Ensuring safety first: GLP-1RAs in reproductive and endometrial research

Abstract

Sir,

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have recently revolutionized the pharmacological management of type 2 diabetes and demonstrated significant potential in addressing other diseases, most notably obesity and metabolic disorders. Furthermore, these novel therapeutics show promise in treating conditions such as neurodegenerative diseases, fatty liver disease, dyslipidemia, atherosclerosis, and cardiovascular diseases.¹

Sola-Leyva and coauthors recently reviewed the role of GLP-1 and GLP-1R in modulating female reproductive function and proposed a future research agenda to elucidate the molecular mechanisms underlying the effects of GLP-1 and its agonists on the endometrium.² Their review emphasized the impact of GLP-1RAs on various cellular activities within endometrial tissue. On the one hand, available evidence suggests that GLP-1RAs induce autophagy and inhibit cell growth in endometrial cancer cell lines; on the other, they reduce histological degeneration and fibrosis in the endometrium of animal models, primarily by counteracting inflammation and oxidative stress. Based on this evidence, the authors proposed that GLP-1RAs might alleviate endometrial dysfunction and potentially enhance assisted reproductive technology (ART) outcomes in women with obesity or polycystic ovary syndrome. Their proposed research agenda included investigating the effects of GLP-1RAs on the multiomics landscape and metabolic profile of endometrial tissue, as well as their impact on in vitro embryo implantation models.²

Overall, the review of Sola-Leyva and coauthors² provides us several points with an interesting link to different aspects in the field of human reproduction. However, while the review abstract mentioned the potential teratogenic effects of GLP-1RAs, surprisingly this critical clinical issue was not adequately addressed throughout the main text. According to recent US Food and Drug Administration labels for semaglutide, the drug should be discontinued at least 2 months before any planned pregnancy due to its potential adverse developmental outcomes and long washout period.^{3, 4} The notes reported embryofetal mortality, structural abnormalities and alterations to growth in pregnant rats. In rabbits, early pregnancy losses and increased incidences of minor visceral (kidney, liver) and skeletal abnormalities were documented at clinically relevant exposures. Similarly, in a pre- and postnatal development study in cynomolgus monkeys, subcutaneous administration from gestation Day 16 to 140 resulted in increased early pregnancy losses and smaller offspring at doses ≥2× human exposure levels.^{3, 4} Likewise, the European Medicines Agency also informed in 2024 that women of childbearing potential should use contraception during semaglutide treatment. Thereof, if a patient plans to conceive or becomes pregnant, semaglutide should be discontinued.⁵

Overall, before initiating studies on the molecular effects of these drugs on the endometrium, the research priority should be to expand data on the drug-associated risks of adverse developmental outcomes. At present, GLP-1RAs should not be recommended in women during the periconceptional period or during an IVF cycle. However, given the exceptional efficacy of GLP-1RAs in improving metabolic profiles, we concur with Sola-Leyva and colleagues that these drugs may indirectly enhance future fertility outcomes by reducing obesity or improving ovarian function.² Furthermore, we are also confident about the extraordinary opportunities that GLP-1RAs will be able to offer to the male component of the infertile couples.

PV conceptualized, PV and MC drafted, and ES and AS revised the Letter.