Anti-Mullerian Hormone Activity and Regulation in the Ovary and in the polyCystic ovarian syndrome – AMHAROC

Anti-Müllerian hormone (AMH), also called Müllerian inhibiting substance, is a member of the transforming growth factor beta family synthesized by growing ovarian follicles and involved in the control of follicular development. AMH has been recognized as one of the best hormonal markers of the ovarian reserve and for this reason it is increasingly used in reproductive medicine. However, few data are available on the regulation and the role of AMH in the ovary. The aim of this proposal is to fill the lack of data on normal ovarian AMH physiology and to understand the role of AMH and its specific receptor (AMHR2) in the polycystic ovarian syndrome (PCOS), the most common cause of female infertility. Indeed, some of the features of PCOS include an abnormally rich pool of small follicles which could be due to the dysregulation of the AMH/AMHR2 system. The project is divided in four tasks corresponding to these objectives.
More precisely, the two first tasks aim to explore the regulation of the AMH/AMHR2 system. The objective of the Task 1 is to study the regulation of AMH and AMHR2 expression by different hormones of pituitarian (gonadotropins) or ovarian (oestradiol, Bone Morphogenetic Proteins or BMPs) origin in granulosa cells from fully differentiated luteinized and small growing follicles .The Task 2 aims to further explore, at the promoter level, the hormonal regulations studied in Task 1, and to get new insights into their mechanism of action . We will take advantage of species differences of expression and regulation, of in silico analysis of the AMH and AMHR2 coding sequences and promoters and of in vitro comparisons of promoter activity.
The third Task is to better understand the effects of AMH on follicular maturation. For that, we plan to identify new AMH target genes involved in this process, in particular those which are regulated in an opposite way to BMPs, and the different signalling pathways activated by AMH in granulosa cells.
In the Task 4, we will take advantage of the results obtained in the previous tasks to study the role of the AMH/AMHR2 system in the PCOS. We will try to find out why AMH and AMHR2 are overexpressed in these women and what are the consequences of these high levels of AMH and AMHR2 in PCOS ovaries on AMH signalling pathways and target gene expression. Because the amount of PCOS granulosa cells is limited, and because only luteinized granulosa cells are available in human, we will also work on a prenatally-androgenized sheep model which recapitulates several features of PCOS and allows studying the role of androgens in the aetiology of this syndrome.
The novelty of this project comes mainly from the fact that we will work in parallel on human, ovine and porcine material because there are complementary and have characteristics fitting very well with our scientific questions. Moreover, it should lead to numerous new results ranging from basic research to clinical and agronomic applications such as the improvement of reproductive biotechnologies.
It will be coordinated by Nathalie di Clemente, a specialist of AMH since 20 years, who heads an Inserm team. It will gather two complementary partners worldwide known in their domain of expertise: an Inserm team specialist of AMH and Reproductive Medicine, and an INRA team specialist of ovarian physiology and AMH/BMPs systems in farm animals. All these aspects make the project feasible in the given time.