An Adolescent with Food-Dependent Cushing's Syndrome Secondary to Ectopic Expression of GIP Receptor in Unilateral Adrenal Adenoma

Abstract

ACTH-independent Cushing's syndrome may be secondary to the expression of ectopic hormone receptors in adrenal tissue. In food-dependent Cushing's syndrome the adrenals aberrantly express receptors for gastric inhibitory polypeptide (GIP). We present the first case of food- and GIP-dependent adrenal adenoma in an adolescent. A 15 year-old girl presented with signs of hypercortisolism. Urinary cortisol excretion was clearly elevated. Upon the finding of very low fasting plasma cortisol levels with a rise during the morning, food-dependent cortisol secretion was suspected. Hourly measurements of plasma cortisol and GIP levels during a day with and a day without meals showed meal- and GIP-related cortisol secretion. Plasma ACTH levels were undetectable. Abdominal computed tomography showed a tumor of 2.5 x 2.5 x 2 cm in the left adrenal. Unilateral adrenalectomy was performed and microscopic examination of the tumor showed an adrenocortical adenoma. Incubation of adenomatous cells prepared from this tumor with GIP resulted in increased cortisol secretion. Using RT-PCR amplification and cDNA hybridization, the GIP receptor was found to be overexpressed in the adenoma tissue but not in the adjacent adrenal tissue. Twelve months after the operation, hourly measurements of plasma cortisol, GIP and ACTH levels on a day with and a day without meals no longer showed GIP-related cortisol production. The present report shows that in an adolescent with corticotrophin-independent Cushing's syndrome, food-dependent hypercortisolism is a possible diagnosis.

ACTH-Independent Hypercorticism in Adrenal Tumors and Adrenocortical Hyperplasia

“…66 GIP level is elevated after the ingestion of fat-rich and glucose-rich meals. 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.…”

“…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.…”

“…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.…”

Expression profiles of the glucose-dependent insulinotropic peptide receptor and LHCGR in sporadic adrenocortical tumors

“…GIPR is expressed in human pancreatic b-cells but not in normal adrenocortical tissue (Lacroix et al 1992, Chabre et al 1998, Lebrethon et al 1998. During the last decade, aberrant GIPR expression was demonstrated in ACTH-independent macronodular adrenal hyperplasia and adrenocortical adenomas (Reznik et al 1992, Chabre et al 1998, Lebrethon et al 1998, Luton et al 1998, N'Diaye et al 1998, 1999, Tsagarakis et al 2001, Noordam et al 2002. More recently, overexpression has also been shown in the adrenals of patients with Cushing's disease and in primary pigmented nodular adrenocortical disease (Swords et al 2005).…”

Analysis of the putative regulatory region of the gastric inhibitory polypeptide receptor gene in food-dependent Cushing’s syndrome

“…GIP-dependent CS was found to result from the ectopic expression of non-mutated GIPR in adrenal tissues [16][17][18][19][20][21]. So far, at least 24 cases of GIP-dependent CS have been reported, in AIMAH and in unilateral adenomas [12][13][14][15][16][17][18][19][20][21].…”