Cumulus Cells Gene Expression Profiling in Terms of Oocyte Maturity in Controlled Ovarian Hyperstimulation Using GnRH Agonist or GnRH Antagonist

Rok Devjak,Irma Virant Klun,Eda Vrtačnik Bokal,Damjana Rozman,Klementina Fon Tacer,Peter Juvan,Jason Glenn Knott

doi:10.1371/journal.pone.0047106

Abstract

In in vitro fertilization (IVF) cycles controlled ovarian hyperstimulation (COH) is established by gonadotropins in combination with gonadotropin-releasing hormone (GnRH) agonists or antagonists, to prevent premature luteinizing hormone (LH) surge. The aim of our study was to improve the understanding of gene expression profile of cumulus cells (CC) in terms of ovarian stimulation protocol and oocyte maturity. We applied Affymetrix gene expression profiling in CC of oocytes at different maturation stages using either GnRH agonists or GnRH antagonists. Two analyses were performed: the first involved CC of immature metaphase I (MI) and mature metaphase II (MII) oocytes where 359 genes were differentially expressed, and the second involved the two GnRH analogues where no differentially expressed genes were observed at the entire transcriptome level. A further analysis of 359 differentially genes was performed, focusing on anti-Müllerian hormone receptor 2 (AMHR2), follicle stimulating hormone receptor (FSHR), vascular endothelial growth factor C (VEGFC) and serine protease inhibitor E2 (SERPINE2). Among other differentially expressed genes we observed a marked number of new genes connected to cell adhesion and neurotransmitters such as dopamine, glycine and γ-Aminobutyric acid (GABA). No differential expression in CC between the two GnRH analogues supports the findings of clinical studies where no significant difference in live birth rates between both GnRH analogues has been proven.

Highlights

In vitro fertilization (IVF) has become one of the most common treatments of infertility
CC MI: cumulus cells of metaphase I oocytes; CC MII-NF: cumulus cells of unfertilized metaphase II oocytes; CC MII oocytes developed to blastocyst stage embryo (MII-BL): cumulus cells of metaphase II oocytes developed to the blastocyst stage; CC MIINF vs. CC MI: contrast between CC MII-NF and CC MI; CC MII-BL vs. CC MI: contrast between CC MII-BL and CC MI; CC MII-BL vs. CC MII-NF: contrast between CC MII-BL and CC MII-NF; CC MII vs. CC MI: contrast between CC MII and CC MI. doi:10.1371/journal.pone.0047106.g002
The proportions of degenerated, MI, MII, MII-NF and MII-BL oocytes were similar in both groups

Summary

Introduction

In vitro fertilization (IVF) has become one of the most common treatments of infertility. In an IVF cycle, ovarian stimulation is established by gonadotropins in combination with gonadotropinreleasing hormone (GnRH) analogues, i.e. GnRH agonists or GnRH antagonists. GnRH analogues are used to prevent premature luteinizing hormone (LH) surge during ovarian stimulation, which improves oocyte yield and increases pregnancy rate [1]. GnRH antagonists have several advantageous effects over GnRH agonists [6,7], of which the most important is having fewer follicles and lower oestradiol level on the day of human chorionic gonadotropin (hCG) application [4] leading to a lower incidence of ovarian hyperstimulation syndrome (OHSS) [8], a serious complication of assisted reproductive therapy. Earlier studies have shown that GnRH antagonists result in lower pregnancy and delivery rates compared to GnRH agonists [6], whereas recent meta analyses show that the difference between them is not significant [9,10]

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