GnRH agonist improves CLBR after one IVF cycle: a propensity score-matched and molecular mechanism study

Abstract: The effectiveness of GnRH antagonist protocol remains controversial due to inconsistent conclusions and inadequate subgroup analyses. The aim of this study was to provide some references for clinicians when choosing GnRH antagonist protocol for patients. A retrospective cohort study analyzed 1845 infertility patients aged 20-50 years who underwent IVF/ICSI treatment. They used the GnRH agonist or GnRH antagonist protocol at the Assisted Reproduction Center of Wuhan Union Hospital from June 2023 to June 2024. One-to-one PSM was used to match the population characteristics. The difference of cumulative live birthrates (CLBR) was analyzed by multivariate logistic regression. Endometrial tissues were obtained and the endometrial receptivity was determined by detecting the expression of mesenchymal-epithelial transition (MET), decidualization markers and cell implantation in vitro. There was a significantly higher CLBR in GnRH agonist compared with GnRH antagonist protocol (81.54 versus 73.07%, P<0.05). The GnRH agonist also had significantly higher clinical pregnancy rate (CPR) and live birth rate (LBR) per fresh ET cycle compared to the GnRH antagonist. Multivariate logistic regression analysis showed that ovarian stimulation protocol was an independent risk factor for CLBR. Age and endometrial thickness were significantly correlated with CLBR. Furthermore, GnRH antagonist reduces endometrial receptivity mainly by hindering the formation of MET in stromal cells and affecting endometrial decidualization. The GnRH antagonist protocol may be associated with inferior LBR per fresh ET cycle and CLBR per cycle compared with GnRH agonist protocol, likely due to its negative impact on endometrial receptivity.

Lay summary: Doctors aren't sure how well one of the methods used for IVF treatment-the GnRH antagonist method-works. It uses drugs to temporarily block brain signals to the ovaries, controlling egg maturation and preventing early egg release (critical for IVF success). It isn't known how effective this method at achieving pregnancy or live birth. We analysed previous data and lab tests to guide doctors using this method. Results showed another common method-the GnRH agonist method (using drugs that first boost, then lower brain signals to ovaries to control eggs)-had much higher pregnancy rates and live birth rates per fresh embryo transfer cycle than the GnRH antagonist one. Data showed three key factors affected the cumulative live birth rate: the ovarian stimulation plan used, the patient's age, and the thickness of their womb lining (where embryos attach). Overall, the GnRH antagonist method may lead to lower live birth rates (per transfer and per cycle) than the agonist one-most likely because it makes the womb lining less able to support embryos.

Cumulative live birth rate (CLBR); Endometrial receptivity; GnRH agonist; GnRH antagonist; Mesenchymal-epithelial transition.