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

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).

Correlations between follicular fluid AMH and IVF/ICSI outcomes among polycystic ovary syndrome women using different controlled hyperstimulation protocols

“…PlGF is an angiogenic growth factor that plays a pivotal role in regulating ovarian angiogenesis, follicular development, and ovulation [66][67][68]. Since FF AMH levels in PCOS subjects are not only related to the antral follicle counts (AFCs) but also to the overproduction of AMH per GC [20,21], the results of the current study and of our previous work ( [36]) suggest that the negative effect of FF AMH on folliculogenesis and in subsequence on the number of retrieved oocytes would be noted during both; the long GnRH agonist protocol and the exible GnRH antagonist one as well. However, other factors like follicular angiogenesis and the FF PlGF levels can also in uence the oocytes' yield.…”

“…In addition, FF AMH were comparable between pregnant and non-pregnant women, independently of the protocol used, which also had been con rmed by the ROC curve analysis. According to our recent work, lower levels of placental growth factor (PlGF) can be noted in the follicular uid of PCOS women during the exible GnRH antagonist protocol compared to the long agonist one [36]. In addition, in the PCOS population, FF PlGF levels positively correlate with the number of MII oocytes and the OSI index during the GnRH antagonist protocol, but not the long agonist protocol ().…”

“…The current study is a re-analysis of our previous work. The data were adopted from a prospective clinical trial [36] that was registered on the clinicaltrials.gov site on registration numbers NCT04727671. The trial was conducted on women who were referred to the Assisted Reproductive Unit of Orient Hospital, Damascus, Syrian Arab Republic, from December 2019 to August 2021.…”

Follicular fluid PlGF and IVF/ICSI outcomes among PCOS and normo-ovulatory women using different controlled hyperstimulation protocols: A prospective case-control study

“…The case-control study is a re-analysis of our previous work. The data were adopted from two prospective clinical trials [ 27 , 28 ] that were registered on the clinicaltrials.gov site on registration numbers NCT04727671 ( https://clinicaltrials.gov/ct2/show/NCT04727671 ) and NCT04724343 ( https://clinicaltrials.gov/ct2/show/NCT04724343 ). The trials were conducted on women who were referred to the Assisted Reproductive Unit of Orient Hospital, Damascus, Syrian Arab Republic, from December 2019 to August 2021.…”

“…However, that study used a combination of GnRH agonist and GnRH antagonist protocols. Based on our recent work, FF PlGF levels differ significantly between the long GnRH agonist and the flexible GnRH antagonist protocols both; in PCOS and normo-ovulatory women [ 27 , 28 ]. Thus, it is unclear whether these differences in FF PlGF levels between PCOS and controls would still be important after adjusting to the type of protocol used.…”