Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

An individualized approach to the management of Cushing disease

Nature Reviews Endocrinology volume 19, pages 581–599 (2023)Cite this article

Subjects

Abstract

Cushing disease caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary corticotroph adenoma leads to hypercortisolaemia with high mortality due to metabolic, cardiovascular, immunological, neurocognitive, haematological and infectious conditions. The disorder is challenging to diagnose because of its common and heterogenous presenting features and the biochemical pitfalls of testing levels of hormones in the hypothalamic–pituitary–adrenal axis. Several late-night salivary cortisol and 24-h urinary free cortisol tests are usually required as well as serum levels of cortisol after a dexamethasone suppression test. MRI might only identify an adenoma in 60–75% of patients and many adenomas are small. Therefore, inferior petrosal sinus sampling remains the gold standard for confirmation of ACTH secretion from a pituitary source. Initial treatment is usually transsphenoidal adenoma resection, but preoperative medical therapy is increasingly being used in some countries and regions. Other management approaches are required if Cushing disease persists or recurs following surgery, including medications to modulate ACTH or block cortisol secretion or actions, pituitary radiation, and/or bilateral adrenalectomy. All patients require lifelong surveillance for persistent comorbidities, clinical and biochemical recurrence, and treatment-related adverse effects (including development of treatment-associated hypopituitarism). In this Review, we discuss challenges in the management of Cushing disease in adults and provide information to guide clinicians when planning an integrated and individualized approach for each patient.

Key points

  • Cushing disease, an adrenocorticotropic hormone-secreting pituitary adenoma, is the most frequent cause of endogenous Cushing syndrome; sustained hypercortisolism produced by increased levels of adrenocorticotropic hormone leads to substantial morbidity and mortality.

  • Surgery is the first-line treatment for most patients, with preoperative medical therapy increasingly being used in some countries; biochemical postoperative remission largely depends on adenoma size and surgeon experience.

  • Up to 35% of cases recur after surgery, and recurrence might be delayed by decades; patient management should be individualized and lifelong follow-up is required.

  • Practice standards for the use of pituitary-directed agents, adrenal steroidogenesis inhibitors and glucocorticoid receptor antagonists as well as for repeat surgery and for radiotherapy differ and are often specific to the centre and region.

  • Bilateral adrenalectomy is often recommended for patients desiring pregnancy and those with severe persistent hypercortisolaemia; resultant permanent adrenal insufficiency and potential for corticotroph adenoma progression are precautionary clinical considerations.

  • Clinical and biochemical responses to therapy and quality-of-life changes should be assessed within weeks of treatment initiation; all patients require lifelong monitoring and management of comorbidities and treatment-related adverse effects.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Algorithm for individualizing management of Cushing disease.
Fig. 2: Mechanisms of medical therapies for Cushing disease.
Fig. 3: Case examples: effectiveness of surgical tumour resection in challenging cases.
Fig. 4: Case example: corticotroph tumour progression after bilateral adrenalectomy.
Fig. 5: Assessment of comorbidities and complications in patients with Cushing disease.

References

  1. Fleseriu, M. et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 9, 847–875 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jones, P. S. & Swearingen, B. Pituitary surgery in Cushing’s disease: first line treatment and role of reoperation. Pituitary 25, 713–717 (2022).

    Article  CAS  PubMed  Google Scholar 

  3. Melmed, S. Pituitary-tumor endocrinopathies. N. Engl. J. Med. 382, 937–950 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Ragnarsson, O. et al. The incidence of Cushing’s disease: a nationwide Swedish study. Pituitary 22, 179–186 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Broder, M. S., Neary, M. P., Chang, E., Cherepanov, D. & Ludlam, W. H. Incidence of Cushing’s syndrome and Cushing’s disease in commercially-insured patients <65 years old in the United States. Pituitary 18, 283–289 (2015).

    Article  PubMed  Google Scholar 

  6. Melmed, S. et al. Clinical biology of the pituitary adenoma. Endocr. Rev. 43, 1003–1037 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Limumpornpetch, P. et al. The effect of endogenous Cushing syndrome on all-cause and cause-specific mortality. J. Clin. Endocrinol. Metab. 107, 2377–2388 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Nieman, L. K. Molecular derangements and the diagnosis of ACTH-dependent Cushing’s syndrome. Endocr. Rev. 43, 852–877 (2022).

