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Investigation of Cumulus Cell Factors Associated with Embryo Development and Pregnancy Outcome in Human Ivf

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Investigation of Cumulus Cell Factors Associated with Embryo Development and Pregnancy Outcome in Human Ivf INVESTIGATION OF CUMULUS CELL FACTORS ASSOCIATED WITH EMBRYO DEVELOPMENT AND PREGNANCY OUTCOME IN HUMAN IVF JOZSEF EKART A thesis submitted to the Victoria University of Wellington in fulfilment of the requirements for the degree of Doctor of Philosophy in Cell Biology Victoria University of Wellington 2013 2 ABSTRACT Recent evidence suggests that the expression of some candidate genes in cumulus cells (CC) have the potential to serve as markers of oocyte quality. The aims of this study were: 1) to validate a multiplex quantitative polymerase chain reaction (QPCR) method to measure four genes simultaneously in extracts from individual CC and; 2) to investigate the relationships in individual cumulus-oocyte-complexes (COC) amongst the expression levels of a range of candidate genes (N=8) from individual CC, the numbers of CC per COC and developmental indicators (good blastocyst development and live birth outcome) of the associated oocytes following in vitro fertilization (IVF) with intra-cytoplasmic sperm injection (ICSI). Sixty eight women were recruited for this study following approval from NZ Multi-Regional Ethics Committee and classified into four research groups: young and healthy women (<38 years, N=25), young women with polycystic ovarian syndrome (<38 years, N=11), young with diminished ovarian reserve (<38 years, N=12) and older and healthy women (≥40 years, N=20). Following exogenous rFSH-assisted ovarian stimulation, 608 COC were collected and subjected to ICSI. Oocyte and embryo quality, and pregnancy outcomes were recorded. Expression levels of the following candidate genes HAS2, FSHR, SLC2A4 (GLUT4), ALCAM, SFRP2, VCAN, NRP1 and PR in CC extracts from individual COC were measured by TaqMan QPCR and normalized against the house-keeping gene, RPL19. The numbers of CC from individual COC were calculated from RPL19 expression levels plotted against a standard curve of CC number. These results were then assessed against the outcomes of the associated oocytes following ICSI. HAS2, FSHR, ALCAM, VCAN, NRP1 and PR mRNA were detectable in most samples (98.5%) whereas those for SLC2A4 and SFRP2 were generally undetectable. The minimum number of CC required for QPCR was estimated to be ~70. The mean levels of FSHR mRNA were up-regulated in young women with PCOS compared to those in the other two groups of women <38y. Expression levels of HAS2 across all four groups of women were correlated to both biological (age, basal serum FSH and serum AMH) and treatment (amount of rFSH used for stimulation, follicle numbers and COC retrieved) variables. Investigations related to oocyte development in young and healthy women showed that 1) mean mRNA levels of VCAN, HAS2 and PR were higher (P=0.002, P<0.05, P<0.05, respectively) in CC associated with oocytes that resulted in good quality blastocysts and those of VCAN were higher 3 (P<0.05) in CC associated with oocytes that resulted in a live birth, compared with those with developmental failure. However, the expression levels of all measurable candidate genes were highly variable for individual CC from COC from each woman. Indeed, 99.7% of individual COC were different in CC mRNA levels and cell composition. The application of a ranking method to score the relative CC mRNA levels of selected candidate genes from each COC recovered from individual women was evaluated. This approach demonstrated a predictive power of 80% efficiency for selecting good quality oocytes (at least one), whilst requiring the insemination of no more than three oocytes in any treatment cycle. Furthermore, this selection method resulted in a pregnancy and live birth rate of 60 and 52% respectively (N=25 women). This outcome is similar to that achieved when all metaphase II (MII) oocytes are inseminated. In conclusion, this study has validated a multiplex QPCR method to quantify the expression levels of four genes in CC of individual human COC simultaneously using as few as 70 cells. Moreover, that there is sufficient cDNA so that many more candidate genes can be measured in the same extract. From the knowledge of the mRNA levels of at least four genes, VCAN, FSHR, HAS2 and PR in CC, it is possible to improve upon existing biological indicators the potential to predict good blastocyst formation and a successful pregnancy outcome. It is concluded that the application of a multiplex QPCR approach to assess the expression levels of a limited number of marker genes in CC can be used to select the best oocytes for successful pregnancy outcomes. 