Skip to main content

Advertisement

SpringerLink
Log in

Cushing’s disease: the burden of illness

  • Review
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Cushing’s syndrome is caused by prolonged exposure to elevated cortisol levels. The most common form of endogenous Cushing’s syndrome is Cushing’s disease, which results from an adrenocorticotropic hormone-secreting pituitary tumour. Cushing’s disease is associated with increased mortality, mostly attributable to cardiovascular complications, and a host of comorbidities such as metabolic and skeletal disorders, infections and neuropsychiatric disturbances. As a consequence, Cushing’s disease substantially impairs health-related quality of life. It is crucial that the condition is diagnosed as early as possible, and that rapid and effective treatment is initiated in order to limit long-term morbidity and mortality. The initial treatment of choice for Cushing’s disease is selective transsphenoidal pituitary surgery; however, the risk of recurrence after initial surgery is high and remains so for many decades after surgery. A particular concern is the growing body of evidence indicating that the negative physical and psychosocial sequelae of chronic hypercortisolism may persist in patients with Cushing’s disease even after long-term surgical ‘cure’. Current treatment options for post-surgical patients with persistent or recurrent Cushing’s disease include second surgery, radiotherapy, bilateral adrenalectomy and medical therapy; however, each approach has its limitations and there is an unmet need for more efficacious treatments. The current review provides an overview of the burden of illness of Cushing’s disease, underscoring the need for prompt diagnosis and effective treatment, as well as highlighting the need for better therapies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Figure adapted from Johnson et al. [49]

Fig. 4

Similar content being viewed by others

References

  1. R. Pivonello, M.C. De Martino, M. De Leo, G. Lombardi, A. Colao, Cushing’s syndrome. Endocrinol. Metab Clin. North Am. 37, 135–149 (2008)

    Article  CAS  PubMed  Google Scholar 

  2. J. Newell-Price, X. Bertagna, A.B. Grossman, L.K. Nieman, Cushing’s syndrome. Lancet 367, 1605–1617 (2006)

    Article  CAS  PubMed  Google Scholar 

  3. R. Pivonello, M. De Leo, A. Cozzolino, A. Colao, The treatment of Cushing’s disease. Endocr. Rev. 36, 385–486 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. C. Steffensen, A.M. Bak, K.Z. Rubeck, J.O. Jorgensen, Epidemiology of Cushing’s syndrome. Neuroendocrinology 92(Suppl 1), 1–5 (2010)

    Article  CAS  PubMed  Google Scholar 

  5. A. Lacroix, R.A. Feelders, C.A. Stratakis, L.K. Nieman, Cushing’s syndrome. Lancet 386, 913–927 (2015)

    Article  CAS  PubMed  Google Scholar 

  6. R. Pivonello, A.M. Isidori, M.C. De Martino et al., Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 2016 (in press)

  7. E. Valassi, A. Santos, M. Yaneva et al., The European Registry on Cushing’s syndrome: 2-year experience. Baseline demographic and clinical characteristics. Eur. J. Endocrinol. 165, 383–392 (2011)

    Article  CAS  PubMed  Google Scholar 

  8. L.K. Nieman, B.M. Biller, J.W. Findling et al., Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 100, 2807–2831 (2015)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. J. Newell-Price, P. Trainer, M. Besser, A. Grossman, The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr. Rev. 19, 647–672 (1998)

    CAS  PubMed  Google Scholar 

  10. L.K. Nieman, B.M. Biller, J.W. Findling et al., The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 93, 1526–1540 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  12. J. Lindholm, S. Juul, J.O. Jorgensen et al., Incidence and late prognosis of Cushing’s syndrome: a population-based study. J. Clin. Endocrinol. Metab. 86, 117–123 (2001)

    CAS  PubMed  Google Scholar 

  13. D. Graversen, P. Vestergaard, K. Stochholm, C.H. Gravholt, J.O. Jorgensen, Mortality in Cushing’s syndrome: a systematic review and meta-analysis. Eur. J. Intern. Med. 23, 278–282 (2012)

    Article  CAS  PubMed  Google Scholar 

  14. G. Ntali, A. Asimakopoulou, T. Siamatras et al., Mortality in Cushing’s syndrome: systematic analysis of a large series with prolonged follow-up. Eur. J. Endocrinol. 169, 715–723 (2013)

    Article  CAS  PubMed  Google Scholar 

  15. O.M. Dekkers, N.R. Biermasz, A.M. Pereira et al., Mortality in patients treated for Cushing’s disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma. J. Clin. Endocrinol. Metab. 92, 976–981 (2007)

    Article  CAS  PubMed  Google Scholar 

  16. G.D. Hammer, J.B. Tyrrell, K.R. Lamborn et al., Transsphenoidal microsurgery for Cushing’s disease: initial outcome and long-term results. J. Clin. Endocrinol. Metab. 89, 6348–6357 (2004)