    Article  PubMed  Google Scholar 

  9. Asa, S. L., Mete, O., Perry, A. & Osamura, R. Y. Overview of the 2022 WHO classification of pituitary tumors. Endocr. Pathol. 33, 6–26 (2022).

    Article  CAS  PubMed  Google Scholar 

  10. Reincke, M. et al. Mutations in the deubiquitinase gene USP8 cause Cushing’s disease. Nat. Genet. 47, 31–38 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Fukuoka, H. et al. EGFR as a therapeutic target for human, canine, and mouse ACTH-secreting pituitary adenomas. J. Clin. Invest. 121, 4712–4721 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Neou, M. et al. Pangenomic classification of pituitary neuroendocrine tumors. Cancer Cell 37, 123–134 e125 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Stroud, A. et al. Outcomes of pituitary surgery for Cushing’s disease: a systematic review and meta-analysis. Pituitary 23, 595–609 (2020).

    Article  PubMed  Google Scholar 

  14. Honegger, J. & Grimm, F. The experience with transsphenoidal surgery and its importance to outcomes. Pituitary 21, 545–555 (2018).

    Article  PubMed  Google Scholar 

  15. Zamanipoor Najafabadi, A. H. et al. Starting point for benchmarking outcomes and reporting of pituitary adenoma surgery within the European Reference Network on Rare Endocrine Conditions (Endo-ERN): results from a meta-analysis and survey study. Endocr. Connect. 12, e220349 (2023).

    Article  PubMed  Google Scholar 

  16. Casanueva, F. F. et al. Criteria for the definition of Pituitary Tumor Centers of Excellence (PTCOE): a pituitary society statement. Pituitary 20, 489–498 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Couselo, M., Frara, S., Giustina, A. & Casanueva, F. F. Pituitary Tumor Centers of Excellence for Cushing’s disease. Pituitary 25, 772–775 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yang, A. B., Henderson, F. Jr. & Schwartz, T. H. Surgical strategies in the treatment of MR-negative Cushing’s disease: a systematic review and treatment algorithm. Pituitary 25, 551–562 (2022).

    Article  PubMed  Google Scholar 

  19. Sharifi, G. et al. MRI-negative Cushing’s disease: management strategy and outcomes in 15 cases utilizing a pure endoscopic endonasal approach. BMC Endocr. Disord. 22, 154 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wind, J. J. et al. The lateralization accuracy of inferior petrosal sinus sampling in 501 patients with Cushing’s disease. J. Clin. Endocrinol. Metab. 98, 2285–2293 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Oldfield, E. H. Surgical management of Cushing’s disease: a personal perspective. Clin. Neurosurg. 58, 13–26 (2011).

    Article  PubMed  Google Scholar 

  22. Akirov, A. et al. Clinical study and systematic review of pituitary microadenomas vs. macroadenomas in Cushing’s disease: does size matter? J. Clin. Med. 11, 1558 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Balomenaki, M., Vassiliadi, D. A. & Tsagarakis, S. Cushing’s disease: risk of recurrence following trans-sphenoidal surgery, timing and methods for evaluation. Pituitary 25, 718–721 (2022).

    Article  CAS  PubMed  Google Scholar 

  24. Paluzzi, A. et al. Endoscopic endonasal infrasellar approach to the sellar and suprasellar regions: technical note. Skull Base 21, 335–342 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Broersen, L. H. A. et al. Endoscopic vs. microscopic transsphenoidal surgery for Cushing’s disease: a systematic review and meta-analysis. Pituitary 21, 524–534 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhang, T., Zhang, B., Yuan, L., Song, Y. & Wang, F. Superiority of endoscopic transsphenoidal pituitary surgery to microscopic transseptal pituitary surgery for treatment of Cushing’s disease. Rev. Assoc. Med. Bras. 67, 1687–1691 (2021).

    Article  PubMed  Google Scholar 

  27. Sabahi, M. et al. MRI-negative Cushing’s disease: a review on therapeutic management. World Neurosurg. 162, 126–137 (2022).

