Extragonadal FSH receptor: is it real?

Abstract

Follicle-stimulating hormone (FSH) is a pituitary gonadotroph-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 because null mice lacking either the FSH ligand [4] or FSHR [5, 6] are sterile as a result of preantral 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 the mitogen-activated protein kinase pathway, has also been identified [8, 10]. Interestingly, several FSHR isoforms are expressed in ovary (presumably on granulosa cells of preantral follicles) prior to the well-known FSH actions during early folliculogenesis [11–14]. However, the functional significance of these FSHR isoforms is unknown. Although the classical prevailing view is that pituitary-derived FSH acts on ovarian granulosa cells in the female, emerging evidence suggests FSH may exert physiological effects on extragonadal tissues and organs as well. A series of studies document that FSH acts on osteoclasts by activating FSHRs via a nonclassical pathway and regulates bone mass in mice [15–19]. Consistent with this, women carrying a polymorphism in FSHR resulting in hyperactivation of FSHRs are more prone to bone loss [20]. However, FSH actions on bone osteoclasts remain controversial [21, 22]. Moreover, FSH actions on monocytes [23, 24] and human umbilical vein endothelial cells [25] and expression of FSHRs on endothelial cells of the tumor vasculature [26] have been reported. In a recent issue of Biology of Reproduction (BOR), Stilley and colleagues present their remarkable findings on FSHR expression in the human female reproductive tract and developing placenta and feto-placental defects in an Fshr mutant mouse model [27].