    Article  CAS  PubMed  Google Scholar 

  17. Z.K. Hassan-Smith, M. Sherlock, R.C. Reulen et al., Outcome of Cushing’s disease following transsphenoidal surgery in a single center over 20 years. J. Clin. Endocrinol. Metab. 97, 1194–1201 (2012)

    Article  CAS  PubMed  Google Scholar 

  18. R. Pivonello, P. Vitale, L. Mantovani et al., MISSION study. A worldwide epidemiological study on the mortality associated with Cushing’s syndrome performed in nearly 5000 patients. 95th annual meeting of The Endocrine Society. San Francisco, CA, USA, 15–18 Jun abst SAT-LB-07 (2013)

  19. J.K. Lambert, L. Goldberg, S. Fayngold et al., Predictors of mortality and long-term outcomes in treated Cushing’s disease: a study of 346 patients. J. Clin. Endocrinol. Metab. 98, 1022–1030 (2013)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. H. Prasad, D.A. Ryan, M.F. Celzo, D. Stapleton, Metabolic syndrome: definition and therapeutic implications. Postgrad. Med. 124, 21–30 (2012)

    Article  PubMed  Google Scholar 

  21. R. Pivonello, M. De Leo, P. Vitale et al., Pathophysiology of diabetes mellitus in Cushing’s syndrome. Neuroendocrinology 92(Suppl 1), 77–81 (2010)

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  23. A. Colao, R. Pivonello, S. Spiezia et al., Persistence of increased cardiovascular risk in patients with Cushing’s disease after five years of successful cure. J. Clin. Endocrinol. Metab. 84, 2664–2672 (1999)

    CAS  PubMed  Google Scholar 

  24. A. Faggiano, R. Pivonello, S. Spiezia et al., 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, 2527–2533 (2003)

    Article  CAS  PubMed  Google Scholar 

  25. R.M. Gomez, N.M. Albiger, A.G. Diaz et al., Effect of hypercortisolism control on high blood pressure in Cushing’s syndrome. Medicina (B Aires) 67, 439–444 (2007)

    CAS  Google Scholar 

  26. A.L. Espinosa-de-los-Monteros, E. Sosa, N. Martinez, M. Mercado, Persistence of Cushing’s disease symptoms and comorbidities after surgical cure: a long-term, integral evaluation. Endocr. Pract. 19, 252–258 (2013)

    Article  PubMed  Google Scholar 

  27. G. Kaltsas, P. Makras, Skeletal diseases in Cushing’s syndrome: osteoporosis versus arthropathy. Neuroendocrinology 92(Suppl 1), 60–64 (2010)

    Article  CAS  PubMed  Google Scholar 

  28. A. Faggiano, R. Pivonello, M. Filippella et al., Spine abnormalities and damage in patients cured from Cushing’s disease. Pituitary 4, 153–161 (2001)

    Article  CAS  PubMed  Google Scholar 

  29. M.J. Barahona, N. Sucunza, E. Resmini et al., Deleterious effects of glucocorticoid replacement on bone in women after long-term remission of Cushing’s syndrome. J. Bone Miner. Res. 24, 1841–1846 (2009)

    Article  CAS  PubMed  Google Scholar 

  30. C. di Somma, R. Pivonello, S. Loche et al., 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, 302–308 (2003)

    Article  Google Scholar 

  31. L.A. Cohn, Glucocorticosteroids as immunosuppressive agents. Semin. Vet. Med. Surg. (Small Anim) 12, 150–156 (1997)

    Article  CAS  Google Scholar 

  32. N. Auphan, J.A. DiDonato, C. Rosette, A. Helmberg, M. Karin, Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science 270, 286–290 (1995)

    Article  CAS  PubMed  Google Scholar 

  33. R.I. Scheinman, P.C. Cogswell, A.K. Lofquist, A.S. Baldwin Jr, Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 270, 283–286 (1995)

    Article  CAS  PubMed  Google Scholar 

  34. M.S. Lionakis, D.P. Kontoyiannis, Glucocorticoids and invasive fungal infections. Lancet 362, 1828–1838 (2003)

    Article  CAS  PubMed  Google Scholar 

  35. G.G. Fareau, R. Vassilopoulou-Sellin, Hypercortisolemia and infection. Infect. Dis. Clin. North Am. 21, 639–657 (2007)

    Article  PubMed  Google Scholar 

  36. N.J. Sarlis, S.J. Chanock, L.K. Nieman, Cortisolemic indices predict severe infections in Cushing syndrome due to ectopic production of adrenocorticotropin. J. Clin. Endocrinol. Metab. 85, 42–47 (2000)

