New Anti-Mullerian Hormone Target Genes Involved in Granulosa Cell Survival in Women With Polycystic Ovary Syndrome

Purpose: A protective effect of anti-Mullerian hormone (AMH) on follicle atresia was recently demonstrated using long-term treatments, but this effect has never been supported by mechanistic studies. This work aimed to gain an insight into the mechanism of action of AMH on follicle atresia and on how this could account for the increased follicle pool observed in women with polycystic ovary syndrome (PCOS). Methods: In vivo and in vitro experiments were performed to study the effects of AMH on follicle atresia and on the proliferation and apoptosis of granulosa cells (GCs). RNA-sequencing was carried out to identify new AMH target genes in GCs. The expression of some of these genes in GCs from control and PCOS women was compared using microfluidic real time quantitative RT-PCR. Results: A short-term AMH treatment prevented follicle atresia in prepubertal mice. Consistent with this result, AMH inhibited apoptosis and promoted proliferation of different models of GCs. Moreover, integrative biology analyses of 965 AMH target genes identified in 1 of these GC models, confirmed that AMH had initiated a gene expression program favoring cell survival and proliferation. Finally, on 43 genes selected among the most up- and down-regulated AMH targets, 8 were up-regulated in GCs isolated from PCOS women, of which 5 are involved in cell survival. Main conclusions: Our results provide for the first time cellular and molecular evidence that AMH protects follicles from atresia by controlling GC survival and suggest that AMH could participate in the increased follicle pool of PCOS patients.

Automated summary

This study demonstrates the protective effect of AMH on follicle atresia by controlling granulosa cell survival, providing both cellular and molecular evidence for the increased follicle pool observed in PCOS patients. Furthermore, RNA sequencing identified new AMH target genes, some of which were up-regulated in granulosa cells from PCOS women, suggesting a potential role of AMH in the pathogenesis of PCOS.