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Cushing’s Syndrome in a Patient with Bilateral Macronodular Adrenal Hyperplasia Responding to Cisapride: An in Vivo and in Vitro Study

Endocrine Unit, Department of Clinical Physiopathology, University of Florence, 50139 Florence, Italy

Address all correspondence and requests for reprints to: Massimo Mannelli, M.D., Endocrine Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini, 6, 50139 Florence, Italy. E-mail: m.mannelli{at}dfc.unifi.it.

Cortisol secretion in adrenal Cushing’s syndrome can be regulated by aberrant hormone receptors, such as gastric inhibitory polypeptide, V1 vasopressin, catecholamines, LH/human chorionic gonadotropin, and serotonin receptors. We report the case of a patient with Cushing’s syndrome due to bilateral adrenal macronodular hyperplasia. Extensive in vivo testing for the presence of aberrant receptors revealed a 5-fold increase of plasma cortisol after the administration of cisapride, an agonist of the serotonin 4 (5-HT₄) receptor. Primary cell cultures were established from adrenocortical specimens obtained at surgery, and in vitro studies also showed that cisapride determined an increase [133.7 ± 5.5% (mean ± SE) of baseline, considered 100%) of cortisol secretion from cultured cells. The presence of 5-HT₄ receptor transcript, and in particular of isoforms c, g, and n, was confirmed by RT-PCR, and the determination of the mRNA levels by real-time RT-PCR revealed a higher expression than in normal adrenal glands. To our knowledge, this is one of the first reports of Cushing’s syndrome in which cortisol secretion is regulated mainly by the 5-HT₄ receptor, among known aberrant receptors. In addition, it is noteworthy that hypocortisolism ensued after the removal of the most enlarged adrenal gland, but the in vivo response to cisapride persisted.

This work was partially supported by Ministero dell’Istruzione, dell’Università e della Ricerca (Grant 2001062719).

Abbreviations: AIMAH, ACTH-independent macronodular adrenal hyperplasia; AT-1, angiotensin II type 1; AVP arginin-vasopressin; CT, computed tomography; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; hCG, human chorionic gonadotropin; 5-HT₄, serotonin 4.

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