Impact of dramatic weight loss with the new injectable medications on reproduction in healthy non–polycystic ovary syndrome obese women

The intake of glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) in obese women with polycystic ovary syndrome (PCOS) demonstrated improvement in metabolic and reproductive symptoms; however, their impact in non-PCOS state is unclear. This review critically analyzes data pertaining to GLP-1 RAs in non-PCOS females in both humans and animals, with a focus on their impact on the hypothalamic-pituitary-ovarian axis and the uterine function. In animal models, studies showed controversial results. The intracerebroventricular GLP-1 administration caused stimulatory reproductive effects, where it increased the amplitude of the luteinizing hormone surge, follicle-stimulating hormone (FSH) secretion, serum progesterone levels, up-regulation in <i>Kiss-1r</i> expression in the hypothalamus, and increase in ovarian Graafian follicles and corpora lutea. However, the intracerebroventricular GLP-1 RA Exendin-4 and the subcutaneous GLP-1 RA liraglutide resulted in opposite effects. Even though GLP-1 up-regulated FSH receptor messenger ribonucleic acid expression in granulosa cells, it led to a suppression in FSH-induced progesterone synthesis. The effect of GLP-1 RA on the uterus also showed controversial findings. Although some data showed that GLP-1 RA had a beneficial antifibrotic effect in intrauterine adhesions model by reducing the deposition area of collagen fibers, other data showed that exposure to GLP-1 RA resulted in destruction of the luminal epithelium with shrinkage in muscle fiber. It is unclear how these GLP-1 RA medications impact future fertility in humans because most studies to date had significant limitations and were performed in animals with contentious findings. There is a clear need to study this relationship because many reproductive-aged women without PCOS are resorting to these medications for weight loss purposes.