Hyperghrelinemia from COH delays embryo development in mice, reversible by ghrelin receptor antagonists

Infertility treatments often rely on Controlled Ovarian Hyperstimulation (COH), a critical component of assisted reproductive technologies. However, COH is paradoxically associated with reduced reproductive success in some cases. While previous research identified that COH increases circulating ghrelin levels, the precise role of this hyperghrelinemia in COH-induced alterations to reproductive outcomes and the therapeutic potential of ghrelin inhibition have remained largely unexplored. Understanding this mechanism could lead to improved fertility protocols.

Researchers utilized a murine model to investigate the impact of COH on preimplantation embryo development and implantation. Female mice were divided into groups: natural estrous cycles (controls), hyperstimulation, or hyperstimulation with concurrent treatment using ghrelin receptor antagonists, either (D-Lys3)-GHRP-6 or PF-5190457. The study evaluated hormonal profiles, gamete and embryo quality, implantation rates, and decidual characteristics. Key assays included hormone level measurements, oocyte and embryo staging, and uterine histology and IL-6 expression analysis.

COH significantly increased ovulation rate, plasma progesterone, and ghrelin levels compared to controls, without initially altering oocyte quality or early estradiol concentrations. A notable finding was that COH induced a significant delay in embryo development by gestational day (GD) 3.5. This developmental delay was completely reversed by the administration of either (D-Lys3)-GHRP-6 or PF-5190457, indicating a direct role for ghrelin signaling. Although COH showed a non-significant trend toward lower implantation, this was not linked to hyperghrelinemia. COH did not affect decidual histology or the balance of embryotropic/embryotoxic factors, nor did it alter uterine leukocyte infiltration. However, it specifically reduced uterine IL-6 expression, a crucial cytokine for uterine receptivity. > This reduction in uterine IL-6 expression was fully restored by ghrelin receptor blockade, strongly suggesting that ghrelin-mediated suppression of IL-6 is a key mechanism underlying the delayed embryo development observed after COH.