Effect of Flexible GnRH antagonist and long GnRH agonist protocols on follicular fluid levels of PlGF, AMH, oocyte’s morphology, and other IVF/ICSI outcomes in polycystic ovary syndrome women
Authors: kadoura sally , Alhalabi Marwan , Nattouf Abdul Hakim 
Published: March 2022

Abstract
Background: Gonadotropin-releasing hormone (GnRH) analogues are commonly used in clinical practice to prevent premature luteinizing hormone (LH) surge during In-Vitro Fertilization/ Intra-Cytoplasmic Sperm Injection (IVF/ICSI) cycles. However, the impacts of the GnRH analogues on the follicular microenvironment in women with polycystic ovary syndrome (PCOS) are still not elucidated.Settings: This study was performed at Orient Hospital, Damascus, Syrian Arab Republic, from December 2019 to August 2021.Methods: In this interventional, prospective, parallel, non-randomized, open-label controlled clinical trial, a total of 75 PCOS women (Rotterdam criteria) were allocated to take either the long GnRH agonist protocol (n=53) or the flexible GnRH antagonist protocol (n=22). The trial was originally designed to be a randomized control trial. However, due to a lack in the drug supply during a certain point of the study duration, we used a non‐random study design. Follicular fluid (FF) samples were collected on the retrieval day, and the FF levels of Placental growth factor (PlGF) and Anti-Müllerian hormone (AMH) were measured using ELISA Kits. Before being subjected to ICSI, the mature oocytes from both groups were morphologically assessed under an inverted microscope at 400x magnification. In addition, the embryological and clinical IVF/ICSI outcomes were detected.Results: The two groups did not differ significantly at baseline characteristics. The FF PlGF levels were significantly lower, while FFAMH levels were insignificantly higher in the GnRH antagonist group (FF PlGF; GnRH agonist = 142.75 ± 51.48 pg/ml vs. GnRH antagonist = 117.70 ± 35.86 pg/ml; P value = 0.028). (FF AMH; GnRH agonist = 13.62 ± 15.25 ng/ml vs. GnRH antagonist = 16.93 ± 18.08 ng/ml; P value = 0.492). The stimulation duration was significantly lower in the GnRH antagonist group compared to the long-agonist one (GnRH agonist = 8.04 ± 0.81 days vs. GnRH antagonist = 7.64 ± 1.22 days; P value = 0.011). On the other hand, although the consumed dose of gonadotropin was lower in the antagonist group, the difference between the two groups was not statistically significant (GnRH agonist = 1868.40 ± 668.29 IUs vs. GnRH antagonist = 1779.55 ± 702.87 IUs; P value = 0.432). Similarly, the number of retrieved oocytes, MII oocytes, MI oocytes, GV oocytes, fertilized oocytes, and embryos obtained were lower in the GnRH antagonist group, but the differences between the two groups were not statistically significant. In addition, there were not any significant differences between the two groups in oocytes morphology or other embryological or clinical IVF/ICSI outcomes.Conclusions: Flexible GnRH antagonist protocol and the long GnRH agonist protocol regulate the follicular microenvironment and angiogenesis differently in PCOS subjects. However, these differences have no influence on the oocyte’s morphology or the IVF/ICSI clinical outcomes. Thus, since flexible GnRH antagonist protocol represents a more friendly and cost-effective protocol, it may be a better treatment choice for PCOS women undergoing IVF/ICSI.Study registration: This trial was prospectively registered at clinicaltrials.gov site under registration number (NCT04727671).