Commentary Extra-Gonadal FSH Receptor: Is It Real? 1

Follicle stimulating hormone (FSH) is a pituitary gonadotrope-derived heterodimeric glycoprotein that binds G-protein coupled FSH-receptors (FSHRs) on ovarian granulosa cells [1-3]. This FSH/FSHR signaling pathway is essential for female fertility since null mice lacking either the FSH ligand [4] or FSHR [5, 6] are sterile as a result of pre-antral stage block in ovarian folliculogenesis. These FSH ligand/receptor null mice phenocopy women harboring inactivating mutations (homozygous recessive) in corresponding alleles encoding the hormone-specific FSH beta subunit and FSHR [7, 8]. A number of in vitro and in vivo studies have documented the cascade of signaling events elicited by FSH binding to FSHRs on granulosa cells [2, 3, 9]. Although, the predominant signaling pathway activated by FSH is cAMP-mediated phosphorylation of PKA and CREB, activation of other signaling pathways including MAP-Kinase pathway have also been identified [8, 10]. Interestingly, several FSH receptor isoforms are expressed in ovary (presumably on granulosa cells of pre-antral follicles) prior to the well-known FSH actions during early folliculogenesis [11-14]. However, the functional significance of these FSHR isoforms is unknown. While the classical prevailing view is that pituitary-derived FSH acts on ovaria