Secretory-phase endometrial Ki67 predicts benefit of GnRHa pretreatment in unexplained recurrent implantation failure

Recurrent implantation failure (RIF) is a major barrier to successful assisted reproduction, often linked to impaired endometrial receptivity. Gonadotropin-releasing hormone agonist (GnRHa) pretreatment may improve outcomes in frozen embryo transfer (FET) cycles, but evidence in unexplained RIF remains inconclusive. Ki67, a marker of cellular proliferation, has been proposed as being associated with receptivity. This retrospective study included 182 women with unexplained RIF who underwent FET at Nanjing Drum Tower Hospital between January 2020 and December 2023. Patients were divided into a GnRHa-HRT group (n = 121) and an HRT group (n = 61). Endometrial tissue was collected during the mid-secretory phase, and Ki67 expression was assessed by immunohistochemistry. Patients were stratified into high and low Ki67 groups according to integrated optical density (IOD fold). The GnRHa-HRT group achieved higher clinical pregnancy rates than the HRT group (68.6% vs. 52.5%, P = 0.033) and showed a trend toward higher live birth rates (57.9% vs. 42.6%, P = 0.052). Importantly, in patients with high Ki67 expression (IOD fold >1.5), GnRHa pretreatment significantly increased the clinical pregnancy rate (P = 0.004), whereas no significant differences were observed in patients with low Ki67 expression. These findings suggest that secretory phase Ki67 expression may serve as a predictive biomarker for tailoring GnRHa pretreatment in unexplained RIF, supporting more individualised strategies to optimise clinical outcomes.