Food-dependent androgen and cortisol secretion by a gastric inhibitory polypeptide-receptor expressive adrenocortical adenoma leading to hirsutism and subclinical Cushing's syndrome: In vivo and in vitro studies

Aberrant gastric inhibitory polypeptide (GIP) receptor expression in bilate rally hyperplastic adrenals or unilateral adrenal adenomas is a rare form o f adrenal hyperfunction. So far, only few cases have been described. In all these cases, cortisol was the predominant steroid released in a food-depen dent manner, leading to the development of non-ACTH-dependent Gushing's syn drome. In the present study, we describe a novel case of a GIP receptor-exp ressive adrenocortical adenomatous nodule, detected incidentally by compute d tomography scanning in a 41-yr-old lady with hirsutism but no clinical si gns of Gushing's syndrome, on physical examination. Hormonal investigations in morning fasting samples showed slightly elevated androgen levels, low-n ormal 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 possibili ty of an aberrant stimulation of cortisol production by the adrenal tumor. Further studies demonstrated food-dependent secretion of cortisol, which wa s abolished by prior octreatide administration. Notably, substantial amount s of adrenal androgens were also secreted after food consumption. Removal o f the tumor resulted in undetectable cortisol and androgen levels that did not respond to food consumption. Histological examination of the excised tu mor revealed an adrenocortical adenomatous nodule originating from the inne r zona reticularis, consisting mainly of compact cells. A steroidogenic sec retory pattern, indicating the concomitant release of adrenal androgens and cortisol, was also observed in. vitro from tumor cells cultured in the pre sence of GIP. The in vitro secretory response to GIP was higher for the adr enal androgen DHEA, compared with cortisol. The expression of the GIP recep tor in tumor cells, but not in the adjacent normal adrenal, was demonstrate d by RT-PCR), using specific oligonucleotide probes for this receptor. In summary, we describe a patient with a GIP-expressive cortisol and androg en oversecreting adrenocortical nodule with the unusual presentation of hir sutism and not the typical clinical signs of Cushing's syndrome. It is of n ote that food intake in this patient provoked a substantial increase in bot h 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 i nvolve cells of a zona fasciculata phenotype, as previously reported, but m ay also occur in other types of differentiated adrenocortical cells.