Conventional GnRH Antagonist Protocols Versus GnRH Agonist Long Protocol on IVF/ICSI Outcomes in Women With Polycystic Ovary Syndrome: A Systematic Review and Meta- Analysis of Randomized Controlled Trials

Abstract

BackgroundGonadotropin-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. This review aimed to summarize the available evidence comparing the effects of conventional GnRH antagonist protocols, the most commonly used GnRH antagonist protocols, and GnRH agonist protocols on IVF/ICSI outcomes in women with polycystic ovary syndrome (PCOS). MethodsA comprehensive electronic search was carried out in Pubmed, Cochrane CENTRAL, Scopus, Web of Science, CINAHL, TRIP, ClinicalTrials.gov and ISRCTN registry from inception until 24 November 2020 without any language or date restrictions. In addition, reference lists of eligible studies and previous meta-analyses were hand-searched to identify relevant studies. Eligible randomized controlled trials were those designed to compare the effects of conventional GnRH antagonist protocols and GnRH agonist protocols on IVF/ICSI outcomes in PCOS subjects. The Cochrane ROB 2.0 tool was used to assess the risk of bias of each study, and the GRADE assessment was used to evaluate the overall quality of evidence. Data synthesis and analyses were done using Review Manager 5.3 with the assistance of Revman Web. A random-effects model was used for all meta-analysis. Dichotomous outcomes were reported as Relative Risk (RR) and continuous outcomes as Weighted Mean Difference (WMD), both with 95% CIs. 2 Resultswe included ten studies with 1214 randomized PCOS women. Using GnRH antagonist protocols led to a significantly shorter stimulation duration (WMD=-0.91; 95% CI: [-1.45 to-0.37] day, P=0.0009), lower gonadotropin consumption (WMD=-221.36; 95% CI: [-332.28 to-110.45] IU, P< 0.0001), lower E2 levels on hCG day (WMD=-259.21; 95% CI: [-485.81 to-32.60] pg/ml, P=0.02), thinner endometrial thickness on hCG day (WMD=-0.73; 95% CI: [-1.17 to-0.29] mm, P=0.001), lower number of retrieved oocytes (WMD=-1.82; 95% CI: [-3.48 to-0.15] oocytes, P=0.03), and lower OHSS rate (RR= 0.58; 95% CI: [0.44 to 0.77], P=0.0002). However, no significant differences in live birth rate, clinical pregnancy rate, ongoing pregnancy rate, multiple pregnancy rate, miscarriage rate and cycle cancellation rate were seen between the GnRH antagonist protocols and the long GnRH agonist one. Although more cycles were cancelled due to poor ovarian response in the GnRH antagonist protocol (RR= 4.63; 95% CI: [1.49 to 14.41], P=0.008), similar rates of cancellation due to risk of OHSS were noticed in both groups. DiscussionThe differences in IVF/ICSI outcomes may arise from the different patterns of gonadotropins suppression that the GnRH analogues exhibit during the early follicular phase of IVF/ICSI cycles and the divergent direct impacts of these analogues on ovaries and endometrial receptivity. The main evidence limitation was Imprecision. ConclusionsConventional GnRH antagonist protocols represent a safer and more cost-effective treatment choice for PCOS women undergoing IVF/ICSI cycles than the standard long GnRH agonist protocol without compromising the IVF/ICSI clinical outcomes.

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

“…Nevertheless, unlike stimulation duration, the effects on gonadotropins consumption and the number of retrieved oocytes were insigni cant. However, based on our recent systematic review and meta-analysis on PCOS women [77], using conventional GnRH antagonist protocols led to a signi cantly lower gonadotropin consumption and a signi cantly lower number of retrieved oocytes compared to the long agonist one. (Gonadotropin consumption; WMD= -221.36, 95% CI: [-332.28 to -110.45] IUs; P < 0.0001; I 2 = 43%; χ ² -P = 0.1; high-quality evidence), (number of retrieved oocytes; WMD = 1.82, 95% CI: [-3.48 to -0.15] oocytes; P = 0.03; I2 = 58%; χ² P = 0.02; low-quality evidence), Thus, the insigni cant result may relate to the relatively low sample size of the current trial.…”

“…In addition, the differences in the consumed dose of gonadotropins and the divergent effects of GnRH analogues on steroidogenesis may affect the regulation of ovarian Moreover, FSH induces the expression of transforming growth factor-β (TGF-β) [91], which also controls VEGF expression and acts synergically with HIF-1α in upregulating VEGF expression [92]. Above that, Based on our recent systematic review and meta-analysis [77], treating PCOS women with the conventional GnRH antagonist protocols led to lower levels of estradiol on hCG day compared to the standard long agonist protocol (WMD= -259.21, 95% CI: [-485.81 to -32.60] pg/ml; P = 0.02; I 2 = 42%; χ ² -P = 0.10; moderate-quality evidence), which agrees with the previous in vitro studies that demonstrated lower aromatase activity and expression from granulosa lutein cells of GnRH antagonist-treated women compared to those of GnRH agonist-treated women [93]. Estrogen upregulates VEGF expression in ovarian [94] and endometrial cells [95,96].…”