GnRH signaling, the gonadotrope and endocrine control of fertility

Abstract

Mammalian reproductive cycles are controlled by an intricate interplay between the hypothalamus, pituitary and gonads. Central to the function of this axis is the ability of the pituitary gonadotrope to appropriately respond to stimulation by gonadotropin-releasing hormone (GnRH). This review focuses on the role of cell signaling and in particular, mitogen-activated protein kinase (MAPK) activities regulated by GnRH that are necessary for normal fertility. Recently, new mouse models making use of conditional gene deletion have shed new light on the relationships between GnRH signaling and fertility in both male and female mice. Within the reproductive axis, GnRH signaling is initiated through discrete membrane compartments in which the receptor resides leading to the activation of the extracellular signal-regulated kinases (ERKs 1/2). As defined by gonadotrope-derived cellular models, the ERKs appear to play a central role in the regulation of a cohort of immediate early genes that regulate the expression of late genes that, in part, define the differentiated character of the gonadotrope. Recent data would suggest that in vivo, conditional, pituitary-specific disruption of ERK signaling by GnRH leads to a gender-specific perturbation of fertility. Double ERK knockout in the anterior pituitary leads to female infertility due to LH biosynthesis deficiency and a failure in ovulation. In contrast, male mice are modestly LH deficient; however, this does not have an appreciable impact on fertility.

Figure 1

Model for GnRH receptor (GnRHR) signaling within the pituitary gonadotrope that leads to LH biosynthesis. The GnRHR resides within discrete plasma membrane compartments (membrane rafts) characterized by increased presence of cholesterol (green within membrane) and sphingolipids (orange within membranes). Activation of the ERK signaling pathway occurs within the membrane rafts facilitated by local influx of extracellular calcium through voltage dependent calcium channels (VGCC).

Figure 2

Temporal relationship between transient ERK activation, immediate early gene (IEGs) upregulation and activation of late genes that lead to LH biosynthesis following a pulse of GnRH.