Top

Pituitary

Published in:

Open Access 01-04-2015

Comorbidities in Cushing’s disease

Authors: S. T. Sharma, L. K. Nieman, R. A. Feelders

Published in: Pituitary | Issue 2/2015

Abstract

Introduction

Cushing’s disease is a rare disorder characterized by overproduction of ACTH from a pituitary adenoma leading to hypercortisolemia that in turn leads to increased morbidity and mortality.

Methods

Here we review the comorbidities associated with Cushing’s disease and their impact on quality of life and mortality.

Results

Recent evidence suggests that correction of hypercortisolemia may not lead to complete resolution of comorbidities associated with this condition. In particular, increased cardiovascular risk may persist despite long-term remission of hypercortisolemia. This may be related to persistence of visceral adiposity, adverse adipokine profile, glucose intolerance, hypertension, dyslipidemia, atherosclerosis and a procoagulant phenotype. Prior prolonged exposure to glucocorticoids also may have irreversible effects on the central nervous system, leading to persistent cognitive and mood alterations. Osteoporosis and fractures, especially vertebral fractures, can further add to morbidity and a poor quality of life. Normalization of cortisol levels leads to significant improvement in comorbidities but long-term data regarding complete resolution are lacking and need further study.

Conclusion

Early diagnosis and treatment of hypercortisolemia, aggressive management of comorbidities along with long-term follow-up is crucial for the optimal recovery of these patients.

Newell-Price J, Bertagna X, Grossman AB, Nieman LK (2006) Cushing’s syndrome. Lancet 367:1605–1617CrossRefPubMed

Lindholm J, Juul S, Jorgenson JO, Astrup J, Bjerre P, Feldt-Rasmussen U, Hagen C, Jorgensen J, Kosteljanetz M, Kristensen L, Laurberg P, Schmidt K, Weeke J (2001) Incidence and late prognosis of Cushing’s syndrome: a population based study. J Clin Endocrinol Metab 86:117–123PubMed

Etxabe J, Vazquez JA (1994) Morbidity and mortality in Cushing’s disease: an epidemiological approach. Clin Endocrinol (Oxf) 40:479–484CrossRef

Bolland MJ, Holdaway IM, Berkeley JE, Lim S, Dransfield WJ, Conaglen JV, Croxson MS, Gamble GD, Hunt PJ, Toomath RJ (2011) Mortality and morbidity in Cushing’s syndrome in New Zealand. Clin Endocrinol 75:436–442CrossRef

Valassi E, Santos A, Yaneva M, Toth M, Strasburger CJ, Chanson P, Wass JA, Chabre O, Pfeifer M, Feelders RA, Tsagarakis S, Trainer PJ, Franz H, Zopf K, Zacharieva S, Lamberts SW, Tabarin A, Webb SM (2011) The European registry on Cushing’s syndrome: 2-year experience. Baseline, demographic and clinical characteristics. Eur J Endocrinol 165:383–392CrossRefPubMed

Dekkers OM, Biermasz NR, Pereira AM, Roelfsema F, van Aken MO, Voormolen JH, Romijn JA (2007) Mortality in patients treated for Cushing’s disease is increased compared to patients treated for nonfunctioning pituitary macroadenomas. J Clin Endocrinol Metab 92:976–981CrossRefPubMed

Feelders RA, Pulgar SJ, Kempel A, Pereira AM (2012) The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol 167(3):311–326CrossRefPubMed

Clayton RN, Raskauskiene D, Reulen RC, Jones PW (2011) Mortality and morbidity in Cushing’s disease over 50 years in Stokeon-Trent, UK: audit and meta-analysis of literature. J Clin Endocrinol Metab 96:632–642CrossRefPubMed

Hassan-Smith ZK, Sherlock M, Reulen RC, Arlt W, Ayuk J, Toogood AA, Cooper MS, Johnson AP, Stewart PM (2012) Outcome of Cushing’s disease following transsphenoidal surgery in a single center over 20 years. J Clin Endocrinol Metab 97:1194–1201CrossRefPubMed

10.

Graversen D, Vestergaard P, Stochholm K, Gravholt CH, Jørgensen JO (2012) Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur J Intern Med 23(3):278–282CrossRefPubMed

11.

Colao A, Pivonello R, Spiezia S, Faggiano A, Ferone D, Filippella M, Marzullo P, Cerbone G, Siciliani M, Lombardi G (1999) Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. J Clin Endocrinol Metab 84(8):664–672

12.

Neary NM, Booker OJ, Abel BS, Matta JR, Muldoon N, Sinaii N, Pettigrew RI, Nieman LK, Gharib AM (2013) Hypercortisolism is associated with increased coronary arterial atherosclerosis: analysis of noninvasive coronary angiography using multidetector computerized tomography. J Clin Endocrinol Metab 98:2045–2052CrossRefPubMedCentralPubMed

13.