    CAS  PubMed  Google Scholar 

  37. R.C. Bakker, P.R. Gallas, J.A. Romijn, W.M. Wiersinga, Cushing’s syndrome complicated by multiple opportunistic infections. J. Endocrinol. Invest. 21, 329–333 (1998)

    Article  CAS  PubMed  Google Scholar 

  38. R. Pivonello, C. Simeoli, M.C. De Martino et al., Neuropsychiatric disorders in Cushing’s syndrome. Front. Neurosci. 9, 129 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  39. N. Sonino, G.A. Fava, A.R. Raffi, M. Boscaro, F. Fallo, Clinical correlates of major depression in Cushing’s disease. Psychopathology 31, 302–306 (1998)

    Article  CAS  PubMed  Google Scholar 

  40. J. Tiemensma, N.R. Biermasz, H.A. Middelkoop et al., Increased prevalence of psychopathology and maladaptive personality traits after long-term cure of Cushing’s disease. J. Clin. Endocrinol. Metab. 95, E129–E141 (2010)

    Article  CAS  PubMed  Google Scholar 

  41. C. Dimopoulou, M. Ising, H. Pfister et al., Increased prevalence of anxiety-associated personality traits in patients with Cushing’s disease: a cross-sectional study. Neuroendocrinology 97, 139–145 (2013)

    Article  CAS  PubMed  Google Scholar 

  42. A.A. Kasperlik-Zaluska, J. Slowinska-Srzednicka, W. Zgliczynski, A woman who gained weight and became schizophrenic. Lancet 361, 705 (2003)

    Article  PubMed  Google Scholar 

  43. E. Singer, S. Strohm, U. Gobel et al., Cushing’s disease, hypertension, and other sequels. Hypertension 52, 1001–1005 (2008)

    Article  CAS  PubMed  Google Scholar 

  44. M.N. Starkman, B. Giordani, S.S. Gebarski et al., Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease. Biol. Psychiatry 46, 1595–1602 (1999)

    Article  CAS  PubMed  Google Scholar 

  45. N.E. Simmons, H.M. Do, M.H. Lipper, E.R. Laws Jr, Cerebral atrophy in Cushing’s disease. Surg. Neurol. 53, 72–76 (2000)

    Article  CAS  PubMed  Google Scholar 

  46. I. Bourdeau, C. Bard, B. Noel et al., Loss of brain volume in endogenous Cushing’s syndrome and its reversibility after correction of hypercortisolism. J. Clin. Endocrinol. Metab. 87, 1949–1954 (2002)

    CAS  PubMed  Google Scholar 

  47. C.D. Andela, S.J. van der Werff, J.N. Pannekoek et al., Smaller grey matter volumes in the anterior cingulate cortex and greater cerebellar volumes in patients with long-term remission of Cushing’s disease: a case-control study. Eur. J. Endocrinol. 169, 811–819 (2013)

    Article  CAS  PubMed  Google Scholar 

  48. H. Forget, A. Lacroix, H. Cohen, Persistent cognitive impairment following surgical treatment of Cushing’s syndrome. Psychoneuroendocrinology 27, 367–383 (2002)

    Article  PubMed  Google Scholar 

  49. D.P. Merke, J.N. Giedd, M.F. Keil et al., Children experience cognitive decline despite reversal of brain atrophy one year after resolution of Cushing syndrome. J. Clin. Endocrinol. Metab. 90, 2531–2536 (2005)

    Article  CAS  PubMed  Google Scholar 

  50. J. Tiemensma, N.E. Kokshoorn, N.R. Biermasz et al., Subtle cognitive impairments in patients with long-term cure of Cushing’s disease. J. Clin. Endocrinol. Metab. 95, 2699–2714 (2010)

    Article  CAS  PubMed  Google Scholar 

  51. O. Ragnarsson, P. Berglund, D.N. Eder, G. Johannsson, 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–E1648 (2012)

    Article  CAS  PubMed  Google Scholar 

  52. L. Pikkarainen, T. Sane, A. Reunanen, The survival and well-being of patients treated for Cushing’s syndrome. J. Intern. Med. 245, 463–468 (1999)

    Article  CAS  PubMed  Google Scholar 

  53. M.D. Johnson, C.J. Woodburn, M.L. Vance, Quality of life in patients with a pituitary adenoma. Pituitary 6, 81–87 (2003)

    Article  PubMed  Google Scholar 

  54. S.M. Webb, X. Badia, M.J. Barahona et al., Evaluation of health-related quality of life in patients with Cushing’s syndrome with a new questionnaire. Eur. J. Endocrinol. 158, 623–630 (2008)

    Article  CAS  PubMed  Google Scholar 

  55. M.O. van Aken, A.M. Pereira, N.R. Biermasz et al., Quality of life in patients after long-term biochemical cure of Cushing’s disease. J. Clin. Endocrinol. Metab. 90, 3279–3286 (2005)

