Ghrelin Imbalance Disrupts Uterine Immunity, Impairing Mouse Embryo Implantation

Ghrelin, a hormone primarily known for regulating appetite and metabolism, also plays a crucial role in reproductive processes. While its involvement in fertility is recognized, the precise mechanisms by which ghrelin misbalance affects embryo implantation and pregnancy success through uterine immune regulation and oxidative stress remain poorly understood. This study specifically investigates how both ghrelin deficiency and overexpression impact uterine immune cell populations, cytokine profiles, and nitrosative stress during early pregnancy.

Both ghrelin deficiency and overexpression significantly impaired reproductive outcomes. Ghrelin-deficient mice exhibited a reduced number of implantation sites and lower pregnancy rates compared to WT controls. Uterine analysis revealed a clear immune dysregulation in these mice, with an increase in pro-inflammatory M1-like macrophages and a decrease in anti-inflammatory M2-like macrophages. The most critical finding was that ghrelin deficiency led to a significant decrease in the anti-inflammatory cytokine IL-10 and marked increases in pro-inflammatory TNF-α and IFN-γ within the uterus, alongside elevated nitrosative stress markers (iNOS and nitrotyrosine) and apoptosis. Ghrelin-overexpressing mice also showed similar reductions in implantation and pregnancy success, accompanied by comparable alterations in uterine immune cells and increased nitrosative stress, indicating that a precise balance of ghrelin is essential for reproductive health.