Horm Metab Res 2018; 50(04): 280-289
DOI: 10.1055/a-0580-0460
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

Cushing’s Syndrome: A Historic Review of the Treatment Strategies and Corresponding Outcomes in a Single Tertiary Center over the Past Half-Century

Anelia Nankova
1   Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Bulgaria
,
Maria Yaneva
1   Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Bulgaria
2   Centre Hospitalier du Nord, Ettelbruck, Luxembourg
,
Atanaska Elenkova
1   Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Bulgaria
,
Dimitar Tcharaktchiev
1   Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Bulgaria
,
Marin Marinov
3   Department of Neurosurgery, University Hospital “St. Ivan Rilski”, Medical University, Sofia, Bulgaria
,
Asen Hadzhiyanev
3   Department of Neurosurgery, University Hospital “St. Ivan Rilski”, Medical University, Sofia, Bulgaria
,
Tanyo Sechanov
1   Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Bulgaria
,
Georgi Gantchev
1   Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Bulgaria
,
Georgi Todorov
4   Department of Surgery, Medical University of Sofia, Alexandrovska University Hospital, Sofia, Bulgaria
,
Georgi Kirilov
1   Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Bulgaria
,
Krasimir Kalinov
5   New Bulgarian University, Sofia, Bulgaria
,
Maria Andreeva
1   Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Bulgaria
,
Sabina Zacharieva
1   Clinical Center of Endocrinology and Gerontology, Medical University, Sofia, Bulgaria
› Author Affiliations
Further Information

Publication History

received 07 November 2017

accepted 13 February 2018

Publication Date:
05 April 2018 (online)

Abstract

Cushing’s syndrome (CS) is associated with serious comorbidities and an increased mortality rate that could be reduced only if strict biochemical control is achieved. The aim of this study was to show the 50-year experience of a single tertiary center in the management of CS patients – the different treatment modalities used over the years and the corresponding outcomes. It was a retrospective study of a large cohort of patients from the Bulgarian CS database: 613 patients (374 with ACTH-dependent and 239 with ACTH-independent CS). Pituitary surgery was applied to 242 patients with Cushing’s disease (CD) with initial remission rate of 74% of which 10% relapsed. Approximately 36% manifested with active disease during the long-term follow-up (26% with persistent disease, 10% relapses) most of which were subjected to a secondary treatment (13.6% to pituitary resurgery, 14% to pituitary radiotherapy, and 5.4% to bilateral adrenalectomy). A total of 294 CD patients received medical therapy with overall remission rates for the most commonly used drugs: dopamine agonists 20%, pasireotide 30%, and ketoconazole 63%. Significant improvement of results was achieved by combining drugs with different mechanisms of action. Regardless of the progress in the neurosurgery and radiotherapy techniques and new drugs discovery, the management of patients with CS remains a real challenge for physicians. Not only patients with adrenal carcinoma but also significant percentage of subjects with persistent and recurrent Cushing’s disease often require a polymodal approach and the efforts of a multidisciplinary highly qualified, experienced, and motivated team in order to achieve a long-term remission.

