The hidden impact of GLP-1 receptor agonists on endometrial receptivity and implantation

Abstract

Increasing infertility rates represent a growing medical challenge in modern societies resulting from a complex interplay of sociocultural trends, lifestyle factors, exposure to environmental toxins, and underlying health problems. Women's fertility is particularly vulnerable to these shifts. The obesogenic lifestyle not only accelerates weight gain, but also disrupts ovulation driving the rise in infertility. Among several medications used for treating obesity and type 2 diabetes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) show promising improvement in female fertility most likely by stimulating ovulation. However, the effects of GLP-1RAs on the endometrium remain unclear. Further studies are needed to investigate the impact of GLP-1RAs on endometrial receptivity and embryo implantation and early development. The aim of this study is to address the knowledge gap regarding the effects of GLP-1RAs on human reproduction, with special focus on the endometrium. Understanding these mechanisms may help to develop new strategies for improving fertility treatment, reduce implantation failure and address potential safety concerns regarding teratogenicity and adverse developmental outcomes for children born to women conceiving during or soon after GLP-1RA treatment.

Keywords: endocrinology; glucagon‐like peptide‐1 receptor agonists; infertility; obesity; polycystic ovary syndrome.

FIGURE 1

Glucagon‐like peptide‐1 (GLP‐1) and its functional mechanisms associated with weight loss. The proglucagon gene consists of 6 exons, one on which is the encoding region of GLP‐1. GLP‐1 exists in 3 active forms, GLP‐1 (7–36) amide, GLP‐1 (7–37), and GLP‐1 (7–37 glycine extended). The GLP‐1 binds the G protein–coupled receptor GLP‐1R and mainly promotes (i) low blood glucose levels by promoting insulin secretion by the mTOR‐dependent HIF‐1α activation pathway; (ii) decrease in food intake and long‐term weight loss; and (iii) anti‐inflammatory effects, targeting GLP‐1R expressed on distinct populations of circulating immune cells and reducing systemic inflammation by decreasing NF‐κB signaling. Finally, GLP‐1/GLP‐1R agonist (GLP‐1RA) have an important role in weight loss. This figure was made using BioRender.

FIGURE 2

Approach to study the impact of glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) on endometrial receptivity and embryo implantation. The endometrial molecular changes induced by weight loss present a substantial gap in our current knowledge. Consequently, there is a compelling need for research focused on these groups of patients to elucidate how weight loss, facilitated by metabolic regulation via GLP‐1RA, influences reproductive success. Novel strategies must be implemented to look deeper into the impact of GLP‐1RA on endometrial receptivity and embryo implantation. To delineate the molecular changes occurring in endometrial tissue influenced by GLP‐1RA single‐cell RNA‐seq (sc‐RNA‐seq), spatial transcriptomic and metabolic profiling of cells (using SCENITH protocol, single‐cell energetic metabolism by profiling translation inhibition) will provide the capacity for molecular profiling at the single‐cell resolution. Advanced in vitro models, such as endometrial epithelial organoids (EEOs), assembloids (EEOs incubated with stromal cells), and blastocyst‐like structures derived from naïve human pluripotent stem cells (hPSCs), can attach to hormonally stimulated endometrial cells. This attachment replicates the initial stages of implantation and will enhance our understanding of the complex processes that lead to endometrial receptivity and mediate the molecular dialog between the embryo and the maternal endometrial cells during implantation. This figure was made using BioRender.