Some elegant clinical observations of dysregulated cortisol-secretion in cases of ACTH-independent macronodular hyperplasia (AIMAH) and more rarely adrenocortical adenomas (ACA) have led to the concept of aberrant or illegitimate membrane receptors (AR) in adrenal Cushing syndrome. It this situation cortisol secretion is regulated by an extra-cellular ligand that usually does not stimulate cortisol secretion in normal adrenals. This abnormal response might be due to an ectopic expression or overexpression of a receptor. It is also possible that post-receptors signalling alterations play a role in this phenomenon. The most investigated example of AR is the case of food-dependent Cushings syndrome due to illegitimate expression of the GIP receptor. This receptor stimulates intracellular levels of cAMP as does ACTH. Others G-protein-coupled receptors (i.e. receptors for LH/HCG, ß-adrenergic ligands, vasopressine, serotonin …) have been described. In vitro studies have shown that stimulation of these receptors often stimulate cAMP signaling. Ligands of these receptors might circulate from the general circulation, but also, as demonstrated for vasopressine or serotonin, be produced by the adrenal tumor itself. Clinical screening of AIMAH patients have shown that an abnormal response suggestive of the presence of one or several AR is very frequent. In some cases this has been used for targeted therapy of cortisol oversecretion. The list of receptors that could be aberrant might not be yet complete. In vitro studies of cortisol secretion regulation by various ligands as well as gene profiling studies are interesting tools for a systematic extensive screening. The concept of AR raised two interesting issues: 1) its role in the development of cortisol-secreting tumors 2) its pathogenesis. The expression of a functional AR clearly takes part in cortisol dysregulation. However animals studies have shown that ectopic expression of LH/HCG or GIP receptors also stimulates tumor growth. Concerning the mechanisms leading to AR in adrenal Cushings syndrome no genetic alteration of the gene encoding these receptors have been reported so far. Transcriptome studies have shown that the gene expression profile of AIMAH varies according to the type of AR. The genetic study of familial cases of AIMAH with AR might in the future give new insights in the pathogenesis of this disorder.
25 - 29 Apr 2009
European Society of Endocrinology