 
  • References

  • 1 Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BM, Colao A. Complications of Cushing's syndrome: State of the art. Lancet Diabetes Endocrinol 2016; 4: 611-629
  • 2 Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet 2015; 386: 913-927
  • 3 Yaneva M, Kalinov K, Zacharieva S. Mortality in Cushing's syndrome: Data from 386 patients from a single tertiary referral center. Eur J Endocrinol 2013; 169: 621-627
  • 4 Ntali G, Asimakopoulou A, Siamatras T, Komninos J, Vassiliadi D, Tzanda M, Tsagarakis S, Grossman AB, Wass JAH, Karavitaki N. Mortality in Cushing’s syndrome: Systematic analysis of a large series with prolonged follow-up. Eur J Endocrinol 2013; 169: 715-723
  • 5 Pereira AM, Delgado V, Romijn JA, Smit JW, Bax JJ, Feelders RA. Cardiac dysfunction is reversed upon successful treatment of Cushing’s syndrome. Eur J Endocrinol 2010; 162: 331-340
  • 6 Battocchio M, Rebellato A, Grillo A, Dassie F, Maffei P, Bernardi S, Fabris B, Carretta R, Fallo F. Ambulatory arterial stiffness indexes in Cushing's syndrome. Horm Metab Res 2017; 49: 214-220
  • 7 Solak M, Kraljevic I, Dusek T, Melada A, Kavanagh MM, Peterkovic V, Ozretic D, Kastelan D. Management of Cushing's disease: A single-center experience. Endocrine 2016; 51: 517-523
  • 8 Hassan-Smith ZK, Sherlock M, Reulen RC, Arlt W, Ayuk J, Toogood AA, Cooper MS, Johnson AP, Stewart PM. Outcome of Cushing's disease following transsphenoidal surgery in a single center over 20 years. J Clin Endocrinol Metab 2012; 97: 1194-1201
  • 9 Espinosa-de-Los-Monteros AL, Sosa-Eroza E, Espinosa E, Mendoza V, Arreola R, Mercado M. Long-term outcome of the different treatment alternatives for recurrent and persistent Cushing’s disease. Endocr Pract 2017; 23: 759-767
  • 10 Drange MR, Fram NR, Herman-Bonert V, Melmed S. Pituitary tumor registry:a novel clinical resource. J Clin Endocrinol Metab 2000; 85: 168-174
  • 11 Tcharaktchiev D, Dimitrov H, Zacharieva S, Marinov M, Vandeva S, Vasilev V, Yaneva M, Elenkova A, Natchev E, Kirilov G, Atanasova I, Ivanova R. Data base for patients with pituitary and adrenal tumors. Social Med 2010; 2: 73-79
  • 12 Nieman LK, Biller BM, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A. Endocrine Society. Treatment of Cushing's Syndrome: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2015; 100: 2807-2831
  • 13 Guignat L, Bertherat J. The diagnosis of Cushing's syndrome: An endocrine society clinical practice guideline: Commentary from a European perspective. Eur J Endocrinol 2010; 163: 9-13
  • 14 Nieman LK, Biller BM, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The diagnosis of Cushing's syndrome: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008; 93: 1526-1540
  • 15 Newell-Price J, Trainer P, Besser M, Grossman A. The Diagnosis and differential diagnosis of Cushing’s syndrome and Pseudo-Cushing’s states. Endocr Rev 1998; 19: 647-672
  • 16 Yaneva M, Mosnier-Pudar H, Dugué MA, Grabar S, Fulla Y, Bertagna X. Midnight salivary cortisol for the initial diagnosis of Cushing's syndrome of various causes. J Clin Endocrinol Metab 2004; 89: 3345-3351
  • 17 Andreeva M. Investigation of the effect of different treatment modalities applied in patients with Cushing's disease. DM Thesis, Sofia 1984;
  • 18 Guerin C, Taieb D, Treglia G, Brue T, Lacroix A, Sebag F, Castinetti F. Bilateral adrenalectomy in the 21st century: When to use it for hypercortisolism?. Endocr Relat Cancer 2016; 23: R131-R142
  • 19 Alexandraki KI, Grossman AB. Therapeutic strategies for the treatment of severe Cushing's syndrome. Drugs 2016; 76: 447-458