4 ACKNOWLEDGEMENTS First and foremost, I would like to thank those women who consented to this study. Further, I would like to aknowledge the guidance and help of several individuals who generously and willingly contributed their expertise and knowledge for the completion of this thesis. I offer my sincerest gratitude to my supervisors, Prof. Ken McNatty from Victoria University of Wellington, and Prof. John Hutton from University of Otago, Wellington. Words cannot describe how privileged and honoured I feel for having had the opportunity to work with such fantastic individuals. I would like to thank Ken for believing in me, encouraging me throughout the years, for his infinite knowledge, and for his kindness and patience whilst allowing me the room to work in my own way. I would like to thank John for believing in me since the very beginning, for his tremendous help in managing the women recruited for this study, for his friendship, and last but not least, for his sense of humour. Dr Janet Pitman, my secondary supervisor from Victoria University of Wellington, for her invaluable expertise in the validation of the multiplex QPCR methodology and in the preparation of manuscripts. I would further like to thank her for her patience and unfailing support throughout the completion of this dissertation. Dr Kevin Coetzee, my laboratory supervisor from Fertility Associates, for his help, encouragement and his great friendship throughout the study. Fertility Associates Ltd, for their financial and strategic support, without which this study would not have been possible. I would also like to thank my embryologist colleagues from Fertility Associates Wellington and my colleagues from the Reproduction Team from Victoria University (especially Adrian Bibby) for their time, support and knowledge. Last but not least, I would like to thank to my family, my girlfriend and my fellow students (especially Shalen) for their great friendship and great memories spent together. It has been a very rewarding opportunity to study at Victoria University of Wellington, an experience for which I will be eternally grateful. 5 PRESENTATIONS 2012 The Fertility Society of Australia 31st Annual Scientific Meeting, Auckland, New Zealand Title: “Cumulus cell mRNA markers for identifying healthy oocytes” American Society of Reproductive Medicine (ASRM) 68th Annual Meeting, San Diego, USA Title: “The use of cumulus cell (CC) mRNA levels to predict blastocyst development and live birth outcomes in women undergoing intracytoplasmic sperm injection (ICSI) and single embryo transfer” Controversies in Reproductive Medicine, Taupo, New Zealand Title: “Cracking Good Eggs – An “in-gene-ious” method! Oocyte quality and the use of cumulus cell markers for the selection of oocytes with developmental potential in young and healthy, POF, PCOS and older women undergoing ICSI” 2011 IVF Scientists Meeting, Auckland, New Zealand Title: “The use of cumulus cells to predict embryological and pregnancy outcomes in women undergoing IVF” 2010 The Fertility Society of Australia 29th Annual Scientific Meeting, Adelaide, Australia Title: “Can cumulus cell gene expressions predict embryology outcome?” AWARDS 2012 ASRM CMC In-Training Travel Award, 68th Annual Meeting of ASRM, San Diego, USA 2011 Obex Award for Best Paper, IVF Scientists Meeting, Auckland, New Zealand 6 TABLE OF CONTENTS Content Page number ABSTRACT ........................................................................................................................ 3 ACKNOWLEDGEMENTS ................................................................................................ 5 PRESENTATIONS ............................................................................................................. 6 AWARDS ............................................................................................................................. 6 LIST OF TABLES AND FIGURES ................................................................................. 11 ABBREVIATIONS ............................................................................................................. 12 Chapter 1 INTRODUCTION 1.1 Short history of ART and the development of human IVF ..................... 15 1.2 The origin of the female gametes ........................................................... 16 1.3 The ovarian cycle ................................................................................... 18 The hormonal regulation of folliculogenesis ......................................... 23 1.4 Ovarian stimulation in human IVF ......................................................... 24 1.5 The oocyte’s central role in follicular development ............................... 27 The role of oocyte secreted factors (OSF) ............................................. 27 1.6 The outcome of human oocytes following oocyte collection: IVF, pre-implantation genetic diagnosis and fertility preservation ................ 31 IVF treatment and associated therapies for increasing healthy offspring outcomes
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