Effect of FSH Receptor-Binding Inhibitor-8 on FSH-Mediated Granulosa Cell Signaling and Proliferation

Follicle-stimulating hormone is important for mamma-lian reproduction. It acts through specific receptorslocated on the plasma membrane of granulosa cells inovaries and Sertoli cells in testes. The binding offollicle-stimulating hormone to its receptor activatesintracytoplasmic signaling pathways leading to steroi-dogenesis. These steroids in turn regulate the follicle-stimulating hormone action from the anterior pituitarythrough exerting negative feedback effect. In additionto steroids, non-steroidal factors secreted by theovaries are believed to modulate follicle-stimulatinghormone action through autocrine/paracrine mode.One such low molecular weight peptide referred to asfollicle-stimulating hormone receptor-binding inhibitor-8 purified from human follicular fluid has been exten-sively studied. Follicle-stimulating hormone receptor-binding inhibitor-8 has been shown to inhibit bindingof follicle-stimulating hormone to its receptor. Thepresent article describes the effect of follicle-stimulat-ing hormone receptor-binding inhibitor-8 on follicle-stimulating hormone-induced signaling in rat granulosacells. Follicle-stimulating hormone receptor-bindinginhibitor-8 inhibited the follicle-stimulating hormone-induced cAMP, and the effect was observed to bemediated through the protein kinase A. Further, aninhibitory effect of follicle-stimulating hormone recep-tor-binding inhibitor-8 on the granulosa cell prolifera-tion was evaluated using COV434 cell line which isderived from the human granulosa cell tumor. Theeffect of the peptide on the cell cycle analysis showedan increase in apoptotic population and the arrest ofG1 phase. These findings suggest that follicle-stimulat-ing hormone receptor-binding inhibitor-8 acts as afollicle-stimulating hormone antagonist and affects thefollicle-stimulating hormone-mediated signaling andproliferation in the granulosa cells.Key words: COV434, follicle-stimulating hormone, FSHreceptor, FSH receptor-binding inhibitor, granulosa cells, sig-nal transduction assaysReceived 2 August 2012, revised 26 February 2013 andaccepted for publication 15 April 2013