user effect that we previously mentioned, or the mitigation of vasomotor symptoms is contributing.