Ghrelin impairs embryo development after ovarian hyperstimulation

Controlled ovarian hyperstimulation (COH) is essential in assisted reproductive technologies, although some studies have associated it with reduced reproductive success. We have recently demonstrated that COH increases circulating ghrelin; however, its role in COH-induced alterations and the potential therapeutic impact of its inhibition remain unclear. Using a murine model, this study evaluated the effects of COH on preimplantation embryo development and implantation and examined whether the COH-induced alterations in these parameters are associated with hyperghrelinemia. Here, we evaluated hormonal profiles, gamete and embryo quality, implantation, and decidual characteristics in female mice, either in natural estrous cycles (controls) or following hyperstimulation, with or without treatment with ghrelin receptor antagonists ((D-Lys3)-GHRP-6 or PF-5190457). We found that COH increased ovulation rate and plasma progesterone and ghrelin levels compared with controls, without altering oocyte quality or early estradiol concentrations, although estradiol rose later (gestational day (GD) 7.5). COH also induced a delay in embryo development (on GD 3.5), which was reversed by the administration of (D-Lys3)-GHRP-6 or PF-5190457. COH showed a non-significant trend toward lower implantation, unrelated to hyperghrelinemia. COH did not affect decidual histology, embryotropic or embryotoxic factors, or uterine leukocyte infiltration; however, it reduced uterine IL-6 expression, which was restored by ghrelin receptor blockade, suggesting a mechanism for the delayed embryo development. Thus, COH-induced hyperghrelinemia negatively affects embryo development, potentially altering the uterine immune microenvironment.