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. R. Pivonello, M.C. De Martino, M. De Leo et al., Cushing’s syndrome: aftermath of the cure. Arq. Bras. Endocrinol. Metabol. 51, 1381–1391 (2007)

    Article  PubMed  Google Scholar 

  58. J.T. Chow, G.B. Thompson, C.S. Grant et al., Bilateral laparoscopic adrenalectomy for corticotrophin-dependent Cushing’s syndrome: a review of the Mayo Clinic experience. Clin. Endocrinol. (Oxf) 68, 513–519 (2008)

    Article  Google Scholar 

  59. Ketoconazole HRA summary of product characteristics. 2015. http://www.medicines.org.uk/emc/medicine/30077

  60. Metopirone summary of product characteristics. 2015. http://www.medicines.org.uk/emc/medicine/26460

  61. E. Daniel, J.D. Newell-Price, Therapy of endocrine disease: steroidogenesis enzyme inhibitors in Cushing’s syndrome. Eur. J. Endocrinol. 172, R263–R280 (2015)

    Article  CAS  PubMed  Google Scholar 

  62. M. Fleseriu, R. Pivonello, J. Young et al., Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing’s disease. Pituitary 19, 138–148 (2016)

    Article  CAS  PubMed  Google Scholar 

  63. Corcept Therapeutics. Mifepristone (Korlym) prescribing information. 2012. http://www.korlym.com/docs/KorlymPrescribingInformation.pdf

  64. H.G. Fein, T.B. Vaughan III, H. Kushner, D. Cram, D. Nguyen, Sustained weight loss in patients treated with mifepristone for Cushing’s syndrome: a follow-up analysis of the SEISMIC study and long-term extension. BMC. Endocr. Disord. 15, 63 (2015)

    Article  PubMed  PubMed Central  Google Scholar 

  65. M. Fleseriu, B.M. Biller, J.W. Findling et al., Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J. Clin. Endocrinol. Metab. 97, 2039–2049 (2012)

    Article  CAS  PubMed  Google Scholar 

  66. N.A. Tritos, B.M.K. Biller, Advances in medical therapies for Cushing’s syndrome. Discov. Med. 13, 171–179 (2012)

    PubMed  Google Scholar 

  67. Novartis Pharmaceuticals Corporation. Signifor prescribing information. 2015. http://www.pharma.us.novartis.com/product/pi/pdf/signifor.pdf

  68. Novartis Pharma AG. Signifor summary of product characteristics. 2013. http://www.signifor.com/european-product-characteristics.jsp

  69. A. Colao, S. Petersenn, J. Newell-Price et al., A 12-month phase 3 study of pasireotide in Cushing’s disease. N. Engl. J. Med. 366, 914–924 (2012)

    Article  CAS  PubMed  Google Scholar 

  70. R. Pivonello, S. Petersenn, J. Newell-Price et al., Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing’s disease: results from a Phase III study. Clin. Endocrinol. (Oxf) 81, 408–417 (2014)

    Article  CAS  Google Scholar 

  71. A.R. Lila, R.A. Gopal, S.V. Acharya et al., Efficacy of cabergoline in uncured (persistent or recurrent) Cushing disease after pituitary surgical treatment with or without radiotherapy. Endocr. Pract. 16, 968–976 (2010)

    Article  PubMed  Google Scholar 

  72. R. Pivonello, M.C. De Martino, P. Cappabianca et al., The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J. Clin. Endocrinol. Metab. 94, 223–230 (2009)

    Article  CAS  PubMed  Google Scholar 

  73. R.A. Feelders, C. de Bruin, A.M. Pereira et al., Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. N. Engl. J. Med. 362, 1846–1848 (2010)

    Article  CAS  PubMed  Google Scholar 

  74. R.A. Feelders, S.J. Pulgar, A. Kempel, A.M. Pereira, The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur. J. Endocrinol. 167, 311–326 (2012)

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. We thank Richard Ogilvy-Stewart, PhD, Mudskipper Business Ltd, for medical editorial assistance with this manuscript.

Author information

Authors and Affiliations

  1. Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Via S. Pansini, 5, 80131, Naples, Italy

    Rosario Pivonello, Maria Cristina De Martino, Monica De Leo, Chiara Simeoli & Annamaria Colao

Authors
  1. Rosario Pivonello
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Cristina De Martino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Monica De Leo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chiara Simeoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Annamaria Colao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rosario Pivonello.

Ethics declarations

Conflict of interest

RP and AC have received speaker and consultancy fees from Novartis. MCDM, MDL and CS have no conflicts of interest to declare.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Pivonello, R., De Martino, M.C., De Leo, M. et al. Cushing’s disease: the burden of illness. Endocrine 56, 10–18 (2017). https://doi.org/10.1007/s12020-016-0984-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-016-0984-8

Keywords

Search

Navigation