title: ACTH-independent macronodular adrenocortical hyperplasia reveals prevalent aberrant in vivo and in vitro responses to hormonal stimuli and coupling of arginine-vasopressin type 1a receptor to 11β-hydroxylase.
abstract: BACKGROUND
  Adrenal Cushing's syndrome caused by ACTH-independent macronodular adrenocortical hyperplasia (AIMAH) can be accompanied by aberrant responses to hormonal stimuli. We investigated the prevalence of adrenocortical reactions to these stimuli in a large cohort of AIMAH patients, both in vivo and in vitro.
  
  
  METHODS
  In vivo cortisol responses to hormonal stimuli were studied in 35 patients with ACTH-independent bilateral adrenal enlargement and (sub-)clinical hypercortisolism. In vitro, the effects of these stimuli on cortisol secretion and steroidogenic enzyme mRNA expression were evaluated in cultured AIMAH and other adrenocortical cells. Arginine-vasopressin (AVP) receptor mRNA levels were determined in the adrenal tissues.
  
  
  RESULTS
  Positive serum cortisol responses to stimuli were detected in 27/35 AIMAH patients tested, with multiple responses within individual patients occurring for up to four stimuli. AVP and metoclopramide were the most prevalent hormonal stimuli triggering positive responses in vivo. Catecholamines induced short-term cortisol production more often in AIMAH cultures compared to other adrenal cells. Short- and long-term incubation with AVP increased cortisol secretion in cultures of AIMAH cells. AVP also increased steroidogenic enzyme mRNA expression, among which an aberrant induction of CYP11B1. AVP type 1a receptor was the only AVPR expressed and levels were high in the AIMAH tissues. AVPR1A expression was related to the AVP-induced stimulation of CYP11B1.
  
  
  CONCLUSIONS
  Multiple hormonal signals can simultaneously induce hypercortisolism in AIMAH. AVP is the most prevalent eutopic signal and expression of its type 1a receptor was aberrantly linked to CYP11B1 expression.
authors.affiliation: Department of Internal Medicine, Section of Endocrinology, P,O, Box 2040, Rotterdam, CA, 3000, The Netherlands. j.hofland@erasmusmc.nl.
authors.forename: Johannes
authors.initials: J
authors.lastname: Hofland
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Koetsveld
authors.forename: Jacobie
authors.initials: J
authors.lastname: Steenbergen
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
authors.forename: Casper H
authors.initials: CH
authors.lastname: van Eijck
authors.forename: Ronald R
authors.initials: RR
authors.lastname: de Krijger
authors.forename: Francien H
authors.initials: FH
authors.lastname: van Nederveen
authors.forename: Maarten O
authors.initials: MO
authors.lastname: van Aken
authors.forename: Johannes W
authors.initials: JW
authors.lastname: de Groot
authors.forename: Thera P
authors.initials: TP
authors.lastname: Links
authors.forename: Frank H
authors.initials: FH
authors.lastname: de Jong
authors.forename: Richard A
authors.initials: RA
authors.lastname: Feelders
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000368:Aged; D001127:Arginine Vasopressin / Q000378:metabolism*; D002395:Catecholamines / Q000494:pharmacology; D002478:Cells, Cultured; D003480:Cushing Syndrome / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism*; D005260:Female; D005934:Glucagon / Q000378:metabolism / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008787:Metoclopramide / Q000378:metabolism / Q000494:pharmacology; D008875:Middle Aged; D013252:Steroid 11-beta-Hydroxylase / Q000378:metabolism*; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism / Q000494:pharmacology
chemical_list: D002395:Catecholamines; D001127:Arginine Vasopressin; D007987:Gonadotropin-Releasing Hormone; D013973:Thyrotropin-Releasing Hormone; D000324:Adrenocorticotropic Hormone; D005934:Glucagon; D013252:Steroid 11-beta-Hydroxylase; D008787:Metoclopramide; D006854:Hydrocortisone
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