Castillo, V.; Giacomini, D.; Páez-Pereda, M.; Stalla, J.; Labeur, M.; Theodoropoulou, M.; Holsboer, F.; Grossman, A.B.; Stalla, G.K.; Arzt, E. "Retinoic acid as a novel medical therapy for Cushing's disease in dogs" (2006) Endocrinology. 147(9):4438-4444
Este artículo es de Acceso Abierto y puede ser descargado en su versión final desde nuestro repositorio
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


Cushing's disease is almost always caused by an ACTH-secreting pituitary tumor, but effective medical therapy is currently limited. Because retinoic acid has been shown to be potentially useful in decreasing corticotroph secretion and proliferation in rodent models, we have studied its action in dogs with Cushing's disease. A randomized treatment with retinoic acid (n = 22) vs. ketoconazole (n = 20) in dogs with Cushing's disease was assigned for a period of 180 d. Clinical signs, plasma ACTH and α-MSH, the cortisol/creatinine urine ratio, and pituitary magnetic resonance imaging were assessed and compared at different time points. We recorded a significant reduction in plasma ACTH and α-MSH, and also in the cortisol/ creatinine urine ratio, of the dogs treated with retinoic acid. Pituitary adenoma size was also significantly reduced at the end of retinoic acid treatment. Survival time and all the clinical signs evaluated showed an improvement in the retinoic-acid-treated dogs. No adverse events or signs of hepatotoxicity were observed, suggesting that the drug is not only effective but also safe. Retinoic acid treatment controls ACTH and cortisol hyperactivity and tumor size in dogs with ACTH-secreting tumors, leading to resolution of the clinical phenotype. This study highlights the possibility of using retinoic acid as a novel therapy in the treatment of ACTH-secreting tumors in humans with Cushing's disease. Copyright © 2006 by The Endocrine Society.


Documento: Artículo
Título:Retinoic acid as a novel medical therapy for Cushing's disease in dogs
Autor:Castillo, V.; Giacomini, D.; Páez-Pereda, M.; Stalla, J.; Labeur, M.; Theodoropoulou, M.; Holsboer, F.; Grossman, A.B.; Stalla, G.K.; Arzt, E.
Filiación:Unidad de Endocrinología, Hospital Escuela, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina
Laboratorio de Fisiología Y Biología Molecular, Departamento de Fisiología, Biología Molecular Y Celular, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina
Max-Planck-Institute of Psychiatry, 80804 Munich, Germany
Affectis Pharmaceuticals, 80804 Munich, Germany
Department of Endocrinology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1A 7BE, United Kingdom
Instituto de Fisiología, Biología Molecular Y Neurociencias, Argentine National Research Council, Consejo Nacional de Investigaciones Cientificas Y Técnicas, 1428 Buenos Aires, Argentina
Department of Endocrinology, St. Bartholomew's Hospital, London EC1A 7BE, United Kingdom
Laboratorio Fisiología Y Biología Molecular, Departimento de Fisiología, Biología Molecular Y Celular, Pabellon II, 1428 Buenos Aires, Argentina
Palabras clave:alpha intermedin; corticotropin; creatinine; hydrocortisone; ketoconazole; retinoic acid; animal experiment; animal model; article; controlled study; corticotropin blood level; creatinine urine level; Cushing disease; dog; drug efficacy; drug safety; female; hormone blood level; hydrocortisone urine level; hypophysis; hypophysis adenoma; male; nonhuman; nuclear magnetic resonance imaging; priority journal; survival; tumor volume; Adenoma; Adrenocorticotropic Hormone; alpha-MSH; Animals; Body Weight; Creatinine; Dog Diseases; Dogs; Female; Hydrocortisone; Ketoconazole; Magnetic Resonance Imaging; Male; Pituitary ACTH Hypersecretion; Pituitary Gland; Pituitary Neoplasms; Survival Rate; Tretinoin
Página de inicio:4438
Página de fin:4444
Título revista:Endocrinology
Título revista abreviado:Endocrinology
CAS:corticotropin, 11136-52-0, 9002-60-2, 9061-27-2; creatinine, 19230-81-0, 60-27-5; hydrocortisone, 50-23-7; ketoconazole, 65277-42-1; retinoic acid, 302-79-4; Adrenocorticotropic Hormone, 9002-60-2; alpha-MSH, 581-05-5; Creatinine, 60-27-5; Hydrocortisone, 50-23-7; Ketoconazole, 65277-42-1; Tretinoin, 302-79-4


