New Developments in Cushing’s Syndrome

PL Prof. André Lacroix, M.D.

Personal Information

Nationality: Canadian

Professor, Department of Medicine, Division of Endocrinology CHUM

Director, Laboratory of endocrine pathophysiology, CRCHUM

Tour Viger, 900, rue Saint-Denis, Rm R08-474, Montréal (Québec) H2X 0A9

E-mail: andre.lacroix@umontreal.ca

Pr. Lacroix completed M.D. degree in 1972 and specialization in endocrinology in 1977 at Université de Montréal. This was followed by Endocrine fellowship at Vanderbilt University in Nashville, TN from 1976-78 with Grant W Liddle, David N Orth, TJ McKenna, and at the National Institutes of Health in Bethesda, MD from 1978-80 with Marc E Lippman and during a sabbatical year of biotechnology in 1986 with MB Sporn and Anita Roberts. Since 1980, he has been Director of Endocrine Pathophysiology laboratory at Institut de Recherches Cliniques de Montréal (IRCM) until 1992 and now at the CHUM Research center (CRCHUM). He served as chief of Endocrine Division at Hôtel-Dieu hospital and as Director of the Endocrinology Training Program of Université de Montréal. He was Chairman of the Department of Medicine from 2002-2008 and Associate Director General for Medical and Academic Affairs at CHUM (2008-2012). He served as president of the Canadian Society of Endocrinology and Metabolism (2005-2007) and on the executive board of the International Society of Endocrinology (2010-16). He is currently co-editor of the Adrenal Section of UpToDate (Boston, MA), Senior Editor of the European Journal of Endocrinology, editorial board member of Journal of Clinical Endocrinology and Metabolism. He received the Medical Leadership award from CHUM Foundation in 1999 and the Robert Volpé 2010 award from CSEM in recognition for his contributions to Endocrinology in Canada. He was elected Fellow of the Canadian Academy of Health Sciences in 2008 (FCAHS).

Major Areas of Research:

Genetics and pathophysiology of adrenal tumors and hyperplasias leading to Cushing’s syndrome, primary aldosteronism and adrenal tumorigenesis. Role of aberrant adrenal hormone receptors in adrenal overfunction. New drugs in the therapy of Cushing’s disease and primary aldosteronism, of adrenocortical cancer and pheochromocytomas.

He has published more than 180 articles or book chapters, 250 scientific meeting abstracts and was invited to give 250 conferences at national and international institutions or scientific meetings.

Selected publications

1.Lacroix, A., Bolté, E., Tremblay, J., Dupré, J., Poitras, P., Fournier, H., Garon, J., Garrel, D.,

Bayard, F., Taillefer, R., Flanagan, R., and Hamet, P. Gastric inhibitory polypeptide-dependent cortisol hypersecretion - a new cause of Cushing’s syndrome. N. Engl. J. Med.; 327:974-980. 1992 (274citations) IF 47.05 2.Gagner, M., Lacroix, A., and Bolté, E. Laparoscopic approach to adrenalectomy in Cushing’s syndrome and pheochromocytoma. Letter to the Editor. N. Engl. J. Med.; 327:1033. 1992 (1361 citations) IF 47.05

3.Lacroix, A., N’Diaye, N., Tremblay, J., and Hamet, P. Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocrine Reviews, 22 :75-110, 2001 (278 citations). IF 19.76 4.Lacroix, A., Tremblay, J., Rousseau, G., Bouvier, M., and Hamet, P. Propranolol therapy for ectopic b-adrenergic receptors in adrenal Cushing’s syndrome. New Engl. J. Med.; 337:1429-1434. 1997 (178 citations) IF 47.05 5.Lacroix, A., Hamet, P., Boutin, JM. Leuprolide acetate therapy in Luteinizing Hormone-dependent

Cushing’s syndrome. New England Journal of Medicine. 341:1577-81. 1999 (169 citations). IF 47.05 6.Arnaldi, G., Angeli, A., Atkinson, A.B., Bertagna, X., Cavagnini, F., Chrousos, G., Fava, G.A.,

Findling, J., Gaillard, R.C., Grossman, A.B., Kola, B., Lacroix, A., Mancini, T., Mantero F.,

Newell-Price, J., Nieman, L.K., Sonino, N., Vance M.L., Giustina A., Boscaro M. Diagnosis and complications of Cushing’s syndrome : A consensus statement. J. Clin. Endocrinol. Metab., 88(12):5593-602, 2003. (927 citations) IF 6.20 7.Biller B.M.K., Grossman A.B., Stewart P.M., Melmed S., Bertagna X., Bertherat J., Buchfelder

M., Colao A., Hermus A.R., Hofland L.J., Klibanski A., Lacroix A., Lindsay J.R., Newell-Price J.,

Nieman L.K., Petersenn S., Sonino N., Stalla G.K., Swearingen B., Vance M.L., Wass J.A.H. and

Boscaro M. Treatment of ACTH-dependent Cushing’s Syndrome: A Consensus Statement. J. Clin.

Endocrinol. Metab. 93: 2454-62, 2008 (452 citations) 8.Lampron A, Bourdeau I, Oble S, Godbout A, Schurch W, Arjane P, Hamet P, and Lacroix A.

