GLP-1 RAs linked to broad menstrual adverse event signals in reproductive-aged patients

Semaglutide demonstrated the broadest and strongest signal profile for menstrual adverse events among GLP-1 receptor agonists (GLP-1 RAs) analyzed in a pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) data, recently published in Obstetrics & Gynecology. Tirzepatide also generated signals, though more limited, while liraglutide produced none.

GLP-1 RAs are increasingly prescribed to reproductive-aged female patients for type 2 diabetes and obesity, yet menstrual dysregulation was not systematically captured or reported as an adverse effect in the pivotal clinical trials for these agents, “leaving a critical gap in our understanding of their gynecologic safety profile,” stated researchers Connor Frey, MD, and Mahyar Etminan, PharmD, MSc, from the University of British Columbia.

Frey and Etminan performed a disproportionality analysis of FAERS data from database inception through March 2026, restricted to female patients aged 12 to 55 years, analyzing a total of 14,104,743 reports. Drug-associated reports after age restriction numbered 4024 for liraglutide, 27,469 for tirzepatide, and 6060 for semaglutide.

What menstrual signals did semaglutide generate?

Semaglutide generated signals across the widest range of menstrual adverse events. Heavy menstrual bleeding showed disproportionate reporting for semaglutide (reporting odds ratio [ROR] 3.51; 95% CI, 2.42–5.10; IC₀₂₅ 1.25) but not for tirzepatide or liraglutide. Menstrual clots produced the highest signal observed in the analysis for semaglutide (ROR 31.63; 95% CI, 12.62–79.28; IC₀₂₅ 3.54), while abnormal menstrual clots also generated a semaglutide signal (ROR 10.75; 95% CI, 1.47–78.82; IC₀₂₅ 0.23).

Additional semaglutide signals included:

• Intermenstrual bleeding (ROR 2.91; 95% CI, 1.51–5.61; IC₀₂₅ 0.53)
• Oligomenorrhea (ROR 3.09; 95% CI, 1.54–6.20; IC₀₂₅ 0.56)
• Anovulatory cycle (ROR 8.96; 95% CI, 2.20–36.51; IC₀₂₅ 0.87)
• Menstrual disorder (ROR 2.54; 95% CI, 1.65–3.90; IC₀₂₅ 0.69)

What signals emerged for tirzepatide and liraglutide?

Tirzepatide generated signals for intermenstrual bleeding (ROR 1.64; 95% CI, 1.09–2.48; IC₀₂₅ 0.09) and menstrual clots (ROR 5.41; 95% CI, 1.96–14.96; IC₀₂₅ 0.82). Liraglutide produced no significant menstrual signals in this age-restricted cohort. Both frequentist and Bayesian analyses were applied to each drug-event combination, with Bayesian analyses corroborating all frequentist findings. Differently, amenorrhea, irregular menstruation, dysmenorrhea, and polymenorrhea showed no positive associations for any of the 3 agents.

What do these signals suggest about GLP-1 RA pharmacology?

The authors noted that the pattern of menstrual dysregulation identified, characterized by bleeding irregularities, clotting, and ovulatory disruption without signals for amenorrhea, dysmenorrhea, or irregular menstruation, suggests effects that are not simply attributable to the metabolic consequences of obesity or weight loss.

“The mechanistic basis for these findings is likely multifactorial and include direct GLP-1 RA in endometrial tissue, weight-loss-driven alterations in estrogen metabolism, and downstream effects on coagulation pathways,” the authors wrote.

Study limitations

Confounding by indication cannot be excluded, as obesity independently affects menstrual regularity. The researchers also disclosed that FAERS data are subject to underreporting, variable report quality, and notoriety bias, and some events had low counts that produced unstable estimates.

“Nonetheless, these findings have clinical relevance. The peer-reviewed literature on GLP-1 RA-associated menstrual effects remains sparse relative to the volume of patient-reported experiences, and the signals identified here suggest that menstrual dysregulation may be underrecognized in clinical practice,” said Frey and Etminan, who added the results support the necessity for prospective epidemiologic studies to determine “true incidence and risk.”

Reference:

Etminan, M., & Frey, C. Association of Glucagon-Like Peptide-1 Receptor Agonists With Menstrual Events in Reproductive-Aged Patients. Obstetrics & Gynecology. https://doi.org/10.1097/AOG.0000000000006367