In vivo and in vitro effects of AVP and V_1a receptor antagonist on Cushing's syndrome due to ACTH‐independent bilateral macronodular adrenocortical hyperplasia

Abstract

We examined the possibility that AVP and V1a receptors were involved in regulating cortisol production in a 49 year old man with ACTH-independent bilateral macronodular adrenocortical hyperplasia (AIMAH), and investigated the effects of a V1a receptor antagonist. An i.v. injection of a small dose (0.1 or 0.3 U) of AVP, insulin-induced hypoglycaemia, upright posture tests, and oral administration of a V1a receptor antagonist (OPC-21268; 300 mg), and its repeated administration at a dose of 600 mg/day for 8 days were performed. An in vitro study of dispersed cells obtained from resected AIMAH tissue was also conducted. Plasma ACTH, AVP and cortisol levels and 24-h urinary free cortisol excretion were measured in the in vivo studies and cortisol concentrations in incubation media in the in vitro study. Injection of small doses of AVP stimulated cortisol secretion without any elevation of plasma ACTH. Insulin-induced hypoglycaemia caused a rise in plasma AVP followed by an increase in plasma cortisol. Although plasma cortisol levels were not affected by single or repeated administrations of OPC-21268, 24-h urinary free cortisol excretion was significantly decreased by the repeated treatment. In the in vitro study, more cortisol was stimulated by AVP from adrenal cells of the AIMAH tissue than from those of a normal adrenal gland, and this secretion was completely suppressed by OPC-21268. These results suggested that hypersensitivity to AVP may have contributed to overproduction of cortisol in this case of ACTH-independent bilateral macronodular adrenocortical hyperplasia, and may have contributed to its pathogenesis.

Expression of vasopressin receptors in ACTH-independent macronodular bilateral adrenal hyperplasia causing Cushing's syndrome: molecular, immunohistochemical and pharmacological correlates

“…In particular, aberrant expression of vasopressin receptors has been described in some cases of AIMAH responding to physiological stimuli of endogenous vasopressin. In these reports, elevation of plasma AVP provoked by upright posture, insulin-induced hypoglycemia, or hypertonic saline infusion test was followed by an increase in plasma cortisol (Lacroix et al 1997, Daidoh et al 1998, Miyamura et al 2003). An abnormal response of cortisol to injection of AVP or lysine vasopressin (LVP) was also observed (Lacroix et al 1997, Daidoh et al 1998, Miyamura et al 2003, Bertherat et al 2005.…”

MECHANISMS IN ENDOCRINOLOGY: Autocrine/paracrine regulatory mechanisms in adrenocortical neoplasms responsible for primary adrenal hypercorticism

“…Conversely, a non-peptidic V1a antagonist administered orally was found to significantly decrease urinary cortisol level in a patient with an AVP-sensitive AIMAH associated with hypercortisolism (123). Concomitant intra-adrenal AVP production and aberrant expression of functional V1a/V2 receptors in adrenocortical neoplasms strongly suggest that AVP is involved in the physiopathology of hypercorticism.…”

“…The role of AVP in glucocorticoid overproduction has been well documented in patients with overt and subclinical Cushing's syndrome due to unilateral adenoma and bilateral macronodular hyperplasia (95,119,120,121). Abnormal adrenal sensitivity to AVP has been shown in patients who displayed high plasma cortisol responses to injection of AVP or physiological tests modifying plasma AVP levels (water or hypertonic saline absorption) (122,123,124), and exaggerated cortisol responses of adrenocortical cells to AVP have been observed in vitro (95,97,119,120,123). The increased sensitivity of adrenocortical cells to AVP has been ascribed to overexpression of the eutopic V1a receptor subtype (120,125,126,127) and/or expression of ectopic V1b and V2 receptors (127,128,129).…”

ACTH-Independent Hypercorticism in Adrenal Tumors and Adrenocortical Hyperplasia

“…[36][37][38][39][40]46 The same effect was observed with lysine-8-vasopressin, 61 but not with desmopressin (DDAVP, a synthetic V2 receptor agonist alternative for vasopressin). [36][37][38][39][40] Cortisol secretion stimulated by AVP was suppressed by oral administration of SR 49059 38 or OPC-21268, 62 both V1-vasopressin-receptor antagonists, only with patients in a horizontal, supine position. 38 In vitro tests showed that AVP triggered cortisol secretion in a dose-dependent manner using V1-A receptors in both normal adrenocortical cells 59,63 and AIMAH tissues.…”

“…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.…”