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Ghrelin Is Produced by and Directly Activates Corticotrope Cells from Adrenocorticotropin-Secreting Adenomas

Departments of Cell Biology, Physiology, and Immunology (A.J.M.-F., R.V.-M., M.D.-P., M.T.-S., M.M.M., J.P.C.) and Morphological Sciences (L.J.-R.), University of Córdoba, E-14014 Córdoba, Spain; Service of Endocrinology and Nutrition (J.M.-F., P.B.-L.) and Service of Neurosurgery (A.d.l.R.), Hospital Reina Sofía, E-14004 Córdoba, Spain; Department of Physiology (C.D.), University of Santiago de Compostela, E-15782 Santiago de Compostela, Spain; Department of Endocrinology (S.M.W.), Hospital Sant Pau, Autonomous University of Barcelona, E-08025 Barcelona, Spain; and Division of Endocrinology (A.P., A.L.-C.), Virgen del Rocio University Hospital, E-41013 Sevilla, Spain

Address all correspondence and requests for reprints to: Dr. Justo P. Castaño, Department of Cell Biology, Physiology, and Immunology, Edificio Severo Ochoa, Planta 3, Campus de Rabanales, University of Córdoba, E-14014 Córdoba, Spain. E-mail: justo{at}uco.es.

Context: In Cushing’s disease, ACTH hypersecretion by pituitary corticotrope adenoma cells and resulting hypercortisolism is accompanied by a severely blunted GH secretory response. Interestingly, in Cushing’s disease, ghrelin markedly increases plasma ACTH, whereas its stimulatory action on GH secretion is reduced. Although the reported expression of ghrelin receptors (GHS-R) in corticotrope tumors offers a potential mechanism for ghrelin-induced ACTH hypersecretion, studies on the direct effects of synthetic GH secretagogues on corticotropinoma cells offered contradictory results.

Objective and Design: To evaluate the direct action of ghrelin on corticotropinoma cells from two patients with Cushing’s disease, we measured its effect on free cytosolic calcium concentration ([Ca²⁺]_i). Additionally, expression of GHS-R and its ligand ghrelin was examined in these cells and in five additional corticotropinomas.

Results: Ghrelin (10^–6 M) induced a marked [Ca²⁺]_i increase in 89.5% (case 1; n = 19 cells) and 85% (case 2; n = 13 cells) of corticotropinoma cells. Moreover, RT-PCR showed that expression of GHS-R isoforms is accompanied by that of ghrelin in all seven corticotrope adenomas examined. Importantly, double immunogold electron microscopy revealed that ghrelin is costored within ACTH secretory vesicles in densely granulated adenomatous corticotropes.

Conclusions: These results constitute the first demonstration that ghrelin acts directly on corticotrope tumor cells derived from patients with Cushing’s disease. The presence of ghrelin and GHS-R suggests that pituitary ghrelin may play an autocrine/paracrine role in regulating ACTH release in Cushing’s disease. Our findings provide a plausible cellular basis for the exaggerated ACTH response to ghrelin in Cushing’s disease and suggest novel research strategies to develop medical treatments for this disease.

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