Leong GM, Abad V, Charmandari E, Reynolds JC, Hill S, Chrousos GP, Nieman LK (2007) Effects of child- and adolescent-onset endogenous Cushing syndrome on bone mass, body composition, and growth: a 7-year prospective study into young adulthood. J Bone Miner Res 22(1):110–118CrossRefPubMed

14.

Barahona MJ, Sucunza N, Resmini E, Fernández-Real JM, Ricart W, Moreno-Navarrete JM, Puig T, Farrerons J, Webb SM (2009) Persistent body fat mass and inflammatory marker increases after long-term cure of Cushing’s syndrome. J Clin Endocrinol Metab 94:3365–3371CrossRefPubMed

15.

Faggiano A, Pivonello R, Spiezia S, De Martino MC, Filippella M, Di Somma C, Lombardi G, Colao A (2003) Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. J Clin Endocrinol Metab 88(6):2527–2533CrossRefPubMed

16.

Mancini T, Kola B, Mantero F, Boscaro M, Arnaldi G (2004) High cardiovascular risk in patients with Cushing’s syndrome according to 1999 WHO/ISH guidelines. Clin Endocrinol (Oxf) 61(6):768–777CrossRef

17.

Fallo F, Sonino N, Barzon L, Pistorello M, Pagotto U, Paoletta A, Boscaro M (1996) Effect of surgical treatment on hypertension in Cushing’s syndrome. Am J Hypertens 9(1):77–80CrossRefPubMed

18.

Gómez RM, Albiger NM, Díaz AG, Moncet D, Pitoia FA, Bruno OD (2007) Effect of hypercortisolism control on high blood pressure in Cushing’s syndrome. Medicina (B Aires) 67:439–444

19.

Toja PM, Branzi G, Ciambellotti F, Radaelli P, De Martin M, Lonati LM, Scacchi M, Parati G, Cavagnini F, Pecori Giraldi F (2012) Clinical relevance of cardiac structure and function abnormalities in patients with Cushing’s syndrome before and after cure. Clin Endocrinol (Oxf) 76:332–338CrossRef

20.

Muiesan ML, Lupia M, Salvetti M, Grigoletto C, Sonino N, Boscaro M, Rosei EA, Mantero F, Fallo F (2003) Left ventricular structural and functional characteristics in Cushing’s syndrome. J Am Coll Cardiol 41:2275–2279CrossRefPubMed

21.

Pereira AM, Delgado V, Romijn JA, Smit JW, Bax JJ, Feelders RA (2010) Cardiac dysfunction is reversed upon successful treatment of Cushing’s syndrome. Eur J Endocrinol 162:331–340CrossRefPubMed

22.

Fatti LM, Bottasso B, Invitti C, Coppola R, Cavagnini F, Mannucci PM (2000) Markers of activation of coagulation and fibrinolysis in patients with Cushing’s syndrome. J Endocrinol Invest 23:145–150CrossRefPubMed

23.

van der Pas R, de Bruin C, Leebeek FW, de Maat MP, Rijken DC, Pereira AM, Romijn JA, Netea-Maier RT, Hermus AR, Zelissen PM, de Jong FH, van der Lely AJ, de Herder WW, Lamberts SW, Hofland LJ, Feelders RA (2012) The hypercoagulable state in Cushing’s disease is associated with increased levels of procoagulant factors and impaired fibrinolysis, but is not reversible after short-term biochemical remission induced by medical therapy. J Clin Endocrinol Metab 97:1303–1310CrossRefPubMed

24.

Manetti L, Bogazzi F, Giovannetti C, Raffaelli V, Genovesi M, Pellegrini G, Ruocco L, Iannelli A, Martino E (2010) Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing’s syndrome: results from a prospective study before and after surgery. Eur J Endocrinol 163:783–791CrossRefPubMed

25.

Van Zaane B, Nur E, Squizzato A, Dekkers OM, Twickler MT, Fliers E, Gerdes VE, Büller HR, Brandjes DP (2009) Hypercoagulable state in Cushing’s syndrome: a systematic review. J Clin Endocrinol Metab 94:2743–2750CrossRefPubMed

26.

Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ III (1998) Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 158:585–593CrossRefPubMed

27.

Stuijver DJ, van Zaane B, Feelders RA, Debeij J, Cannegieter SC, Hermus AR, van den Berg G, Pereira AM, de Herder WW, Wagenmakers MA, Kerstens MN, Zelissen PM, Fliers E, Schaper N, Drent ML, Dekkers OM, Gerdes VE (2011) Incidence of venous thromboembolism in patients with Cushing’s syndrome: a multicenter cohort study. J Clin Endocrinol Metab 96:3525–3532CrossRefPubMed

28.

