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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

Departments of Internal Medicine and Endocrinology (R.A.F., S.W.J.L., L.J.H., P.M.v.K., M.V.-P., A.P.N.T., F.H.d.J., A.-J.v.d.L., W.W.d.H.) and Surgery (H.J.B.), Erasmus University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands; and Department of Endocrinology (A.J.C.), St. Bartholomew’s and the Royal London School of Medicine and Dentistry, EC1A 7BE London, United Kingdom

Address all correspondence and requests for reprints to: R. A. Feelders, M.D., Ph.D., Department of Internal Medicine, Erasmus University Medical Center Rotterdam, 4 Noord, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: feelders{at}inw3.azr.nl.

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 (F), 118 and 106%, respectively], human CG (F, 133 and 44%), LH (F, 73 and 43%), ACTH (F, 89 and 181%), and the 5hydroxy-tryptamine receptor type 4 (5-HT₄) agonists cisapride (F, 141 and 148%) and metoclopramide (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 (F, 45%), cisapride (F, 68%), and metoclopramide (F, 81%). ACTH induced cortisol production by cells from both patients (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.

Abbreviations: APC, Adenomatous polyposis coli; F, change in cortisol; hCG, human CG; 5-HT₄, 5-hydroxy-tryptamine receptor type 4; PRL, prolactin; RNase, ribonuclease.

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