Endocrine Abstracts (2012) 29 OC13.3

Cortisol secretion is dependent on intraadrenal production of ACTH in macronodular bilateral adrenal hyperplasia causing Cushing's syndrome

E. Louiset1, C. Duparc1, J. Young2, I. Boutelet1, S. Renouf1, Z. Bram1, L. Groussin3, P. Caron4, A. Tabarin5, F. Grunenberger6, S. Christin-Maitre7, J. Kuhn1,8, Y. Anouar1, J. Bertherat3 & H. Lefebvre1,8

1Institute for Biomedical Research and Innovation, University of Rouen, Rouen, France; 2Kremlin-Bicêtre University Hospital, APHP, Bicêtre, France; 3Cochin University Hospital, APHP, Paris, France; 4CHU de Toulouse - Hôpital Larrey, Toulouse, France; 5CHU de Bordeaux - Hôpital du Haut Lévêque, Pessac, France; 6Hôpital de Hautepierre, CHU de Strasbourg, Strasbourg, France; 7Hôpital Saint-Antoine, APHP, Paris, France; 8Rouen University Hospital, Institute for Biomedical Research and Innovation, Bois Guillaume, France.

Illicit expression of membrane receptors for circulating regulatory factors, such as gastric inhibitory polypeptide (GIP), luteinizing hormone (LH) and serotonin (5-HT) receptors, has been well documented in ACTH-independent macronodular adrenal hyperplasias (AIMAHs) causing Cushing’s syndrome. In addition, we have observed an abnormal expression of ACTH in some steroidogenic cells in two AIMAH tissues. The aim of the present study was to investigate the role of local production of ACTH in the control of steroidogenesis in a series of 30 AIMAH tissues. Expression of pro-opiomelanocortin (POMC) mRNA and ACTH-like immunostaining were detected in all tissues studied. ACTH co-localized with 17-hydroxylase, the HDL-cholesterol receptor SR-B1, prohormone convertase 1 and secretogranin II immunoreactivities in clusters of cells disseminated throughout hyperplasia tissues. Perifusion experiments demonstrated that adrenal slices spontaneously released detectable amounts of ACTH in a pulsatile fashion. ACTH secretion was significantly increased in vitro by GIP, hCG and 5-HT in tissues previously sensitive in vivo to the stimulatory action of food intake, hCG and 5-HT4 receptor agonists. In addition, measurement of ACTH concentrations in plasma obtained from two AIMAH patients during adrenal vein sampling showed a significant ACTH gradient versus periphery indicating that AIMAH tissues actually secrete ACTH in vivo. The ACTH receptor antagonists corticostatin and ACTH(7–38) reduced basal as well as GIP-induced cortisol production from perifused hyperplasia tissues. These data indicate that, in AIMAH tissues, ACTH released by a subpopulation of steroidogenic cells exerts an intraadrenal stimulatory tone on cortisol secretion. They also suggest that macronodular bilateral adrenal hyperplasia may be regarded as a cause of ACTH-dependent Cushing’s syndrome due to ectopic expression of corticotropin within the adrenal cortex. This work was supported by grants from INSERM, University of Rouen, Assistance Publique des Hôpitaux de Paris, the COMETE network, the Société Française d’Endocrinologie and Novo Nordisk Laboratory.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however funding details are unavailable.