Glucocorticoids Regulate Pituitary Growth Hormone-Releasing Hormone Receptor Messenger Ribonucleic Acid Expression*

Abstract

Glucocorticoids regulate GH synthesis and secretion by influencing both hypothalamic and pituitary function. With respect to GH-releasing hormone (GHRH), an important GH secretagogue, glucocorticoids are reported not only to suppress hypothalamic GHRH expression but also to augment pituitary responsiveness to GHRH. To investigate further this latter observation, we have determined the effects of this steroid on expression of the GHRH receptor (GHRH-R) gene in the rat pituitary in vivo and in pituitary cells in vitro. Adult male rats were adrenalectomized or sham operated and treated with sc implants of cholesterol or corticosterone. Adrenalectomized animals showed substantially reduced pituitary GHRH-R mRNA levels, when compared with untreated sham-operated animals. Conversely, administration of corticosterone increased pituitary GHRH-R mRNA levels in intact, as well as adrenalectomized rats. We also analyzed the effects of the synthetic glucocorticoid, dexamethasone, on GHRH-R mRNA expression in cultured rat anterior pituitary cells. GHRH-R mRNA was significantly increased by dexamethasone, with a maximal response observed in the presence of 100 nM hormone. This dose of dexamethasone substantially elevated GHRH-R mRNA after 6 h, 12 h, and 24 h of treatment. Dexamethasone did not increase GHRH-R mRNA in the presence of the transcriptional inhibitor actinomycin D, indicating that the predominant effect of the hormone is to increase transcription of the GHRH-R gene. These data demonstrate that GHRH-R mRNA levels are directly stimulated by glucocorticoids, both in the presence and absence of hypothalamic influences, providing a probable explanation for the ability of this steroid to alter pituitary responsiveness to GHRH. (Endocrinology 138: 2458 -2465, 1997) G H SYNTHESIS and secretion is regulated predominantly by the opposing actions of the stimulatory hypothalamic peptide GH-releasing hormone (GHRH) and the inhibitory peptide SS (1, 2). These hormones exert their actions on the somatotrope cells of the anterior pituitary by interacting with specific membrane receptors. Recently, cDNAs for the GHRH receptor (GHRH-R) were cloned and characterized from several mammalian species (3-7). These receptors are members of a growing subfamily of G proteincoupled receptors whose ligands are structurally related peptide hormones (8 -10). The interaction of GHRH with its receptor activates adenylate cyclase through a G proteincoupled pathway, increasing the levels of the second messenger cAMP (3, 9, 10). The critical role of the GHRH-R in stimulating GH release is apparent in the little mouse, a dwarf phenotype resulting from a point mutation in the amino-terminal domain of the protein (4, 9, 10) that leads to loss of receptor function. More recently, human GH deficiency has been associated with a nonsense mutation in the amino-terminal domain of the GHRH-R (11).Corticosteroids are important physiological regulators of GH synthesis and secretion (12). In general, glucocorticoids exert a suppressive effect on the G...

A Composite Hormone Response Element Regulates Transcription of the Rat GHRH Receptor Gene

“…Because the promoter activity was extremely low when the transfected cells were cultured in a serum free defined medium, the expression of this gene requires additional factors other than just pit-1, which has been demonstrated to be a prerequisite for GHRH-R expression in mice (10), rats (22), and humans (23). The present results are in agreement with the previous studies (6,(11)(12)(13)(14)(15)31) showing that glucocorticoids, T 3 , and RAs are involved in the GHRH-R gene expression, and the DEX acts synergistically with T 3 or RAs with respect to the GHRH-R mRNA accumulation in GH cells. Therefore, it is strongly suggested that the up-regulation of the rat GHRH-R mRNA levels by these hormones is a results of increased transcription rate of this gene.…”

“…Glucocorticoids (6,(11)(12)(13)(14)(15), T 3 (14,16), and GHRH (17,18) have been shown to up-regulate GHRH-R mRNA expression, whereas estrogens have been shown to down-regulate the expression of the mRNA (13). This down-regulation by estrogen was postulated to account in part for the sexual dimorphic expression of GH.…”

Structure and Regulation of the Human Growth Hormone-Releasing Hormone Receptor Gene

“…Miller and Mayo (64) describe decreased GHRH-R mRNA levels in adrenalectomized rats that increase after corticosterone treatment. GHRH-R expression is elevated in anterior pituitary cells after treatment with dexamethasone (64,65), suggesting a direct effect of glucocorticoids on GHRH-R expression at the level of the pituitary. Lam et al (66) demonstrated increased GHRH-R mRNA levels in dexamethasone-treated rats.…”

Functional maturation of growth hormone cells in the anterior pituitary gland of the fetus

“…The expression of GHRH-receptor gene is also induced by glucocorticoids in the fetal pituitary gland [10]. A number of humoral factors are reported to upregulate GHRH-receptor mRNA expression in the pituitary gland of adult rats, such as thyroid hormone [58][59][60][61], glucocorticoids [10,[62][63][64] and estrogens [62]. GHRH is also implicated in the regulation of its own receptor, and is reported to be either a stimulator [65,66] or a suppressor of GHRH-receptor mRNA expression [67].…”