  • Bevan, J.S., Webster, J., Burke, C.W., Scanlon, M.F., Dopamine agonists and pituitary tumor shrinkage (1992) Endocr Rev, 13, pp. 220-240
  • Bevan, J.S., The antitumoral effects of somatostatin analog therapy in acromegaly (2005) J Clin Endocrinol Metab, 90, pp. 1856-1863
  • Melmed, S., Sternberg, R., Cook, D., Klibanski, A., Chanson, P., Bonert, V., Vance, M.L., Barkan, A., A critical analysis of pituitary tumor shrinkage during primary medical therapy in acromegaly (2005) J Clin Endocrinol Metab, 90, pp. 4405-4410
  • Pivonello, R., Ferone, D., De Herder, W.W., De Krijger, R.R., Waaijers, M., Mooij, D.M., Van Koetsveld, P.M., Hofland, L.J., Dopamine receptor expression and function in human normal adrenal gland and adrenal tumors (2004) J Clin Endocrinol Metab, 89, pp. 4493-4502
  • Boscaro, M., Barzon, L., Fallo, F., Sonino, N., Cushing's syndrome (2001) Lancet, 357, pp. 783-791
  • De Herder, W.W., Lamberts, S.W., Octapeptide somatostatin-analogue therapy of Cushing's syndrome (1999) Postgrad Med J, 75, pp. 65-66
  • Melmed, S., Mechanisms for pituitary tumorigenesis: The plastic pituitary (2003) J Clin Invest, 112, pp. 1603-1618
  • Dahia, P.L., Grossman, A.B., The molecular pathogenesis of corticotroph tumors (1999) Endocr Rev, 20, pp. 136-155
  • Colao, A., Di Sarno, A., Marzullo, P., Di Somma, C., Cerbone, G., Landi, M.L., Faggiano, A., Lombardi, G., New medical approaches in pituitary adenomas (2000) Horm Res, 53 (3 SUPPL.), pp. 76-87
  • Newell-Price, J., Bertagna, X., Grossman, A.B., Nieman, L.K., Cushing's syndrome (2006) Lancet, 367, pp. 1605-1617
  • Newell-Price, J., Trainer, P., Besser, M., Grossman, A., The diagnosis and differential diagnosis of Cushing's syndrome and pseudo-Cushing's states (1998) Endocr Rev, 19, pp. 647-672
  • Arnaldi, G., Angeli, A., Atkinson, A.B., Bertagna, X., Cavagnini, F., Chrousos, G.P., Fava, G.A., Boscaro, M., Diagnosis and complications of Cushing's syndrome: A consensus statement (2003) J Clin Endocrinol Metab, 88, pp. 5593-5602
  • Nieman, L.K., Medical therapy of Cushing's disease (2002) Pituitary, 5, pp. 77-82
  • Morris, D., Grossman, A., The medical management of Cushing's syndrome (2002) Ann NY Acad Sci, 970, pp. 119-133
  • Heaney, A.P., Fernando, M., Yong, W.H., Melmed, S., Functional PPAR-γ receptor is a novel therapeutic target for ACTH-secreting pituitary adenomas (2002) Nat Med, 8, pp. 1281-1287
  • Ambrosi, B., Dall'Asta, C., Cannavo, S., Libe, R., Vigo, T., Epaminonda, P., Chiodini, I., Beck-Peccoz, P., Effects of chronic administration of PPAR-γ ligand rosiglitazone in Cushing's disease (2004) Eur J Endocrinol, 151, pp. 173-178
  • Kurie, J.M., The biologic basis for the use of retinoids in cancer prevention and treatment (1999) Curr Opin Oncol, 11, pp. 497-502
  • Merino, R., Hurle, J.M., The molecular basis of retinoid action in tumors (2003) Trends Mol Med, 9, pp. 509-511
  • Lotan, R., Retinoids in cancer chemoprevention (1996) FASEB J, 10, pp. 1031-1039
  • Kang, H.J., Song, M.R., Lee, S.K., Shin, E.C., Choi, Y.H., Kim, S.J., Lee, J.W., Lee, M.O., Retinoic acid and its receptors repress the expression and transactivation functions of Nur77: A possible mechanism for the inhibition of apoptosis by retinoic acid (2000) Exp Cell Res, 256, pp. 545-554
  • Fanjul, A., Dawson, M.I., Hobbs, P.D., Jong, L., Cameron, J.F., Harlev, E., Graupner, G., Pfahl, M., A new class of retinoids with selective inhibition of AP-1 inhibits proliferation (1994) Nature, 372, pp. 107-111
  • Kovalovsky, D., Refojo, D., Liberman, A.C., Hochbaum, D., Pereda, M.P., Coso, O.A., Stalla, G.K., Arzt, E., Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: Involvement of calcium, protein kinase A, and MAPK pathways (2002) Mol Endocrinol, 16, pp. 1638-1651
  • Maira, M., Martens, C., Philips, A., Drouin, J., Heterodimerization between members of the Nur subfamily of orphan nuclear receptors as a novel mechanism for gene activation (1999) Mol Cell Biol, 19, pp. 7549-7557
