Negative Regulation of Gonadotropin‐Releasing Hormone and Gonadotropin‐Releasing Hormone Receptor Gene Expression by a Gonadotropin‐Releasing Hormone Agonist in the Rat Hypothalamus

Abstract

There exists evidence for the presence of ultrashort loop feedback circuits of gonadotropin-releasing hormone (GnRH) secretion in the hypothalamus. It is, however, uncertain whether a similar mechanism is involved in the regulation of GnRH gene expression in vivo. Furthermore, little is known about the regulation of GnRH receptor (GnRHR) expression in the brain. In the present study, we examined the regulation of GnRH and its receptor gene expression by GnRH in vivo. A GnRH agonist, [D-Ala6, des-Gly10]GnRH-ethylamide (des-Gly GnRH), was administered by intracerebroventricular (i.c.v.) injection via the lateral ventricle of ovariectomized and estradiol (OVX + E)-treated rats. The amounts of GnRH and GnRHR mRNA were measured in the preoptic area (POA) and posterior mediobasal hypothalamus (pMBH) micropunch samples from individual rat brain slices by respective competitive reverse transcription-polymerase chain reactions. The i.c.v. administration of des-Gly GnRH significantly decreased GnRH and GnRHR mRNA expression in a dose-and time-related manner: des-Gly GnRH (6 ng) suppressed GnRH and GnRHR mRNA expression within 2 h, and the suppression was maintained without significant variation until 8 h after treatment. Treatment with Antide, [N-Ac-D-Nal(2)1, pCl-D-Phe2, D-Pal(3)3, Lys(Nic)5, D-Lys(Nic)6, Lys(iPR)8, D-Ala10]GnRH (10 ng), a potent GnRH antagonist, did not alter GnRH mRNA expression, but prevented des-Gly GnRH-induced suppression of GnRH mRNA expression. Antide alone decreased GnRHR mRNA expression, but failed to alter agonist-induced suppression of GnRHR mRNA expression. These results demonstrate the existence of an ultrashort loop feedback mechanism for GnRH gene expression in the POA, along with homologous down-regulation of GnRHR mRNA expression in the pMBH.

Retention and Silencing of Prepro-GnRH-II and Type II GnRH Receptor Genes in Mammals

“…administration of GnRH-I, GnRH-II, and synthetic GnRH receptor agonists or antagonists correlate with particular brain responses in different species [41,42,43]. For example, GnRH elicits reproductive behaviour in rats, mice, shrews and monkeys (including induction of the lordosis reflex in rodents) [44,45,46,47,48,49,50].…”

Gonadotropin‐releasing hormone: regulation of the GnRH gene

“…Recent studies have revealed GnRH as an autocrine and paracrine regulator of gonadotropins in the hypothalamus and ovary. It has been demonstrated that GnRH‐I gene expression is regulated by itself through an ultrashort loop feedback mechanism in rat hypothalamus [56] and ovarian cells [57]. Also, it has been shown that the GnRH‐I and GnRH‐II genes are differentially regulated by themselves.…”

“…Treatment with an antagonist (antide) prevented this biphasic effect in OSE cells, proving the specificity of the response. Moreover, intracerebroventricular injection of a GnRH‐I analog into the lateral ventricle of rat brain resulted in a considerable decrease in GnRH‐I mRNA levels, in a dose‐ and time‐related manner, as detected in the POA [56]. For GnRH‐II, treatment with different concentrations of the homologous ligand and GnRH‐II analog (10 −11 and 10 −7 m ) in hGLCs resulted in a large decrease in GnRH‐II mRNA levels.…”

“…In vitro studies using GT1-7 cells and hypothalamic tissue cultures, and in vivo studies in a rat ovary model, showed that GnRH-I treatment inhibited the expression and secretion of GnRH-I [56,[58][59][60][61]. In hGLCs, GnRH-I has been shown to be regulated by its own ligand [62].…”

Luteinizing Hormone-Releasing Hormone I (LHRH-I) and Its Metabolite in Peripheral Tissues

“…While the developmental origins of these LHRH-Iproducing cells in the periphery remain to be determined, many of its physiological functions in normal and cancer cells have been identified. A number of studies suggest that LHRH-I might have a diversity of actions or may be associated with a number of functions to include the facilitation of steroidogenesis, cell proliferation, apoptosis, fertilization, embryonic implantation, cell-matrix adhesion, and cell migration (36,39,66,90,106,110). A role for LHRH-I and LHRH-RI in regulating tumor growth has been also identified in human ovarian cancer cells, breast tumor tissues, endometrial carcinoma, and in prostate cancer (93) via an autocrine/paracrine role (52).…”