Unexpected Drug Combo May Supercharge Weight Loss in Older Women

Scientists have uncovered a potential drug combo that may supercharge popular weight-loss treatments for older women.

In a small retrospective study of women taking varying doses of tirzepatide for weight loss, after 15 months of treatment, participants who were also using menopausal hormone therapy experienced 35 percent more total bodyweight loss than those not using hormone therapy.

For the research, scientists at the Mayo Clinic and Wayne State University in the US gathered health data from 120 women, the majority of whom were White, and in their 50s.

Eighty of the participants only used tirzepatide for weight loss, and 40 used tirzepatide as well as any type of menopausal hormone therapy, with data tracking their health for an average of 18 months.

On average, women on both tirzepatide (a GLP-1-based drug sold under the brand names Zepbound or Mounjaro) and hormone therapy lost 19.2 percent of their starting body weight, while those taking only tirzepatide lost an average of 14 percent. That 5.2 percentage‑point difference is statistically significant.

A higher proportion of those taking hormone therapy achieved 30 percent or more total bodyweight loss.

Proportion of women in each group reaching each given percentage of total bodyweight loss at the last follow-up. (Castaneda et al., Lancet Obstet. Gynaecol. Women's Health, 2026)

The authors of the study now hope to conduct controlled, randomized studies on the combo to see if this apparent drug synergy stands up under scrutiny and really is causing greater weight loss.

These preliminary findings on tirzepatide join a 2024 study, authored by some of the same Mayo Clinic researchers, which found that after 12 months, a greater proportion of postmenopausal women using semaglutide and hormone therapy achieved 10 percent or more total body weight loss than those taking just the GLP-1 drug.

"The magnitude of this difference warrants future studies that could help clarify how GLP-1-based obesity medications and menopausal hormone therapy may interact," says lead author and women's health researcher Regina Castaneda at the Mayo Clinic Center.

(NIH)

Menopause occurs when menstruation ceases, and it is a monumental transition that brings widespread changes and sweeping hormonal shifts to the body and brain. The transition and the after effects can lead to a whole host of unpleasant physical symptoms, including fatigue, hot flashes, night sweats, poor sleep, and low libido.

Menopause hormone therapy can be used to manage these challenges, and it may offer some protection from menopause-associated illnesses, such as osteoporosis and possibly heart disease. The medicine usually comes in pill, patch, or topical form, and it aims to replace some of the body's lost hormones, such as estrogen or progesterone.

While some studies suggest that menopause replacement therapy may help prevent weight gain in later life, it's unclear if or how they may promote weight loss.

Menopause as a whole is historically underfunded and under-researched. Plus, GLP-1 drugs are a relatively new drug class that scientists are still trying to understand.

What we do know is that weight gain is common for pre- and post-menopausal women, and it is also common for those with reproductive issues impacting their ovaries and uterus.

Patients with polycystic ovary syndrome, for instance, are more likely to experience insulin issues, which can increase the risk of type 2 diabetes and lead to weight gain.

The current research did not distinguish between the type or dose of hormone therapy, analyzing them as a single group.

In October 2025, Castaneda spoke at the Menopause Society Annual Meeting about her team's recent results and how much more we have to learn.

"Millions of women struggle with weight gain during midlife, and the reality is that we don't know what the answer is," she said.

"We don't know why we're observing these superior weight loss outcomes in women using tirzepatide in addition to hormone therapy."

Castaneda points to initial studies in rodents, which have found that estrogen treatments can enhance the body's natural GLP-1 signaling system. But results are inconsistent, and there are other possible explanations, as endocrinologist and senior author Maria Daniela Hurtado Andrade explains.

"It is possible that women using hormone therapy were already engaged in healthier behaviors," Hurtado Andrade says, "or that menopause symptom relief improved sleep and quality of life, making it easier to stay engaged with dietary and physical activity changes."

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The only way to know for sure is to conduct rigorous clinical experiments on the drug combo.

In the future, Hurtado Andrade says she and her team are going to carry out a randomized controlled trial to see if the benefits of menopause hormone therapy "extend beyond weight loss – specifically, whether hormone therapy also enhances the effects of these medications on cardiometabolic measures."

"If confirmed," she argues, "this work could speed the development and adoption of new, evidence-based strategies to reduce this risk for millions of postmenopausal women navigating this life stage."

The study was published in The Lancet Obstetrics, Gynaecology, & Women's Health.