  • 20 Murayama M, Yasuda K, Minamori Y, Mercado-Asis LB, Yamakita N, Morita H, Miura K. Long term follow-up of Cushing's disease treated with reserpine and pituitary irradiation followed by subtotal adrenalectomy. Tohoku J Exp Med 1994; 172: 97-109
  • 21 Andreeva MKh, Bozadzhieva EK, Platonova ES, Zografski SG, Mendizov IKh. Treatment of Cushing's syndrome with large doses of reserpine. Probl Endokrinol (Mosk) 1983; 29: 3
  • 22 Murayama M, Yasuda K, Minamori Y, Mercado-Asis LB, Yamakita N, Miura K. Long term follow-up of Cushing's disease treated with reserpine and pituitary irradiation. J Clin Endocrinol Metab 1992; 75: 935-942
  • 23 Marinov M. Contemporary transsphenoidal surgery of pituitary adenomas. DMSc Thesis, Sofia, 2006;
  • 24 Hadzhiyanev A. The role of transsphenoidal surgery in the complex treatment of the secreting pituitary adenoms. DM Thesis, Sofia, 2014;
  • 25 Honegger J, Schmalisch K, Beuschlein F, Kaufmann S, Schnauder G, Naegele T, Psaras T. Contemporary microsurgical concept for the treatment of Cushing's disease: Endocrine outcome in 83 consecutive patients. Clin Endocrinol (Oxf) 2012; 76: 560-507
  • 26 Shirvani M, Motiei-Langroudi R, Sadeghian H. Outcome of microscopic transsphenoidal surgery in Cushing disease: A Case Series of 96 Patients. World Neurosurg 2016; 87: 170-175
  • 27 Dimopoulou C, Schopohl J, Rachinger W, Buchfelder M, Honegger J, Reincke M, Stalla GK. Long-term remission and recurrence rates after first and second transsphenoidal surgery for Cushing's disease: Care reality in the Munich Metropolitan Region. Eur J Endocrinol 2013; 170: 283-292
  • 28 Atkinson AB, Kennedy A, Wiggam MI, McCance DR, Sheridan B. Long-term remission rates after pituitary surgery for Cushing's disease: The need for long-term surveillance. Clin Endocrinol (Oxf) 2005; 69: 549-559
  • 29 Guilhaume B, Bertagna X, Thomsen M, Bricairec C, Vila-Porcile E, Olivier L, Racadot J, Lautat MH, Girard F, Bricaire H, Luton JP. Transsphenoidal pituitary surgery for the treatment of Cushing’s disease: Results in 64 patients and long term follow-up studies. J Clin Endocrinol Metab 1988; 66: 1056-1064
  • 30 Minniti G, Osti M, Jaffrain-Rea ML, Esposito V, Cantore G, Maurizi Enrici R. Long-term follow-up results of postoperative radiation therapy for Cushing's disease. J Neurooncol 2007; 84: 79-84
  • 31 Vicente A, Estrada J, de la Cuerda C, Astigarraga B, Marazuela M, Blanco C, Lucas T, Barceló B. Results of external pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing's disease. Acta Endocrinol (Copenh) 1991; 125: 470-474
  • 32 Valderrábano P, Aller J, García-Valdecasas L, García-Uría J, Martín L, Palacios N, Estrada J. Results of repeated transsphenoidal surgery in Cushing's disease. Long-term follow-up. Endocrinol Nutr 2014; 61: 176-183
  • 33 Jagannathan J, Sheehan JP, Pouratian N, Laws ER, Steiner L, Vance ML. Gamma Knife surgery for Cushing's disease. J Neurosurg 2007; 106: 980-987
  • 34 Petit JH, Biller BM, Yock TI, Swearingen B, Coen JJ, Chapman P, Ancukiewicz M, Bussiere M, Klibanski A, Loeffler JS. Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas. J Clin Endocrinol Metab 2008; 93: 393-399
  • 35 Wagenmakers MA, Netea-Maier RT, van Lindert EJ, Timmers HJ, Grotenhuis JA, Hermus AR. Repeated transsphenoidal pituitary surgery (TS) via the endoscopic technique: A good therapeutic option for recurrent or persistent Cushing's disease (CD). Clin Endocrinol (Oxf) 2009; 70: 274-280
  • 36 Patil CG, Veeravagu A, Prevedello DM, Katznelson L, Vance ML, Laws Jr. ER. Outcomes after repeat transsphenoidal surgery for recurrent Cushing's disease. Neurosurgery 2008; 63: 266-270