Pivonello R, De Leo M, Vitale P, Cozzolino A, Simeoli C, De Martino MC, Lombardi G, Colao A (2010) Pathophysiology of diabetes mellitus in Cushing’s syndrome. Neuroendocrinology 92(Suppl 1):77–81CrossRefPubMed

29.

Giordano C, Guarnotta V, Pivonello R, Amato MC, Simeoli C, Ciresi A, Cozzolino A, Colao A (2013) Is diabetes in Cushing’s syndrome only a consequence of hypercortisolism? Eur J Endocrinol 170:311–319CrossRefPubMed

30.

Arnaldi G, Scandali VM, Trementino L, Cardinaletti M, Appolloni G, Boscaro M (2010) Pathophysiology of dyslipidemia in Cushing’s syndrome. Neuroendocrinology 92(Suppl 1):86–90CrossRefPubMed

31.

Greenman Y (2010) Management of dyslipidemia in Cushing’s syndrome. Neuroendocrinology 92(Suppl 1):91–95CrossRefPubMed

32.

Maher VM, Trainer PJ, Scoppola A, Anderson JV, Thompson GR, Besser GM (1992) Possible mechanism and treatment of o, p’DDD-induced hypercholesterolaemia. Q J Med 84:671–679PubMed

33.

Neuvonen PJ, Niemi M, Backman JT (2006) Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther 80:565–581CrossRefPubMed

34.

Ohmori N, Nomura K, Ohmori K, Kato Y, Itoh T, Takano K (2003) Osteoporosis is more prevalent in adrenal than in pituitary Cushing’s syndrome. Endocr J 50:1–7CrossRefPubMed

35.

Trementino L, Appolloni G, Ceccoli L, Marcelli G, Concettoni C, Boscaro M, Arnaldi G (2014) Bone complications in patients with Cushing’s syndrome: looking for clinical, biochemical, and genetic determinants. Osteoporos Int 25:913–921CrossRefPubMed

36.

Di Somma C, Pivonello R, Loche S, Faggiano A, Klain M, Salvatore M, Lombardi G, Colao A (2003) Effect of 2 years of cortisol normalization on the impaired bone mass and turnover in adolescent and adult patients with Cushing’s disease: a prospective study. Clin Endocrinol (Oxf) 58:302–308CrossRef

37.

Shaker JL, Lukert BP (2005) Osteoporosis associated with excess glucocorticoids. Endocrinol Metab Clin N Am 34:341–356CrossRef

38.

Kristo C, Jemtland R, Ueland T, Godang K, Bollerslev J (2006) Restoration of the coupling process and normalization of bone mass following successful treatment of endogenous Cushing’s syndrome: a prospective, long-term study. Eur J Endocrinol 154:109–118CrossRefPubMed

39.

Manning PJ, Evans MC, Reid IR (1992) Normal bone mineral density following cure of Cushing’s syndrome. Clin Endocrinol (Oxf) 36:229–234CrossRef

40.

Hermus AR, Smals AG, Swinkels LM, Huysmans DA, Pieters GF, Sweep CF, Corstens FH, Kloppenborg PW (1995) Bone mineral density and bone turnover before and after surgical cure of Cushing’s syndrome. J Clin Endocrinol Metab 80:2859–2865PubMed

41.

Faggiano A, Pivonello R, Melis D, Filippella M, Di Somma C, Petretta M, Lombardi G, Colao A (2003) Nephrolithiasis in Cushing’s disease: prevalence, etiopathogenesis, and modification after disease cure. J Clin Endocrinol Metab 88:2076–2080CrossRefPubMed

42.

Dorn LD, Burgess ES, Dubbert B, Simpson SE, Friedman T, Kling M, Gold PW, Chrousos GP (1995) Psychopathology in patients with endogenous Cushing’s syndrome: ‘atypical’ or melancholic features. Clin Endocrinol (Oxf) 43:433–442CrossRef

43.

Sonino N, Fava GA (2001) Psychiatric disorders associated with Cushing’s syndrome. Epidemiology, pathophysiology and treatment. CNS Drugs 15:361–373CrossRefPubMed

44.

Kelly WF, Kelly MJ, Faragher B (1996) A prospective study of psychiatric and psychological aspects of Cushing’s syndrome. Clin Endocrinol (Oxf) 45:715–720CrossRef

45.

Dorn LD, Burgess ES, Friedman TC, Dubbert B, Gold PW, Chrousos GP (1997) The longitudinal course of psychopathology in Cushing’s syndrome after correction of hypercortisolism. J Clin Endocrinol Metab 82:912–919PubMed

46.

