GnRH pulse frequency-dependent differential regulation of LH and FSH gene expression

Abstract

The pituitary gonadotropin hormones, FSH and LH, are essential for fertility. Containing an identical α-subunit (CGA), they are comprised of unique β-subunits, FSHβ and LHβ, respectively. These two hormones are regulated by the hypothalamic decapeptide, GnRH, which is released in a pulsatile manner from GnRH neurons located in the hypothalamus. Varying frequencies of pulsatile GnRH stimulate distinct signaling pathways and transcriptional machinery after binding to the receptor, GnRHR, on the cell surface of anterior pituitary gonadotropes. This ligand-receptor binding and activation orchestrates the synthesis and release of FSH and LH, in synergy with other effectors of gonadotropin production, such as activin, inhibin and steroids. Current research efforts aim to discover the mechanisms responsible for the decoding of the GnRH pulse signal by the gonadotrope. Modulating the response to GnRH has the potential to lead to new therapies for patients with altered gonadotropin secretion, such as those with hypothalamic amenorrhea or polycystic ovarian syndrome.

Redirecting intracellular trafficking and the secretion pattern of FSH dramatically enhances ovarian function in mice

“…The consequences of modifying these secretion pathways have not been tested in vivo. In the pituitary, GnRH pulse characteristics are critical for differential regulation of LH and FSH (30)(31)(32)(33). Emerging evidence suggests GnRH pulses are interpreted at the level of gonadotropin β-subunit promoters, downstream signaling cascades involving MAPKs and ultimately reflected in corresponding subunit biosynthesis (31,33).…”

Gonadotrope-specific Deletion of Dicer Results in Severely Suppressed Gonadotropins and Fertility Defects

“…GnRH activates the GnRH receptor in gonadotropes, a seven membrane-spanning G-protein-coupled receptor, to maintain the basal expression of gonadotropin subunit gene transcription (12). Activins, members of transforming growth factor-␤ superfamily, regulate Fshb transcription via SMAD-and FOXL2-dependent pathways (13).…”

“…A combinatorial action of several activators and repressors is required for transcription of gonadotrope subunit-encoding genes (10,12,15). Steroidogenic factor-1 (SF-1) is an orphan nuclear receptor protein activator that is required for transcription of gonadotropin subunits in vivo (16).…”

Histidine7.36(305) in the conserved peptide receptor activation domain of the gonadotropin releasing hormone receptor couples peptide binding and receptor activation

“…These gonadotropic hormones, in turn, regulate gametogenesis and gonadal sex hormone production. The GnRH receptor is a rhodopsin-like, class A, G protein-coupled receptor (GPCR) that transduces the GnRH binding signal across the cell membrane via changes in receptor protein conformation that activate intracellular G proteins and inositol phosphate (IP) signaling Naor and Huhtaniemi, 2013;Pincas et al, 2014;Sefideh et al, 2014;Thompson and Kaiser, 2014).…”