title: Luteinizing hormone (LH)-responsive Cushing's syndrome: the demonstration of LH receptor messenger ribonucleic acid in hyperplastic adrenal cells, which respond to chorionic gonadotropin and serotonin agonists in vitro.
abstract: In a substantial part of adrenal adenomas and hyperplasias from patients with Cushing's syndrome, cortisol production is controlled by the expression of aberrant hormone receptors on adrenocortical cells. We present in vivo and in vitro data of two patients with a LH-responsive Cushing's syndrome based on ACTH-independent bilateral adrenal hyperplasia. Patients 1 and 2 are women who presented with Cushing's syndrome and bilateral adrenal hyperplasia. Endocrine testing demonstrated absence of cortisol diurnal rhythm, insufficient cortisol suppression after 1 mg dexamethasone orally, and undetectable ACTH levels in both patients. Both patients were treated by laparoscopic biadrenalectomy. In in vivo testing, in patients 1 and 2, a profound cortisol rise was found after administration of GnRH [change in cortisol (Delta F), 118 and 106%, respectively], human CG (Delta F, 133 and 44%), LH (Delta F, 73 and 43%), ACTH (Delta F, 89 and 181%), and the 5-hydroxy-tryptamine receptor type 4 (5-HT(4)) agonists cisapride (Delta F, 141 and 148%) and metoclopramide (Delta F, 189 and 95%). In in vitro testing, adrenal cells from patient 2 responded, in a dose-dependent fashion, with cortisol production after exposure to human CG (Delta F, 45%), cisapride (Delta F, 68%), and metoclopramide (Delta F, 81%). ACTH induced cortisol production by cells from both patients (Delta F, 135 and 159%). In receptor studies, LH receptor mRNA was demonstrated in adrenal tissue of both patients but also in control adrenal tissue of two patients with persisting pituitary-dependent Cushing's syndrome treated by biadrenalectomy. In neither patient were mutations found in the ACTH receptor gene. LH-responsive Cushing's syndrome associated with bilateral adrenal hyperplasia may result from aberrant (or possibly increased) adrenal LH receptor expression. This variant is further characterized by adrenal responsiveness to 5-HT4 receptor agonists, possibly pointing to an interaction between LH and serotonin in the regulation of cortisol secretion. Despite the regulatory potential of LH and 5-HT4 receptor agonists on cortisol production in our patients, their adrenals seemed to be still sensitive to ACTH, both in vivo and in vitro.
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands. feelders@inw3.azr.nl
authors.forename: Richard A
authors.initials: RA
authors.lastname: Feelders
authors.forename: Steven W J
authors.initials: SW
authors.lastname: Lamberts
authors.forename: Leo J
authors.initials: LJ
authors.lastname: Hofland
authors.forename: Peter M
authors.initials: PM
authors.lastname: van Koetsveld
authors.forename: Miriam
authors.initials: M
authors.lastname: Verhoef-Post
authors.forename: Axel P N
authors.initials: AP
authors.lastname: Themmen
authors.forename: Frank H
authors.initials: FH
authors.lastname: de Jong
authors.forename: H Jaap
authors.initials: HJ
authors.lastname: Bonjer
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Clark
authors.forename: Aart-Jan
authors.initials: AJ
authors.lastname: van der Lely
authors.forename: Wouter W
authors.initials: WW
authors.lastname: de Herder
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology; D000308:Adrenocortical Hyperfunction / Q000209:etiology; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000328:Adult; D006063:Chorionic Gonadotropin / Q000494:pharmacology; D020117:Cisapride / Q000494:pharmacology; D005260:Female; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D006965:Hyperplasia; D007986:Luteinizing Hormone / Q000494:pharmacology*; D008787:Metoclopramide / Q000494:pharmacology; D008875:Middle Aged; D012333:RNA, Messenger / Q000378:metabolism; D011974:Receptors, LH / Q000235:genetics; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
chemical_list: D006063:Chorionic Gonadotropin; D006728:Hormones; D012333:RNA, Messenger; D011974:Receptors, LH; D017366:Serotonin Receptor Agonists; D000324:Adrenocorticotropic Hormone; D007986:Luteinizing Hormone; D008787:Metoclopramide; D020117:Cisapride