Assessing the Presence of Abnormal Regulation of Cortisol Secretion by Membrane Hormone Receptors:In VivoandIn VitroStudies in Patients with Functioning and Non-functioning Adrenal Adenoma

Abstract

Regulation of cortisol secretion by aberrant hormone receptors may play a role in the pathogenesis of ACTH-independent Cushing's syndrome. In this study, the topic was evaluated by combining in vivo and in vitro approaches. Cortisol responses to various stimuli (standard meal, GnRH + TRH, cisapride, vasopressin, glucagon) were assessed in 6 patients with clinical or subclinical adrenal Cushing's syndrome, and non-functioning adrenal adenoma in two cases. Abnormal responses were observed in three patients with Cushing's syndrome; one patient showed a gastric inhibitory polypeptide (GIP)-dependent cortisol rise after meal, together with responses after GnRH and cisapride; the second patient showed an LH-dependent cortisol response to GnRH, and in the third cortisol rose after cisapride. The pattern of receptor expression performed by RT-PCR showed that while GIP-R was only expressed in tumor from the responsive patient, 5-hydroxytryptamine type 4 receptor and LH-R were also present in normal adrenal tissues and tissues from non-responsive patients. Interestingly, an activating mutation of Gsalpha gene was identified in one of these tumors. Therefore, cortisol responses to agents operating via Gs protein coupled receptors (in one case associated with Gsalpha mutation) were found in Cushing's patients, while these responses were absent in the others. The finding of receptor expression in normal and non-responsive tumors suggests that different mechanisms are probably involved in inducing in vivo cortisol responses.

ACTH-Independent Hypercorticism in Adrenal Tumors and Adrenocortical Hyperplasia

“…47,69 The GIP receptor was found to be overexpressed in the adenoma tissue. 47,68,69 Since the GIP receptors are apparently coupled to the cAMP-dependent protein kinase A (AC/PKA) signaling pathway, the PKA inhibitor H-89 suppressed spontaneous cortisol production in cultured AIMAH cells. 44 Activation of GIP receptors reduced the amplitude of both transient and sustained K + currents but enhanced T-type Ca 2+ current, 44 in which both currents contributed to the depolarization of the cell and entry of Ca 2+ as part of the steroidogenic response.…”

“…73 The growth hormone inhibitor octreotide, GCG, and insulin suppressed cortisol production in some patients with Cushing's syndrome and 92% of the patients with subclinical Cushing's syndrome in this study. 68,72 Human chorionic gonadotropin stimulated cortisol production in vivo 48 and in AIMAH cell cultures, 42,47 demonstrating that an effect coupled to AC/PKA pathway. 44 Luteinizing hormone (LH) stimulated cortisol production in vivo 48 and LH receptors were identified in cultured cells, 40,47,48 which can be indirectly induced by gonadotropin-releasing hormone in vivo.…”

“…68,72 Human chorionic gonadotropin stimulated cortisol production in vivo 48 and in AIMAH cell cultures, 42,47 demonstrating that an effect coupled to AC/PKA pathway. 44 Luteinizing hormone (LH) stimulated cortisol production in vivo 48 and LH receptors were identified in cultured cells, 40,47,48 which can be indirectly induced by gonadotropin-releasing hormone in vivo. 43,47 In addition, sex hormones such as estradiol (E2) have been shown to increase cortisol through ACTH in female animals.…”

“…67 Patients with food-dependent Cushing's syndrome experienced symptoms of low fasting plasma cortisol levels but increased cortisol levels induced by a meal, glucose administered orally, 43,47,50,68,69 or responded to GIP stimulation in a dosedependent fashion. 43,62 The meals can be standard, 47 lipid rich, or protein rich 70 for patients with nodular adrenal hyperplasia 50,68,70 or unilateral adrenocortical adenoma. 47,69 The GIP receptor was found to be overexpressed in the adenoma tissue.…”

“…43,62 The meals can be standard, 47 lipid rich, or protein rich 70 for patients with nodular adrenal hyperplasia 50,68,70 or unilateral adrenocortical adenoma. 47,69 The GIP receptor was found to be overexpressed in the adenoma tissue. 47,68,69 Since the GIP receptors are apparently coupled to the cAMP-dependent protein kinase A (AC/PKA) signaling pathway, the PKA inhibitor H-89 suppressed spontaneous cortisol production in cultured AIMAH cells.…”