  • 37 Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing's disease. Endocr Rev 2015; 36: 385-486
  • 38 Ambrogio AG, Cavagnini F. Role of "old" pharmacological agents in the treatment of Cushing's syndrome. J Endocrinol Invest 2016; 39: 957-965
  • 39 Ciato D, Mumbach AG, Paez-Pereda M, Stalla GK. Currently used and investigational drugs for Cushing's disease. Expert Opin Investig Drugs 2017; 26: 75-84
  • 40 Bertagna X. Therapeutic innovations in endocrine diseases – Part 1: New medical treatments for chronic excess of endogenous cortisol (Cushing's syndrome). Presse Med 2016; 45 6 Pt 2 e201-e204
  • 41 Díez JJ, Iglesias P. Pharmacological therapy of Cushing's syndrome: Drugs and indications. Mini Rev Med Chem 2007; 7: 467-480
  • 42 Ferriere A. Cabergoline for Cushing's disease: A large retrospective multicenter study. Eur J Endocrinol 2017; 176: 305-314
  • 43 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 2010; 163: 709-716
  • 44 Ambrosi B, Dall'Asta C, Cannavo S, Libe R, Vigo T, Epaminonda P, Chiodini I, Ferrero S, Trimarchi F, Arosio M, Beck-Peccoz P. Effects of chronic administration of PPAR-gamma ligand rosiglitazone in Cushing's disease. Eur J Endocrinol 2004; 151: 173-178
  • 45 Suri D, Weiss RE. Effect of pioglitazone on adrenocorticotropic hormone and cortisol secretion in Cushing's disease. J Clin Endocrinol Metab 2005; 90: 1340-1346
  • 46 Heaney AP. PPAR-gamma in Cushing's disease. Pituitary 2004; 7: 265-269
  • 47 Moncet D, Morando DJ, Pitoia F, Katz SB, Rossi MA, Bruno OD. Ketoconazole therapy: An efficacious alternative to achieve eucortisolism in patients with Cushing's syndrome. Medicina (B Aires) 2007; 67: 26-31
  • 48 Valassi E, Crespo I, Gich I, Rodríguez J, Webb SM. A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushing's syndrome. Clin Endocrinol (Oxf) 2012; 77: 735-742
  • 49 Castinetti F, Guignat L, Giraud P, Muller M, Kamenicky P, Drui D, Caron P, Luca F, Donadille B, Vantyghem MC, Bihan H, Delemer B, Raverot G, Motte E, Philippon M, Morange I, Conte-Devolx B, Quinquis L, Martinie M, Vezzosi D, Le Bras M, Baudry C, Christin-Maitre S, Goichot B, Chanson P, Young J, Chabre O, Tabarin A, Bertherat J, Brue T. Ketoconazole in Cushing's disease: Is it worth a try?. J Clin Endocrinol Metab 2014; 99: 1623-1630
  • 50 Gentilin E, Tagliati F, Terzolo M, Zoli M, Lapparelli M, Minoia M, Ambrosio MR, Degli Uberti EC, Zatelli MC. Mitotane reduces human and mouse ACTH-secreting pituitary cell viability and function. J Endocrinol 2013; 218: 275-285
  • 51 Berruti A, Grisanti S, Pulzer A, Claps M, Daffara F, Loli P, Mannelli M, Boscaro M, Arvat E, Tiberio G, Hahner S, Zaggia B, Porpiglia F, Volante M, Fassnacht M, Terzolo M. Long-term outcomes of adjuvant mitotane therapy in patients with radically resected adrenocortical carcinoma. J Clin Endocrinol Metab 2017; 102: 1358-1365
  • 52 Bertherat J, Coste J, Bertagna X. Adjuvant mitotane in adrenocortical carcinoma. N Engl J Med 2007; 357: 1256-1257
  • 53 Iacobone M, Albiger N, Scaroni C, Mantero F, Fassina A, Viel G, Frego M, Favia G. The role of unilateral adrenalectomy in ACTH-independent macronodular adrenal hyperplasia (AIMAH). World J Surg 2008; 32: 882-889
  • 54 Debillon E, Velayoudom-Cephise FL, Salenave S, Caron P, Chaffanjon P, Wagner T, Massoutier M, Lambert B, Benoit M, Young J, Tabarin A, Chabre O. Unilateral adrenalectomy as a first-line treatment of cushing's syndrome in patients with primary bilateral macronodular adrenal hyperplasia. J Clin Endocrinol Metab 2015; 100: 4417-4424