Divergent expression patterns of pituitary gonadotropin subunit and GnRH receptor genes to continuous GnRH in vitro and in vivo

Marija M Janjic,Ivana Bjelobaba,Stanko S Stojilkovic,Kosara Smiljanic,Rafael M Prévide,Arthur Sherman,Daniel Abebe,Patrick A Fletcher

doi:10.1038/s41598-019-56480-1

Abstract

Continuous, as opposed to pulsatile, delivery of hypothalamic gonadotropin-releasing hormone (GnRH) leads to a marked decrease in secretion of pituitary gonadotropins LH and FSH and impairment of reproductive function. Here we studied the expression profile of gonadotropin subunit and GnRH receptor genes in rat pituitary in vitro and in vivo to clarify their expression profiles in the absence and continuous presence of GnRH. Culturing of pituitary cells in GnRH-free conditions downregulated Fshb, Cga, and Gnrhr expression, whereas continuous treatment with GnRH agonists upregulated Cga expression progressively and Gnrhr and Fshb expression transiently, accompanied by a prolonged blockade of Fshb but not Gnrhr expression. In contrast, Lhb expression was relatively insensitive to loss of endogenous GnRH and continuous treatment with GnRH, probably reflecting the status of Egr1 and Nr5a1 expression. Similar patterns of responses were observed in vivo after administration of a GnRH agonist. However, continuous treatment with GnRH stimulated LH secretion in vitro and in vivo, leading to decrease in LH cell content despite high basal Lhb expression. These data suggest that blockade of Fshb expression and depletion of the LH secretory pool are two major factors accounting for weakening of the gonadotroph secretory function during continuous GnRH treatment.

Highlights

Mammalian reproduction depends on proper synthesis and release of two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), by specialized endocrine cells of the anterior pituitary named gonadotrophs[1]
There was an initial deep inhibition in Fshb expression followed by a partial recovery of expression (B), and a progressive inhibition of Cga (C) and Gnrhr expression (D)
These results show that expression of Lhb was relatively insensitive to loss of endogenous gonadotropin-releasing hormone (GnRH), in contrast to Fshb, Cga, and Gnrhr expression

Summary

Introduction

Mammalian reproduction depends on proper synthesis and release of two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), by specialized endocrine cells of the anterior pituitary named gonadotrophs[1] These hormones are dimeric glycoproteins composed of a common glycoprotein hormone, α polypeptide (Cga) and unique β subunits (Lhb and Fshb) that confer biological specificity[2]. The gonadotroph subunit genes, Cga, Fshb, and Lhb, exhibit basal and regulated expression, and it has been shown that they are stimulated by pulsatile GnRH application[1]. Shupnik’s group observed stimulation of Fshb and Lhb transcription in static cultures of pituitary fragments from female rats during the first 6 h continuous application of GnRH, but they did not detect inhibition of basal expression of these genes[18]. Our results indicate that continuous GnRH application progressively stimulates Cga expression, blocks Fshb expression after a transient stimulation, and causes a profound effect on LH secretion without major effects on Lhb expression

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