Endocrine Abstracts

The mechanisms regulating cortisol production when ACTH of pituitary origin is suppressed in primary adrenal causes of Cushing’s syndrome (CS) include diverse genetic and molecular mechanisms. These can lead either to constitutive activation of the cAMP system and steroidogenesis or to its regulation exerted by the aberrant adrenal expression of several hormone receptors, particularly G-protein coupled hormone receptors (GPCR) and their ligands. Screening for aberrant expression of GPCR in bilateral macronodular adrenal hyperplasia (BMAH) and unilateral adrenal adenomas of patients with overt or subclinical CS demonstrates the frequent co-expression of several aberrant receptors. In addition, the aberrant GPCR can also exert their activity by regulating the paracrine secretion of ACTH or other ligands for those receptors in BMAH or unilateral tumors. The molecular mechanisms underlying the abnormal tissue-specific expression of the aberrant GPCR remains unclear but may be secondary to dedifferentiation of progenitor cells at the origin of hyperplasia or tumors or to specific genetic alterations. The aberrant expression of hormone receptors is not limited to primary adrenal CS but can be implicated in other endocrine tumors including primary aldosteronism (aldosteronoma or bilateral idiopathic hyperaldosteronism) and Cushing’s disease. Targeted therapies to block the aberrant receptors or their ligands have been effective in selected limited cases to date, but development of novel specific antagonists could become useful in the future.