Regulation of aldosterone secretion by several aberrant receptors including for GIP in a patient with an aldosteronoma. J Clin Endocrinol Metab. 94:750-6, 2009. (27 citations) IF 6.20 9.Hsiao H-P, Verma S, Nandagopal R, Boikos SA, Bourdeau I, Keil MF, Robinson-White AJ,

Kirschner LS, Lacroix A, and Stratakis CA. A Molecular and Clinical Genetic Investigation of ACTH-Independent Macronodular Adrenal Hyperplasia Compared to Other, Common

Adrenocortical Tumors: Evidence for Heterogeneity, Overlap with Other Tumor Syndromes and

Frequent But Atypical Hormonal Secretion. J Clin Endo Metab 94: 2930-37, 2009. (53 citations) IF 6.20 10.Lacroix A. Approach to the patient with adrenal carcinoma. J Clin Endocrinol Metab. 95:4812-22, 2010. (52 citations) IF 6.20 11.Lacroix A, Bourdeau I, Lampron A, Mazzuco TL, Tremblay J, Hamet P. Aberrant G-protein coupled receptor expression in relation to adrenocortical overfunction. Clin Endocrinol (Oxf).73:1-15, 2010 (47 citations) IF 3.32 12.Godbout A, Manavela M, Danilowicz K, Beauregard H, Bruno OD, Lacroix A. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol. 163: 1-9, 2010 (83 citations) IF 3.48 13.Colao AM, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, Schoenherr U, Mills

D, Salgado LR, and Biller BMK, on behalf of the Pasireotide B2305 Study Group (Lacroix A). A 12-Month Phase 3 Study of Pasireotide in Cushing’s Disease. N Engl J Med 366 : 914-24, 2012. IF 47.05 14.Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, Welin S, Schade-Brittinger C,

Lacroix A Jarzab B, Sorbye H, Torpy D, Stepan V, Arlt W, Schteingart D, Kroiss M, Leboulleux

S, Sperone P, Sundin A, Hermsen I, Hahner S, Willenberg HS, Tabarin A, Quinkler M, de la

Fouchardière C, Schlumberger M, Mantero F, Weismann D, Beuschlein F, Gelderblom H, Wilmink

H, Sender M, Edgerly M, Kenn W, Fojo T, Mueller HH, Skogseid B, for the FIRM-ACT study group. Combination Chemotherapy in Advanced Adrenocortical Carcinoma. N Engl J Med

366(23):2189-97, 2012 May 2. (155 citations) IF 47.05 15.Lacroix A. Heredity and cortisol regulation in bilateral macronodular adrenal hyperplaisia. Editorial

N Engl J Med. 369 Nov 28:2147-2149, 2013(8 citations) IF 47.05 16.Alencar, G.A., Lerario, A.M., Nishi, M.Y., Mariani, B.M.M., Almeida, M.Q., Tremblay, J., Hamet,

P., Bourdeau, I., Zerbini, M.C.N., Pereira, M.A.A., Gomes, G.C., Rocha, M.D.S., Chambo, J.L.,

Lacroix, A., Mendonca, B.B., Fragoso, M.C.B.V. ARMC5 Mutations are a frequent cause of primary macronodular adrenal hyperplasia. J. Clin. Endocrinol. Metab. 99: E1501-1509, 2014. (12 citations) IF : 6.20 17.De Venanzi, A., Alencar, G.A., Bourdeau, I., Fragoso, M.C.B.V., and Lacroix, A. Primary bilateral macronodular adrenal hyperplasia. Curr. Opin. Endocrinol. Diabetes Obes. 21: 177-184, 2014 (doi: 10.1097/MED). 18.Bourdeau, I., Oble, S., Magne, S., Lévesque, I. Caceres, K., Nolet, S., Awadalla, P., Tremblay,

J., Hamet, P., Fragoso, M.C.B.V., Lacroix, A. ARMC5 mutations in a large French-Canadian family with cortisol-secreting B-adrenergic/vasopressin responsive bilateral macronodular adrenal hyperplasia. Eur. J. Endocrinol. 174: 85–96, 2016 19.El Ghorayeb, N., Bourdeau, I., Lacroix, A. Multiple aberrant hormone receptors in Cushing’s syndrome. Eur J Endocrinol. Eur J Endocrinol. 2015 Oct;173(4):M45-60. doi: 10.1530/EJE-150200. Epub 2015 May 13. Review 20.Lacroix A, Felders RA, Stratakis CA, Nieman L. Cushing’s syndrome. Invited Seminars. Lancet. 2015 Aug 29; 386(9996):913-27. doi: 10.1016/S0140-6736(14)61375-1. Epub 2015 May 21.

Review

PL New Developments in Cushing's Syndrome

ANDRÉ LACROIX

Professor of Medicine, Division of Endocrinology, Centre hospitalier de l’Université de Montréal (CHUM).

Chronic exposure to excess glucorticoids results in the diverse manifestations of Cushing’s syndrome, including debilitating morbidities and increased mortality. Recent progress revealed genetic and molecular mechanisms responsible for excess cortisol secretion by primary adrenal lesions and of ACTH from corticotroph tumors. These include USP8 mutations in corticotroph tumors, PRKACA mutations in cortisol secreting adenomas, ARMC5 mutations and aberrant receptor regulated paracrine production of ACTH in bilateral macronodular adrenal hyperplasia.

New biochemical and imaging diagnostic approaches and progress in surgical and radiotherapy techniques have improved the management of patients. The therapeutic goal is to normalize tissue exposure to cortisol in order to reverse the increased morbidity and mortality. Optimal treatment is selective and complete resection of the causative tumor, allowing eventual normalization of the hypothalamic-pituitary-adrenal axis, maintenance of pituitary function and avoidance of tumor recurrence. The development of new targeted drugs interfering with the molecular causes should offer clinicians several choices to better treat patients with residual cortisol excess. However, the long-term effects and co-morbidities associated with hypercortisolism require ongoing care of patients affected by this challenging syndrome.