  • Philips, A., Lesage, S., Gingras, R., Maira, M.H., Gauthier, Y., Hugo, P., Drouin, J., Novel dimeric Nur77 signaling mechanism in endocrine and lymphoid cells (1997) Mol Cell Biol, 17, pp. 5946-5951
  • Paez-Pereda, M., Kovalovsky, D., Hopfner, U., Theodoropoulou, M., Pagotto, U., Uhl, E., Losa, M., Stalla, G.K., Retinoic acid prevents experimental Cushing syndrome (2001) J Clin Invest, 108, pp. 1123-1131
  • Lindblad-Toh, K., Wade, C.M., Mikkelsen, T.S., Karlsson, E.K., Jaffe, D.B., Kamal, M., Clamp, M., Fitzgerald, M., Genome sequence, comparative analysis and haplotype structure of the domestic dog (2005) Nature, 438, pp. 803-819
  • Ling, G.V., Stabenfeldt, G.H., Comer, K.M., Gribble, D.H., Schechter, R.D., Canine hyperadrenocorticism: Pretreatment clinical and laboratory evaluation of 117 cases (1979) J Am Vet Med Assoc, 174, pp. 1211-1215
  • Feldman, E.C., Bruyette, D.S., Nelson, R.W., Farver, T.B., Plasma cortisol response to ketoconazole administration in dogs with hyperadrenocorticism (1990) J Am Vet Med Assoc, 197, pp. 71-78
  • Wei, L.N., Retinoid receptors and their coregulators (2003) Annu Rev Pharmacol Toxicol, 43, pp. 47-72
  • Rijnberk, A., Van Wees, A., Mol, J.A., Assessment of two tests for the diagnosis of canine hyperadrenocorticism (1988) Vet Rec, 122, pp. 178-180
  • Orth, D.N., Peterson, M.E., Drucker, W.D., Plasma immunoreactive proopiomelanocortin peptides and cortisol in normal dogs and dogs with Cushing's syndrome: Diurnal rhythm and responses to various stimuli (1988) Endocrinology, 122, pp. 1250-1262
  • Muller, O.A., Stalla, G.K., Von Werder, K., Corticotropin releasing factor: A new tool for the differential diagnosis of Cushing's syndrome (1983) J Clin Endocrinol Metab, 57, pp. 227-229
  • Bosje, J.T., Rijnberk, A., Mol, J.A., Voorhout, G., Kooistra, H.S., Plasma concentrations of ACTH precursors correlate with pituitary size and resistance to dexamethasone in dogs with pituitary-dependent hyperadrenocorticism (2002) Domest Anim Endocrinol, 22, pp. 201-210
  • Tanaka, S., Comparative aspects of intracellular proteolytic processing of peptide hormone precursors: Studies of proopiomelanocortin processing (2003) Zoolog Sci, 20, pp. 1183-1198
  • Ross, E.J., Linch, D.C., Cushing's syndrome - Killing disease: Discriminatory value of signs and symptoms aiding early diagnosis (1982) Lancet, 2, pp. 646-649
  • Lado-Abeal, J., Rodriguez-Arnao, J., Newell-Price, J.D., Perry, L.A., Grossman, A.B., Besser, G.M., Trainer, P.J., Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels (1998) J Clin Endocrinol Metab, 83, pp. 3083-3088
  • Gearing, K.L., Gottlicher, M., Teboul, M., Widmark, E., Gustafsson, J.A., Interaction of the peroxisome-proliferator-activated receptor and retinoid X receptor (1993) Proc Natl Acad Sci USA, 90, pp. 1440-1444
  • Beale, E.G., Hammer, R.E., Antoine, B., Forest, C., Disregulated glyceroneogenesis: PCK1 as a candidate diabetes and obesity gene (2004) Trends Endocrinol Metab, 15, pp. 129-135


---------- APA ----------
Castillo, V., Giacomini, D., Páez-Pereda, M., Stalla, J., Labeur, M., Theodoropoulou, M., Holsboer, F.,..., Arzt, E. (2006) . Retinoic acid as a novel medical therapy for Cushing's disease in dogs. Endocrinology, 147(9), 4438-4444.
---------- CHICAGO ----------
Castillo, V., Giacomini, D., Páez-Pereda, M., Stalla, J., Labeur, M., Theodoropoulou, M., et al. "Retinoic acid as a novel medical therapy for Cushing's disease in dogs" . Endocrinology 147, no. 9 (2006) : 4438-4444.
---------- MLA ----------
Castillo, V., Giacomini, D., Páez-Pereda, M., Stalla, J., Labeur, M., Theodoropoulou, M., et al. "Retinoic acid as a novel medical therapy for Cushing's disease in dogs" . Endocrinology, vol. 147, no. 9, 2006, pp. 4438-4444.
---------- VANCOUVER ----------
Castillo, V., Giacomini, D., Páez-Pereda, M., Stalla, J., Labeur, M., Theodoropoulou, M., et al. Retinoic acid as a novel medical therapy for Cushing's disease in dogs. Endocrinology. 2006;147(9):4438-4444.