Propranolol Therapy for Ectopic β-Adrenergic Receptors in Adrenal Cushing's Syndrome

Abstract

OST patients with corticotropin-independent Cushing's syndrome have an adrenal adenoma or carcinoma, 1 but a few have bilateral adrenal hyperplasia. Three patients with Cushing's syndrome and corticotropin-independent bilateral adrenal hyperplasia 2-4 and two patients with adrenal adenomas 5,6 in whom food stimulated cortisol secretion have been described; the abnormal adrenal tissues in these patients aberrantly overexpressed receptors for gastric inhibitory polypeptide. 6,7 We describe a patient with Cushing's syndrome and corticotropin-independent bilateral adrenal hyperplasia in whom endogenous catecholamines, acting through an ectopic adrenal b -adrenergic receptor, stimulated cortisol secretion; the hyperadrenocorticism was inhibited by b -blockade. CASE REPORTA 56-year-old man presented with a left ileofemoral thrombophlebitis, an 8-kg weight gain, decreased libido, and sleep disturbance. Abdominal computed tomography revealed unsuspected bilateral macronodular adrenal hyperplasia (right adrenal gland, 5.2 by 4.0 by 6.0 cm; left adrenal gland, 6.5 by 6.0 by 8.5 cm). Physical examination revealed hypertension and abdominal obesity, but no cervicodorsal fat pads, abdominal striae, or muscle weakness. Urinary cortisol excretion was 711 and 1070 m g (1963 and 2953 nmol) per 24 hours (normal, 18 to 119 m g [50 to 330 nmol] per 24 hours) on two separate days. The patient's plasma corticotropin concentration was 4.3 pg per milliliter (0.86 pmol per liter; normal, 10 to 55 pg per milliliter [2 to 11 pmol per liter]) at 8 a.m. The plasma cortisol concentration was 26.2 m g per deciliter (723 nmol per liter) at 8 a.m. and 18.1 m g per deciliter (499 nmol per liter) on the morning after the administration of 2 mg of dexamethasone at midnight. The plasma aldosterone concentration, measured while the patient was supine, was 5.5 ng per deciliter (153 nmol per liter; normal, 1.0 to 16.0 ng per deciliter [27.7 to 443.8 nmol per liter]), plasma renin activity was 0.43 ng per milliliter per hour (0.12 ng per liter per second; nor-M mal, 0.50 to 1.58 ng per milliliter per hour [0.14 to 0.44 ng per liter per second]), and the plasma potassium concentration was 3.7 mmol per liter. METHODS Clinical StudiesThe studies were approved by the institutional review committee, and written informed consent was obtained from all subjects. Plasma corticotropin, cortisol, and aldosterone were measured after an overnight fast and every 30 to 60 minutes for up to 3 hours after changes in posture, intake of food or water, and the administration of several hormones and drugs. AssaysPlasma cortisol was measured by an immunofluorometric assay (Technicon Immuno I, Bayer, Tarrytown, N.Y.), corticotropin by an immunoradiometric assay (Allegro, Nichols Diagnostics, San Juan Capistrano, Calif.), and aldosterone, renin, and vasopressin by a radioimmunoassay. b -Adrenergic-Receptor Binding and Adenylyl Cyclase AssaysMembranes from adrenocortical tissues from the patient and from three patients who underwent adrenalectomy for Cushing's disease or radica...

Cushing's syndrome secondary to ACTH-Independent macronodular adrenal hyperplasia

“…The aberrant adrenal expression of β-adrenergic receptors was first reported in a patient with AIMAH and CS whose cortisol and aldosterone secretion increased in response to endogenous changes in catecholamine levels (upright posture, insulin induced hypoglycemia or exercise) (42). The infusion of iso- proterenol, a β-agonist, stimulated both cortisol and aldosterone secretion in this patient, but not in normal subjects (42). Similar findings were reported in other patients with AIMAH (44,49,50).…”

“…However, ACTH-independent stimulation of cortisol following administration or arginine-or lysine-vasopressin has been reported in several patients with either unilateral adenoma or AIMAH and CS who increase their plasma cortisol with upright posture and other physiological stimuli of endogenous vasopressin (2,(42)(43)(44)(45)(46)(47). As pharmacological levels of AVP can stimulate catecholamine secretion and cortisol production indirectly in patients with ectopic adrenal β-adrenergic receptors, it is important to demonstrate that the cortisol production is modulated by endogenous vasopressin through water and hypertonic sodium loading (42,44).…”

“…Pharmacological blockade of postprandial release of GIP using octreotide led to clinical and biochemical improvement of Cushing's syndrome, although without persistent effect probably as the result of eventual desensitization of somatostatin-receptors in GIP-secreting duodenal K cells (33,87). In catecholamine-dependent CS in AIMAH, β-adrenergic receptor antagonists were efficient in the long-term control of hormonal hypersecretion (42,72). In LH/hCG-dependent AIMAH and CS, suppression of endogenous LH levels with long-acting leuprolide acetate controlled steroid secretion and avoided bilateral adrenalectomy (15,55).…”

ACTH-Independent Hypercorticism in Adrenal Tumors and Adrenocortical Hyperplasia

“…33 Beta-2 adrenergic receptors were identified in human adrenocortical cortisol-producing adenomas 34,35 or hyperplasia. [36][37][38] Cell cultures from AIMAH showed hyperresponsiveness to isoproterenol, a nonselective beta-adrenergic receptor agonist, and salbutamol, a beta-2 adrenergic receptor agonist. 37 Propranolol, a beta-adrenergic antagonist usually used to treat hypertension and heart dysrhythmias, greatly decreased the patient's urinary cortisol excretion.…”

“…37 Propranolol, a beta-adrenergic antagonist usually used to treat hypertension and heart dysrhythmias, greatly decreased the patient's urinary cortisol excretion. 37,38 Meanwhile, treatment with isoproterenol, a beta-adrenergic agonist usually used to treat bradycardia and heart block, stimulated cortisol production. 39 Incubation of cultured cells expressing the beta-adrenergic receptors with the peptide hormone AVP and epinephrine together induced a stronger cortisol response than the individual agents alone.…”