A mechanism for the differential regulation of gonadotropin subunit gene expression by gonadotropin-releasing hormone.

Abstract

The hypothalamic hormone gonadotropinreleasing hormone (GnRH) is released in a pulsatile fashion, with its frequency varying throughout the reproductive cycle. Varying pulse frequencies and amplitudes differentially regulate the biosynthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) The hypothalamic decapeptide gonadotropin-releasing hormone (GnRH) plays a critical role in reproductive development and function by regulating the biosynthesis and secretion of the pituitary gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). GnRH is released into the hypophysial portal circulation and transported to the anterior pituitary, where it binds to specific, high-affinity cell surface receptors on gonadotropes, the pituitary cell type that produces gonadotropins. LH and FSH are heterodimers, each composed of a common a subunit associated noncovalently with a unique 1B subunit (1).The stimulation of gonadotropin secretion by GnRH is dependent on the pulsatile nature of GnRH delivery to the anterior pituitary. Administration of exogenous GnRH in a continuous fashion results in the down-regulation of LH and FSH secretion, whereas pulsatile GnRH stimulates LH and FSH secretion, in several species, including primates and rat (2-4). Furthermore, the frequency and amplitude of GnRH pulses secreted by the hypothalamus, which vary during different phases of the menstrual or estrous cycle, regulate differentially . Similarly, the levels of gonadotropin subunit gene expression in the rat pituitary vary by 2-to 4-fold, depending on the GnRH pulse frequency and amplitude (8)(9)(10)(11) GnRHR activation include inositol phospholipid turnover, which leads to calcium mobilization and protein kinase C activation (19,20).The mechanism by which GnRH is able to regulate differentially LH and FSH biosynthesis and secretion is unknown. Previous studies have been limited by the lack of available cell lines that express the LH and FSH subunit genes and respond to GnRH. We have taken advantage of the availability of the GnRHR cDNA to facilitate studies of the mechanisms of action of GnRH. GH3 cells are a well-characterized pituitary cell line generated from a rat pituitary adenoma that express prolactin (PRL) and growth hormone in a regulated fashion (21). These cells express thyrotropin-releasing hormone (TRH) receptors endogenously and respond to TRH with an increase in PRL gene expression, biosynthesis, and secretion (22). Like the GnRHR, the TRH receptor is a member of the family of G protein-coupled receptors and is coupled to pertussis toxin-insensitive G proteins of the Gq/11 family (23).Furthermore, like GnRH, TRH activates its receptor to stimulate inositol phospholipid turnover, leading to calcium mobilization and protein kinase C activation (24). Thus, the effects of TRH and GnRH appear to be mediated through similar intracellular signal transduction pathways.We hypothesized that GH3 cells may present a useful model for the study of the mechanisms of GnRH action...

How does bacterial endotoxin influence gonadoliberin/gonadotropins secretion and action?

“…The fact that TLR4 blockade in the hypothalamus, as well as administration of an anti-LPS antibody to the region of the hypothalamus, restored GnRH mRNA content in the ME but not in the POA indicate that the administration of these compounds rather prevented decreasing the stability of the GnRH mRNA induced by immune stimulation than decreasing the GnRH gene transcription. It could be suggested that inhibition of TLR4 in the hypothalamus led to unlock the inhibition of GnRH secretion, which is the most important modulator of LHβ gene expression (Kaiser et al, 1995). For the direct involvement of LPS in the suppression of the reproductive processes at the level of hypothalamus also indicate the results of the studies performed on rats (Ebisui et al, 1992).…”

LbetaT2 gonadotroph cells secrete follicle stimulating hormone (FSH) in response to active A

“…It is well established that lower pulse frequencies stimulate FSH secretion whereas higher pulse frequencies favor LH secretion and even decrease FSH expression and secretion in primary cultured rat pituitary cells (Ishizaka et al 1992, Kaiser et al 1995. When four pulses of 15 min duration were given every 90 min, LH secretion was stimulated (Turgeon et al 1996); in the current experiments, a one hour daily pulse stimulated FSH secretion in preference to LH (LH data not shown).…”

Growth Differentiation Factor 9 (GDF9) Forms an Incoherent Feed-forward Loop Modulating Follicle-stimulating Hormone β-Subunit (FSHβ) Gene Expression

“…The data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession number GSE52631 syndrome, and underlie the pharmacological treatment of gonadal hormone-dependent diseases, such as endometriosis and prostate cancer. Because of its biological and medical importance, the frequency system underlying gonadotropin regulation has been an area of study for decades, and several factors have been proposed to contribute to FSH␤ frequency sensitivity (2,(5)(6)(7)(8)(9)(10)(11). The major information processing properties of molecular signaling networks are largely determined by simple network motifs, and specific feedback or feed-forward circuits are necessary to create a robust low frequency detector (12)(13)(14).…”