Tiemensma J, Biermasz NR, Middelkoop HA, van der Mast RC, Romijn JA, Pereira AM (2010) Increased prevalence of psychopathology and maladaptive personality traits after long-term cure of Cushing’s disease. J Clin Endocrinol Metab 95:E129–E141CrossRefPubMed

47.

Starkman MN, Gebarski SS, Berent S, Schteingart DE (1992) Hippocampal formation volume, memory dysfunction, and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatry 32:756–765CrossRefPubMed

48.

Hook JN, Giordani B, Schteingart DE, Guire K, Giles J, Ryan K, Gebarski SS, Langenecker SA, Starkman MN (2007) Patterns of cognitive change over time and relationship to age following successful treatment of Cushing’s disease. J Int Neuropsychol Soc 13:21–29CrossRefPubMed

49.

Ragnarsson O, Berglund P, Eder DN, Johannsson G (2012) Long-term cognitive impairments and attentional deficits in patients with Cushing’s disease and cortisol-producing adrenal adenoma in remission. J Clin Endocrinol Metab 97:E1640–E1648CrossRefPubMed

50.

Bourdeau I, Bard C, Noël B, Leclerc I, Cordeau MP, Bélair M, Lesage J, Lafontaine L, Lacroix A (2002) Loss of brain volume in endogenous Cushing’s syndrome and its reversibility after correction of hypercortisolism. J Clin Endocrinol Metab 87:1949–1954PubMed

51.

Starkman MN, Giordani B, Gebarski SS, Berent S, Schork MA, Schteingart DE (1999) Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease. Biol Psychiatry 46:1595–1602CrossRefPubMed

52.

Tiemensma J, Kokshoorn NE, Biermasz NR, Keijser BJ, Wassenaar MJ, Middelkoop HA, Pereira AM, Romijn JA (2010) Subtle cognitive impairments in patients with long-term cure of Cushing’s disease. J Clin Endocrinol Metab 95:2699–2714CrossRefPubMed

53.

van der Werff SJ, Andela CD, Nienke Pannekoek J, Meijer OC, van Buchem MA, Rombouts SA, van der Mast RC, Biermasz NR, Pereira AM, van der Wee NJ (2014) Widespread reductions of white matter integrity in patients with long-term remission of Cushing’s disease. Neuroimage Clin 4:659–667CrossRefPubMedCentralPubMed

54.

Gotch PM (1994) Cushing’s syndrome from the patient’s perspective. Endocrinol Metab Clin N Am 23:607–617

55.

Lindsay JR, Nansel T, Baid S, Gumowski J, Nieman LK (2006) Long-term impaired quality of life in Cushing’s syndrome despite initial improvement after surgical remission. J Clin Endocrinol Metab 91:447–453CrossRefPubMed

56.

van Aken MO, Pereira AM, Biermasz NR, van Thiel SW, Hoftijzer HC, Smit JW, Roelfsema F, Lamberts SW, Romijn JA (2005) Quality of life in patients after long-term biochemical cure of Cushing’s disease. J Clin Endocrinol Metab 90:3279–3286CrossRefPubMed

57.

Carluccio A, Sundaram NK, Chablani S, Amrock LG, Lambert JK, Post KD, Geer EB (2014) Predictors of quality of life in 102 patients with treated Cushing’s disease. Clin Endocrinol (Oxf). doi:10.1111/cen.12521

58.

Andela CD, Scharloo M, Pereira AM, Kaptein AA, Biermasz NR (2015) Quality of life (QoL) impairments in patients with a pituitary adenoma: a systematic review of QoL studies. Pituitary. doi:10.1007/s11102-015-0636-7

59.

Swearingen B, Wu N, Chen SY, Pulgar S, Biller BM (2011) Health care resource use and costs among patients with cushing disease. Endocr Pract 17:681–690CrossRefPubMed

60.

Broder MS, Neary MP, Chang E, Cherepanov D, Ludlam WH (2014) Burden of illness, annual healthcare utilization and costs associated with commercially insured patients with Cushing’s disease in the United States. Endocr Pract. doi:10.4158/EP14126.OR

Title: Comorbidities in Cushing’s disease
Authors: S. T. Sharma
L. K. Nieman
R. A. Feelders
Publication date: 01-04-2015
Publisher: Springer US
Published in: Pituitary / Issue 2/2015
Print ISSN: 1386-341X
Electronic ISSN: 1573-7403
DOI: https://doi.org/10.1007/s11102-015-0645-6

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Introduction

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 2/2015

Pituitary-directed medical therapy in Cushing’s disease

Diagnosis of Cushing’s disease

New potential targets for treatment of Cushing’s disease: epithelial growth factor receptor and cyclin-dependent kinases

Medical combination therapies in Cushing’s disease

Update on radiation therapy in patients with Cushing’s disease

Current status on histological classification in Cushing’s disease

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials