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.
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.
Feelders
Richard A
RA
Department of Internal Medicine, Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands. feelders@inw3.azr.nl
Lamberts
Steven W J
SW
Hofland
Leo J
LJ
van Koetsveld
Peter M
PM
Verhoef-Post
Miriam
M
Themmen
Axel P N
AP
de Jong
Frank H
FH
Bonjer
H Jaap
HJ
Clark
Adrian J
AJ
van der Lely
Aart-Jan
AJ
de Herder
Wouter W
WW
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
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