Glucocorticoid action in the anterior pituitary gland: Insights from corticotroph physiology

Abstract

The anterior pituitary is exposed to ultradian, circadian and stress-induced rhythms of circulating glucocorticoid hormones. Glucocorticoids feedback at the level of the pituitary corticotroph to control their own production through multiple mechanisms. This review highlights key insights from analysis of the dynamics of rapid and early glucocorticoid feedback that reveal both non-genomic and genomic mechanisms mediated by glucocorticoid receptors. Importantly, a common target is control of electrical excitability and calcium signalling although non-genomic effects may also involve control of hormone secretion distal to calcium signalling. Understanding the mechanisms and functional consequences of pulsatile glucocorticoid signalling in the anterior pituitary promises to elucidate the role of glucocorticoids in health and disease, as well as identifying potential diagnostic and therapeutic targets.

Keywords: AVP, Arginine vasopressin; CORT, corticosterone; CRH, Corticotrophin releasing hormone; HPA axis, Hypothalamic pituitary adrenal axis.

Figure 1

Dynamics of glucocorticoid output of the HPA axis.a) Schematic of the key components of the hypothalamic -pituitary-adrenal (HPA) axis. Corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) are the major hypothalamic neuropeptides that stimulate corticotrophs to release adrenocorticotrophic hormone (ACTH) that stimulates glucocorticoid (CORT: cortisol in man, corticosterone in rodents) from the adrenal gland. CORT feedback at the anterior pituitary and hypothalamic level control output of the HPA axis. b) Plasma levels of glucocorticoids display an ultradian rhythm (approximately 1 pulse per hour) and circadian rhythm. In response to acute stress plasma glucocorticoids are elevated with the amplitude and time course dependent on the type and duration of stressor. c) Different time domains of glucocorticoid regulation of the anterior pituitary corticotrophs.

Figure 2

Mechanisms of rapid and early glucocorticoid feedback inhibition of ACTH secretion from anterior pituitary corticotrophs. CRH and AVP activate distinct G-protein coupled receptors linked to the cAMP/PKA and DAG/PKC pathways, respectively that control membrane excitability and calcium influx via regulation of a diverse array of ion channels. Early glucocorticoid inhibition involves glucocorticoid receptor (GR) activation of gene transcription resulting in induction of glucocorticoid induced proteins (GIP). These proteins largely act downstream of cAMP/PKA and PKC signalling to control membrane excitability and calcium influx, although additional pathways may be involved. Two non-genomic pathways have been described, including a rapid cell autonomous pathway and a paracrine pathway involving control of annexin1 (ANXA1) release from folliculostellate (FS) cells. Mechanisms underlying rapid inhibition are unknown but have been proposed to be distal to calcium influx.