Expression of adrenocorticotropin receptor gene in adrenocortical adenomas from patients with Cushing syndrome: Possible contribution for the autonomous production of cortisol

Objective To examine whether inhibition of endogenous adrenocorticotropin (ACTH) secretion in patients with Cushing syndrome affects the expression of the ACTH receptor (ACTH-R) gene in adrenocortical adenoma and attached atrophic normal gland. Summary Background Data ACTH increases adrenal cell growth and steroidogenesis by means of ACTH-R. In vivo and in vitro studies have shown that expression of ACTH-R is upregulated by its own ligand ACTH in several species. In patients with Cushing syndrome resulting from adrenocortical adenoma, there is autonomous production of cortisol from the adenoma. This strongly inhibits endogenous ACTH secretion, giving rise to the speculation that the expression of the ACTH-R gene in these patients is also suppressed. However, previous studies have shown that administration of exogenous ACTH to these patients leads to a further increase in the production of cortisol, suggesting the expression of functional ACTH-R in the adenoma, The authors, therefore, examined the expression of the ACTH-FI gene in these patients. Methods Fourteen patients with Cushing syndrome were studied. Glucocorticoid excess resulting from autonomous production from the adenomas was ascertained, and unilateral adrenalectomy was performed. The levels of ACTH-R and cyto chrome P450 side chain cleavage enzyme (P450scc) mRNAs were determined by Northern blot analysis. The entire coding region of the ACTH-R gene in these patients was sequenced. Results ACTH-R mRNA abundance in the attached atrophic normal adrenals was suppressed and invariably less than that in the normal gland obtained from a patient with renal cancer. How ever, the expression of ACTH-R mRNA was not suppressed in any of the adenomas. Expression of ACTH-R mRNA in the adenomas was four- to sixfold greater than that in the attached atrophic gland. No mutation in the coding sequence of the ACTH-R gene in the adenoma was detected in any of the patients. The mRNA in the adenomas appeared to be translated into functionally active receptor because intramuscular administration of ACTH resulted in significant increases in plasma cortisol before surgery but not 3 months after surgery. In addition, there was a positive linear correlation between the expressions of ACTH-R and P450scc mRNAs in the adenoma tissue. Conclusions Suppressed ACTH secretion in patients with Cushing syndrome results in reduction of the ACTH-R mRNA expression in nonneoplastic adrenocortical cells. However, the regulatory mechanism of ACTH-R expression might be different in adenoma. Persistent expression in the adenoma of ACTH-R alone, even in the absence of ACTH, might result in increased basal adenyl cyclase activity, as observed in the case of thyroid-stimulating hormone receptor, and thereby might play a role in the autonomous production of cortisol.