title: In vivo and in vitro screening for illegitimate receptors in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing's syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism.
abstract: In ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing Cushing's syndrome, cortisol production can be controlled by illegitimate membrane receptors. The aim of the present study was to evaluate in vivo and in vitro the sensitivity of AIMAH to various regulatory factors to detect the expression of illegitimate receptors by the tissues. Four consecutive patients with AIMAH and hypercortisolism (H1-H4) preoperatively underwent a series of pharmacological and/or physiological tests. After adrenalectomy, in vitro studies were conducted to investigate the cortisol responses of cultured cells, derived from hyperplastic tissues, to various membrane receptor ligands. The adrenal tissues of the two patients who responded in vivo to food intake (H2 and H4) were stimulated in vitro by gastric inhibitory polypeptide. GnRH and human chorionic gonadotropin, but not FSH, stimulated cortisol secretion in patients H2 and H4. In these two cases, human chorionic gonadotropin but not GnRH stimulated cortisol production from cultured adrenocortical cells. Cisapride induced a significant increase in cortisol levels in patient H1. In addition, serotonin (5-HT) was more efficient to stimulate cortisol production in H1 cells than in normal adrenocortical cells. Upright stimulation test provoked an increase in cortisol levels in patients H1, H2, and H3. H1 and H2 cells were more sensitive to the stimulatory action of angiotensin II than normal cells. Similarly, arginine vasopressin (AVP) more efficiently activated steroidogenesis in H1 cells than in normal cells. In H1 tissue, immunohistochemical studies revealed the presence of 5-HT- and AVP-like immunoreactivities within clusters of steroidogenic cells, suggesting that these two factors acted through an autocrine/paracrine mechanism to stimulate cortisol secretion. The present study provides the first demonstration of primary adrenal Cushing's syndrome dependent on both gonadotropin and gastric inhibitory polypeptide. Our data also show a hyperresponsiveness of hyperplastic adrenal tissues to 5-HT, angiotensin II, and AVP. Finally, they reveal for the first time the presence of paracrine regulatory signals in adrenal hyperplasia tissues.
authors.affiliation: Institut Fédératif de Recherche Multidisciplinaires sur les Peptides 23, Institut National de la Santé et de la Recherche Médicale U413, Department of Endocrinology, Hospital of Boisguillaume, Centre Hospitalier Universitaire of Rouen, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bertherat
authors.forename: Vincent
authors.initials: V
authors.lastname: Contesse
authors.forename: Estelle
authors.initials: E
authors.lastname: Louiset
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Barrande
authors.forename: Céline
authors.initials: C
authors.lastname: Duparc
authors.forename: Lionel
authors.initials: L
authors.lastname: Groussin
authors.forename: Philippe
authors.initials: P
authors.lastname: Emy
authors.forename: Xavier
authors.initials: X
authors.lastname: Bertagna
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Kuhn
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
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; D000328:Adult; D001127:Arginine Vasopressin / Q000378:metabolism; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000378:metabolism* / Q000494:pharmacology; D020117:Cisapride / Q000008:administration & dosage; D003480:Cushing Syndrome / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism*; D004435:Eating; D005260:Female; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism*; D007987:Gonadotropin-Releasing Hormone / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008875:Middle Aged; D011187:Posture; D011956:Receptors, Cell Surface / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage; D015398:Signal Transduction
chemical_list: D006063:Chorionic Gonadotropin; D011956:Receptors, Cell Surface; D017366:Serotonin Receptor Agonists; D001127:Arginine Vasopressin; D012701:Serotonin; D007987:Gonadotropin-Releasing Hormone; D005749:Gastric Inhibitory Polypeptide; D000324:Adrenocorticotropic Hormone; D020117:Cisapride; D006854:Hydrocortisone