Gonadotropin regulation by pulsatile GnRH: Signaling and gene expression

Abstract

The precise orchestration of hormonal regulation at all levels of the hypothalamic-pituitary-gonadal axis is essential for normal reproductive function and fertility. The pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH) stimulates the synthesis and release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) by pituitary gonadotropes. GnRH acts by binding to its high affinity seven-transmembrane receptor (GnRHR) on the cell surface of anterior pituitary gonadotropes. Different signaling cascades and transcriptional mechanisms are activated, depending on the variation in GnRH pulse frequency, to stimulate the synthesis and release of FSH and LH. While changes in GnRH pulse frequency may explain some of the differential regulation of FSH and LH, other factors, such as activin, inhibin and sex steroids, also contribute to gonadotropin production. In this review, we focus on the transcriptional regulation of the gonadotropin subunit genes and the signaling pathways activated by pulsatile GnRH.

Keywords: Follicle-stimulating hormone; G proteins; GnRH receptor; Gonadotropin-releasing hormone; Luteinizing hormone; Signal transduction.

Figure 1. Proposed model of regulation of Lhb transcription by pulsatile GnRH

High and low GnRH pulse frequencies stimulate different signaling pathways to mediate the synthesis of transcription factors and repressors controlling Lhb transcription. A) At a high GnRH pulse frequency, the PKC/MAPK and Calcium/Calmodulin-dependent kinase II (CaMK II) pathways are activated, causing an increase in Egr1 expression. Egr1 in turn increases activity of the Lhb promoter. B) At a low GnRH pulse frequency, the PKC/MAPK pathway is activated but the transient increase in Egr1 expression is insufficient for maximal activation of the Lhb promoter, an effect further antagonized by increased expression of Nab1/2, corepressors of the Egr family, which are preferentially stimulated at low GnRH pulse frequency.

Figure 2. Proposed model of regulation of Fshb transcription by pulsatile GnRH

High and low GnRH pulse frequencies stimulate different signaling pathways that mediate the synthesis of transcription factors and repressors controlling Fshb transcription. A) At a high GnRH pulse frequency, the GnRHR preferentially couples to Gα_q/11 proteins, activating the PKC/MAPK pathway. This pathway stimulates ICER expression and synthesis. ICER attenuates GnRH stimulation of Fshb expression by antagonizing the binding of CREB to the Fshb CRE-AP1 site. SKIL and TGIF1 are also induced at high GnRH pulse frequencies and also bind to the Fshb gene promoter to prevent any potential action of cFos and cJun. B) At a low GnRH pulse frequency, the GnRHR preferentially couples to Gα_s protein, activating the cAMP/PKA/CREB pathway (indicated by bold arrows). The phosphorylated CREB protein binds to the homologous CRE-AP1 site of the Fshb promoter and recruits the histone acetyltransferase CREB-binding protein (CBP), stimulating Fshb transcription. PKC/MAPK and Calcineurin/NFAT pathways are also activated, but to a lesser extent. They contribute to induction of Fshb transcription by stimulating cFos and cJun expression.