Recent studies have demonstrated that most genetically-determined adrenal lesions responsible for Cushing's syndrome display abnormal cell differentiation resulting in the development of paracrine regulation loops that favor cortisol hypersecretion. In bilateral adrenal macronodular hyperplasia tissues, the causative gene mutations appear to lead to pseudo-gonadal differentiation of a subpopulation of adrenocortical cells, resulting in aberrant ACTH synthesis. In primary pigmented adrenocortical disease (PPNAD) and in some cortisol-secreting adenomas, activation of the protein kinase A (PKA) pathway is directly responsible for upregulation of the serotonergic signaling pathway . These original observations provide new insights into the pathophysiology of primary adrenal Cushing's syndrome. They also suggest that illicit intraadrenal paracrine regulatory mechanisms may be regarded as valuable targets for new pharmacological treatments of hypercortisolism. These original therapeutic approaches could represent valuable alternatives to adrenal surgery and the currently used anticortisolic drugs which are responsible for various side-effects.
Key Words
Cushing's syndrome, hypercortisolism, adrenocorticotropic hormone (ACTH), adrenal hyperplasia , serotonin