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HT Amplifies Weight Loss With Tirzepatide in Menopause
In postmenopausal women treated with the obesity drug tirzepatide, those who also received menopausal hormone therapy (HT) lost significantly more weight than those who did not, consistent with previous findings with semaglutide, and suggesting a key role of HT in improving obesity drug response in this population.
'While previous studies, including our own, have demonstrated enhanced weight loss with hormone therapy in women using semaglutide, no prior data existed on tirzepatide,' senior author Maria Daniela Hurtado, MD, of the Division of Endocrinology, Diabetes, and Metabolism, at the Mayo Clinic, Jacksonville, Florida, told Medscape Medical News.
'This study addresses that gap and suggests that hormone therapy use is associated with a 35% greater total body weight loss compared to nonusers, suggesting a potential synergistic effect,' she said.
The study was presented at ENDO 2025, The Annual Meeting of the Endocrine Society.
In a previous study published in the journal Menopause , Hurtado and colleagues reported that menopausal women on HT who were treated with semaglutide had significantly greater improvements in weight loss and waist circumference than those not receiving HT.
In the current retrospective cohort study, the researchers sought to determine if the effects of the dual agonist glucose-dependent insulinotropic peptide (GIP)/ GLP-1 receptor agonist tirzepatide were likewise improved with HT in postmenopausal women.
Hurtado, along with first author Regina Castaneda, MD, and colleagues, evaluated data on 400 postmenopausal women who had been prescribed tirzepatide for the treatment of overweight or obesity for at least 12 months, either with or without concurrent HT.
Types of menopause HT used by the study participants were either transdermal or oral estrogen, with or without progesterone.
For the propensity score analysis, 120 of the patients were matched 1:2 based on those who were (n = 40) and were not receiving HT (n = 80). The groups were matched according to baseline characteristics and adiposity-related comorbidities, with a mean age of 56 years and 57 years, and mean BMI of 34 and 33, respectively.
Patients in both groups had median follow-up of 18 months, and as of the last follow-up, those in the HT group had a significantly greater total body weight loss compared with those not in the HT group (17% vs 14%; P = .01).
In addition, at the last follow-up, those receiving HT were much more likely to have achieved a 20% or higher total body weight loss than those not receiving HT (45% vs 18%; P = .001).
Does HT Address Lower Obesity Drug-Associated Weight Loss in Menopause?
Consistent with the semaglutide research, the weight loss observed among women on HT was not significantly higher than the typical weight loss observed in nonmenopausal women on tirzepatide — the difference was that women who were not on HT appeared at a disadvantage, Hurtado explained.
'Similar to our findings with semaglutide, women using menopause hormone therapy achieved weight loss comparable to that observed in pivotal tirzepatide trials, which predominantly included younger participants,' she said.
'In contrast, those not using hormone therapy experienced more modest weight loss, falling below expectations based on phase 3 trial data.'
While the findings support the theory that the menopause transition may impair response to weight-loss medications, 'this hypothesis remains unproven, and it is possible that the observed differences are attributable to aging alone, as advancing age is associated with reduced responsiveness to anti-obesity medications,' Hurtado said.
Estrogen/Tirzepatide Synergy?
The current findings, however, do add evidence supporting a menopausal hormone connection.
'Notably, the greater weight loss observed with concurrent hormone therapy use raises the possibility of a synergistic interaction between estrogen and tirzepatide,' Hurtado said.
Estrogen is already recognized to positively influence visceral fat distribution, thermogenesis, insulin sensitivity, and energy expenditure, she explained.
'It also enhances GLP-1 signaling pathways, which may potentiate tirzepatide's appetite-suppressing effects,' she said.
Likewise, 'absence of estrogen may reduce these synergistic effects, thereby attenuating the weight-loss response to GLP-1/GIP agonists.'
The study did not evaluate whether the common adverse events of tirzepatide are any different in patients receiving HT, however, the researchers are considering including that analysis in the study's final publication.
While the evidence suggests dual therapeutic benefits with obesity drugs and HT, 'the risks of hormone therapy must be individually assessed, and treatment decisions should follow a shared decision-making approach,' Hurtado noted.
Commenting on the study, Olena Klindukhova, MD, of the Medical College of Wisconsin, Milwaukee, emphasized that 'with menopause associated with significant weight gain, which can increase distress among women, it is reassuring that the addition of GLP-1 to HRT [hormone replacement therapy] helps to improve outcomes.'
Klindukhova, who comoderated the session, noted that a common concern with GLP-1s is the regaining of weight that has been shown to occur among nearly all patients upon drug discontinuation.
'We don't have data suggesting this is any different among menopausal women,' Klindukhova said.
The findings nevertheless suggest that 'hormone therapy and GLP-1s should be initiated sooner rather than later for symptomatic women in early menopause,'
