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Dopamine Receptor Expression and Function in Corticotroph Pituitary Tumors

Departments of Internal Medicine (R.P., D.F., W.W.d.H., L.J.H., S.W.J.L.) and Pathology (J.M.K.), Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands; Departments of Molecular and Clinical Endocrinology and Oncology (R.P., A.C., G.L.), Pathology (M.L.D.B.D.C.), and Neuroscience, Division of Pharmacology (R.P., L.A.), Federico II University of Naples, 80131 Naples, Italy; and Department of Endocrinological and Metabolic Sciences and Centre for Excellence for Biological Research (D.F., M.A.), University of Genova, 16132 Genova, Italy

Address all correspondence and requests for reprints to: Rosario Pivonello, M.D., Department of Molecular and Clinical, Endocrinology and Oncology, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy. E-mail: rpivone{at}tin.it.

The role of dopamine agonist treatment in corticotroph pituitary tumors is controversial. The aim of this study was to evaluate D₂ receptor expression in 20 corticotroph pituitary tumors and to correlate it to the in vitro effect of dopamine agonists on ACTH secretion and the in vivo effect of short-term cabergoline treatment on cortisol secretion. D₂ expression was evaluated by receptor-ligand binding, immunohistochemistry, and RT-PCR. A 50% or more decrease in daily urinary cortisol levels was considered a significant clinical response. At receptor-ligand binding, specific binding of [¹²⁵I]epidepride was found in 80% of cases. At immunohistochemistry, specific D₂ immunostaining was found in 75% of cases. D₂ expression was found in 83.3% of cases (D_2long in 40%, D_2short in 20%, and both in 40%) by RT-PCR. Significant in vitro inhibition of ACTH secretion was found in 100% of D₂-positive cases, but not in 100% of D₂-negative cases by either bromocriptine or cabergoline. A significant in vivo inhibition of cortisol secretion after 3-month cabergoline treatment was found in 60%, although a normalization of cortisol secretion was found in 40% of cases. All cabergoline-responsive cases were associated with D₂ expression, whereas all noncabergoline-responsive cases but one were not associated with D₂ expression. In conclusion, functional D₂ receptors were expressed in approximately 80% of corticotroph pituitary tumors. The effectiveness of cabergoline in normalizing cortisol secretion in 40% of cases supports its therapeutic use in the management of Cushing’s disease.

This work was supported by Pharmacia-Pfizer and in part by a grant from the Italian Minister of University and Research (no. 2003-068735).

Abbreviations: CD, Cushing’s disease; DR, dopamine receptor; HPRT, hypoxanthine ribosyl transferase; IHC, immunohistochemistry; LiDS, lithium dodecyl sulfate; NS, nonspecific; oligo(dT)₂₅, oligo(deoxythymidine)₂₅; poly(A)⁺, polyadenylated; PRL, prolactin; R-LB, receptor-ligand binding; T, total; TBS-T, Tris-buffered saline-Tween; WGA, wheat-germ agglutinin.

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