Ectopic and abnormal hormone receptors in adrenal Cushing's syndrome

The mechanism by which cortisol is produced in adrenal Gushing's syndrome, when ACTH is suppressed, was previously unknown and was referred to as bein g "autonomous." More recently, several investigators have shown that some c ortisol and other steroid-producing adrenal tumors or hyperplasias are unde r the control of ectopic (or aberrant, illicit, inappropriate) membrane hor mone receptors. These include ectopic receptors for gastric inhibitory poly peptide (GIP), beta -adrenergic agonists, or LH/hCG; a similar outcome can result from altered activity of eutopic receptors, such as those for vasopr essin (V1-AVPR), serotonin (5-HT4), or possibly leptin. The presence of abe rrant receptors places adrenal cells under stimulation by a trophic factor not negatively regulated by glucocorticoids, leading to increased steroidog enesis and possibly to the proliferative phenotype. The molecular mechanism s responsible for the abnormal expression and function of membrane hormone receptors are still largely unknown. Identification of the presence of thes e illicit receptors can eventually lead to new pharmacological therapies as alternatives to adrenalectomy, now demonstrated by the long-term control o f ectopic beta -AR- and LH/hCGR-dependent Gushing's syndrome by propanolol and leuprolide acetate. Further studies will potentially identify a larger diversity of hormone receptors capable of coupling to G proteins, adenylyl cyclase, and steroidogenesis in functional adrenal tumors and probably in o ther endocrine and nonendocrine tumors.