Food-Dependent Androgen and Cortisol Secretion by a Gastric Inhibitory Polypeptide-Receptor Expressive Adrenocortical Adenoma Leading to Hirsutism and Subclinical Cushing’s Syndrome:In Vivoandin VitroStudies

Abstract

Aberrant gastric inhibitory polypeptide (GIP) receptor expression in bilaterally hyperplastic adrenals or unilateral adrenal adenomas is a rare form of adrenal hyperfunction. So far, only few cases have been described. In all these cases, cortisol was the predominant steroid released in a food-dependent manner, leading to the development of non-ACTH-dependent Cushing's syndrome. In the present study, we describe a novel case of a GIP receptor-expressive adrenocortical adenomatous nodule, detected incidentally by computed tomography scanning in a 41-yr-old lady with hirsutism but no clinical signs of Cushing's syndrome, on physical examination. Hormonal investigations in morning fasting samples showed slightly elevated androgen levels, low-normal baseline cortisol, normal suppression of cortisol after dexamethasone administration, and ACTH levels that were not suppressed and did stimulate after CRH administration. The elevated urinary free cortisol excretion, in conjunction with an atypical cortisol diurnal rhythm, raised the possibility of an aberrant stimulation of cortisol production by the adrenal tumor. Further studies demonstrated food-dependent secretion of cortisol, which was abolished by prior octreotide administration. Notably, substantial amounts of adrenal androgens were also secreted after food consumption. Removal of the tumor resulted in undetectable cortisol and androgen levels that did not respond to food consumption. Histological examination of the excised tumor revealed an adrenocortical adenomatous nodule originating from the inner zona reticularis, consisting mainly of compact cells. A steroidogenic secretory pattern, indicating the concomitant release of adrenal androgens and cortisol, was also observed in vitro from tumor cells cultured in the presence of GIP. The in vitro secretory response to GIP was higher for the adrenal androgen DHEA, compared with cortisol. The expression of the GIP receptor in tumor cells, but not in the adjacent normal adrenal, was demonstrated by RT-PCR), using specific oligonucleotide probes for this receptor. In summary, we describe a patient with a GIP-expressive cortisol and androgen oversecreting adrenocortical nodule with the unusual presentation of hirsutism and not the typical clinical signs of Cushing's syndrome. It is of note that food intake in this patient provoked a substantial increase in both adrenal androgen and cortisol levels that, together with the histological appearance of this nodule, was compatible with a zona reticularis-derived tumor. Thus, aberrant expression of the GIP receptor does not exclusively involve cells of a zona fasciculata phenotype, as previously reported, but may also occur in other types of differentiated adrenocortical cells.

The Aberrant Expression of the Gastric Inhibitory Polypeptide (GIP) Receptor in Adrenal Hyperplasia: Does Chronic Adrenocorticotropin Exposure Stimulate Up-Regulation of GIP Receptors in Cushing’s Disease?

“…This lack of suppression of pituitary ACTH and responsiveness to CRH has previously been reported in at least two other cases of food-dependent Cushing's syndrome, and perhaps indicates that the intermittent nature of food-induced cortisol secretion does not always result in complete suppression of the hypothalamic-pituitary-adrenal axis (16,24). In the first case, CRH had no significant effect on cortisol production in vitro, suggesting that the in vivo CRH response is mediated through ACTH (24).…”

“…However, a number of sporadic and familial cases of adrenal Cushing's syndrome have been attributed to expression of hormone receptors other than the ACTH receptor, leading to cAMP accumulation and cortisol release (8 -11). This syndrome, often associated with ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH) but sometimes with a unilateral adenoma, has been most frequently associated with the aberrant expression of receptors for gastric inhibitory peptide (GIP) (12)(13)(14)(15)(16). GIP rises postprandially, which results in inappropriate postprandial cortisol release in the syndrome of food-dependent Cushing's syndrome.…”

Ectopic Expression of the Gastric Inhibitory Polypeptide Receptor Gene Is a Sufficient Genetic Event to Induce Benign Adrenocortical Tumor in a Xenotransplantation Model

“…It is noteworthy that the transplanted animals with GIPR cells had detectable ACTH levels. This lack of suppression of pituitary ACTH had previously been reported in the documented cases of food-dependent CS and might indicate that the discontinuous elevation of plasma GIP levels inducing cortisol secretion does not always result in complete suppression of the hypothalamic-pituitary-adrenal axis (18,21,36).…”

Aberrant cortisol responses to physiological stimuli in patients presenting with bilateral adrenal incidentalomas

“…These illicit receptors were originally implicated in the pathogenesis of ACTH-independent macronodular adrenal hyperplasia (AIMAH) associated with clinically overt Cushing's syndrome. Subsequently, aberrant receptor expression has been implicated in an increasing number of different entities including unilateral cortisol-producing adenomas associated both with overt or subclinical Cushing's syndrome [5][6][7][8], unilateral aldosteronomas and even pure androgen-producing adenomas [9]. Aberrant cortisol responses were also found in a substantial proportion of patients with incidentally detected bilateral lesions associated with subclinical hypercortisolism (SH) [10][11][12].…”