title: Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia.
abstract: BACKGROUND
  Bilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia. We examined the abnormal production of corticotropin in these hyperplastic adrenal glands.
  
  
  METHODS
  We obtained specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease. The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed by means of a polymerase-chain-reaction assay and immunohistochemical analysis. The production of corticotropin and cortisol was assessed in 11 specimens with the use of incubated explants and cell cultures coupled with hormone assays. Corticotropin levels were measured in adrenal and peripheral venous blood samples from 2 patients.
  
  
  RESULTS
  The expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue. Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens. Adrenal corticotropin levels were higher in adrenal venous blood samples than in peripheral venous samples, a finding that was consistent with local production of the peptide within the hyperplastic adrenals. The release of adrenal corticotropin was stimulated by ligands of aberrant membrane receptors but not by corticotropin-releasing hormone or dexamethasone. A semiquantitative score for corticotropin immunostaining in the samples correlated with basal plasma cortisol levels. Corticotropin-receptor antagonists significantly inhibited in vitro cortisol secretion.
  
  
  CONCLUSIONS
  Cortisol secretion by the adrenals in patients with macronodular hyperplasia and Cushing's syndrome appears to be regulated by corticotropin, which is produced by a subpopulation of steroidogenic cells in the hyperplastic adrenals. Thus, the hypercortisolism associated with bilateral macronodular adrenal hyperplasia appears to be corticotropin-dependent. (Funded by the Agence Nationale de la Recherche and others.).
authors.affiliation: From INSERM Unité 982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, Institute for Research and Innovation in Biomedicine, and Rouen University, Mont-Saint-Aignan (E.L., C.D., S.R., M.T.N., I.B., Z.B., J-.M.K., Y.A., H.L.), the Department of Endocrinology, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), University Paris Sud, INSERM Unité 693, Le Kremlin-Bicêtre (J.Y.), INSERM Unité 1016, Institut Cochin (R.L., L.G., X.B., J.B.), the Department of Endocrinology AP-HP, Hôpital Cochin (L.G., X.B., J.B.), Université Paris Descartes (L.G., X.B., J.B.), Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104 (L.G., X.B., J.B.), and the Department of Endocrinology, Hôpital Saint-Antoine, AP-HP (S.C.-M.), Paris; the Department of Endocrinology and Metabolic Diseases, Centre Hospitalier Universitaire Larrey, Toulouse (P.C.); the Department of Endocrinology, Hôpital Haut Lévêque, Centre Hospitalier Universitaire de Bordeaux, Pessac (A.T.); Service de Médecine Interne et Nutrition, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg (F.G.); and the Department of Endocrinology, Diabetes, and Metabolic Diseases, Rouen University Hospital, Rouen (J.M.K., H.L.) - all in France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Louiset
authors.forename: Céline
authors.initials: C
authors.lastname: Duparc
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.forename: Sylvie
authors.initials: S
authors.lastname: Renouf
authors.forename: Milène
authors.initials: M
authors.lastname: Tetsi Nomigni
authors.forename: Isabelle
authors.initials: I
authors.lastname: Boutelet
authors.forename: Rossella
authors.initials: R
authors.lastname: Libé
authors.forename: Zakariae
authors.initials: Z
authors.lastname: Bram
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.forename: Philippe
authors.initials: P
authors.lastname: Caron
authors.forename: Antoine
authors.initials: A
authors.lastname: Tabarin
authors.forename: Fabienne
authors.initials: F
authors.lastname: Grunenberger
authors.forename: Sophie
authors.initials: S
authors.lastname: Christin-Maitre
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Kuhn
authors.forename: Youssef
authors.initials: Y
authors.lastname: Anouar
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Hervé
authors.initials: H
authors.lastname: Lefebvre
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000097:blood / Q000378:metabolism*; D000328:Adult; D000368:Aged; D003480:Cushing Syndrome / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D012333:RNA, Messenger; D005749:Gastric Inhibitory Polypeptide; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone