Ovarian Club X and CoGEN in Asia

SpeakerS

Asgi FAZLEABAS (USA)

Dr. Asgi Fazleabas is a University Distinguished Professor at Michigan State University.  His research focuses on the molecular and cellular mechanisms associated with the establishment of pregnancy and the consequences of gynecological pathologies on pregnancy outcomes. The Fazleabas laboratory has pioneered the development of a baboon model of endometriosis which has provided insight into the pathways involved in the pathogenesis of the disease, the genetic dysregulation of the eutopic endometrium and immune system as well as the role miRNA’s in development and progression of the disease and infertility. Work from his laboratory was the first to demonstrate that the primate embryonic signal chorionic gonadotropin directly modulates the gene expression patterns of a number of genes that play critical roles in immune surveillance, stromal cell differentiation and decidualization and angiogenesis in the preparation for pregnancy. These mechanisms are compromised in the context of endometriosis which leads to infertility as a consequence of this disease. One of the major genes that is regulated by chorionic gonadotropin is the evolutionary conserved cell fate mediator Notch1. These studies have shown that Notch1 modulates multiple signaling mechanisms critical for decidualization. His research program has been continuously supported throughout his career by the National Institutes of Health (USA).   

Abstract

The Endometrial Embryo Response and Use of HCG in Improving Implantation

Impaired endometrial receptivity remains one of the most significant barriers to the establishment of pregnancy. The primate embryo secretes Chorionic Gonadotropin (CG) and in addition to rescuing the corpus luteum, hCG has been shown to enhance endometrial receptivity in both women and non-human primates. The mechanisms by which exogenous administration of intrauterine hCG might improve implantation rates are unknown. Additionally, the task of identifying mechanisms of intrauterine hCG in promoting a receptive endometrium in infertile women undergoing IVF remain difficult. Using a baboon model we demonstrated that intrauterine hCG administration induces gene expression via ERK signaling in endometrial stromal and glandular epithelial cells and stimulates the formation of the luminal epithelial plaque response. HCG induced stromal expression of α-Smooth Muscle Actin and NOTCH1 in the baboon are essential for cell survival and differentiation during decidualization and our previous studies demonstrated the importance of hCG treatment on human endometrial histology and prevention of apoptosis. Subsequent studies on the response to intrauterine hCG administration have been reported, with positive and non-significant clinical findings, leaving the clinical potential and utility of intrauterine hCG administration for improving pregnancy rates with IVF unresolved In a recent study, we performed a single intrauterine infusion hCG in oocyte donors on day 3 following oocyte retrieval to determine potential role of intra-uterine hCG on endometrial function following controlled ovarian stimulation. The dose of 500 IU hCG and the infusion time point were based on a previously published study which showed a positive effect on implantation rates following embryo transfer. Administration of intrauterine luteal phase hCG to oocyte donors in our study have further defined hCG-regulated molecular mechanisms during the putative implantation window including the induction of smooth muscle actin and NOTCH1 which were amongst the  selected genes that an associated role in endometrial receptivity that we had previously reported to be regulated by hCG in the baboon model.  We show from these studies that there is potential clinical benefit for intrauterine hCG prior to embryo transfer in an IVF setting. Our findings suggest a potential clinical benefit for intrauterine hCG prior to embryo transfer on day 3 in counteracting endometrial dyssynchrony from controlled ovarian stimulation and promoting expression of markers important for stromal survival. Finally, there were no obvious negative effects of intrauterine hCG treatment.