    Article  PubMed  Google Scholar 

  28. Monteith, S. J., Starke, R. M., Jane, J. A. Jr. & Oldfield, E. H. Use of the histological pseudocapsule in surgery for Cushing disease: rapid postoperative cortisol decline predicting complete tumor resection. J. Neurosurg. 116, 721–727 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Lonser, R. R., Nieman, L. & Oldfield, E. H. Cushing’s disease: pathobiology, diagnosis, and management. J. Neurosurg. 126, 404–417 (2017).

    Article  PubMed  Google Scholar 

  30. Lim, J. S., Lee, S. K., Kim, S. H., Lee, E. J. & Kim, S. H. Intraoperative multiple-staged resection and tumor tissue identification using frozen sections provide the best result for the accurate localization and complete resection of tumors in Cushing’s disease. Endocrine 40, 452–461 (2011).

    Article  CAS  PubMed  Google Scholar 

  31. Patel, V. et al. Ultra-high field magnetic resonance imaging for localization of corticotropin-secreting pituitary adenomas. Neuroradiology 62, 1051–1054 (2020).

    Article  PubMed  Google Scholar 

  32. Grober, Y., Grober, H., Wintermark, M., Jane, J. A. & Oldfield, E. H. Comparison of MRI techniques for detecting microadenomas in Cushing’s disease. J. Neurosurg. 128, 1051–1057 (2018).

    Article  PubMed  Google Scholar 

  33. Guo, Q., Young, W. F., Erickson, D. & Erickson, B. Usefulness of dynamic MRI enhancement measures for the diagnosis of ACTH-producing pituitary adenomas. Clin. Endocrinol. 82, 267–273 (2015).

    Article  CAS  Google Scholar 

  34. Chatain, G. P. et al. Potential utility of FLAIR in MRI-negative Cushing’s disease. J. Neurosurg. 129, 620–628 (2018).

    Article  PubMed  Google Scholar 

  35. Bashari, W. A. et al. Modern imaging in Cushing’s disease. Pituitary 25, 709–712 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Koh, C. H. et al. The clinical outcomes of imaging modalities for surgical management Cushing’s disease — a systematic review and meta-analysis. Front. Endocrinol. 13, 1090144 (2022).

    Article  Google Scholar 

  37. Boyle, J. et al. CRH stimulation improves 18F-FDG-PET detection of pituitary adenomas in Cushing’s disease. Endocrine 65, 155–165 (2019).

    Article  CAS  PubMed  Google Scholar 

  38. Senanayake, R. et al. New types of localization methods for adrenocorticotropic hormone-dependent Cushing’s syndrome. Best Pract. Res. Clin. Endocrinol. Metab. 35, 101513 (2021).

    Article  CAS  PubMed  Google Scholar 

  39. Koulouri, O. et al. A role for 11C-methionine PET imaging in ACTH-dependent Cushing’s syndrome. Eur. J. Endocrinol. 173, M107–M120 (2015).

    Article  CAS  PubMed  Google Scholar 

  40. Berkmann, S. et al. Selective resection of cushing microadenoma guided by preoperative hybrid 18-fluoroethyl-L-tyrosine and 11-C-methionine PET/MRI. Pituitary 24, 878–886 (2021).

    Article  CAS  PubMed  Google Scholar 

  41. Walia, R. et al. Molecular imaging targeting corticotropin-releasing hormone receptor for corticotropinoma: a changing paradigm. J. Clin. Endocrinol. Metab. 106, e1816–e1826 (2021).

    Article  PubMed  Google Scholar 

  42. Valassi, E. et al. Delayed remission after transsphenoidal surgery in patients with Cushing’s disease. J. Clin. Endocrinol. Metab. 95, 601–610 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fan, Y. et al. Development of machine learning models for predicting postoperative delayed remission in patients with Cushing’s disease. J. Clin. Endocrinol. Metab. 106, e217–e231 (2021).

    Article  PubMed  Google Scholar 

  44. Esposito, F. et al. Clinical review: early morning cortisol levels as a predictor of remission after transsphenoidal surgery for Cushing’s disease. J. Clin. Endocrinol. Metab. 91, 7–13 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Hameed, N. et al. Remission rate after transsphenoidal surgery in patients with pathologically confirmed Cushing’s disease, the role of cortisol, ACTH assessment and immediate reoperation: a large single center experience. Pituitary 16, 452–458 (2013).

    Article  CAS  PubMed  Google Scholar 

  46. Wang, F. et al. Postoperative day 1 morning cortisol value as a biomarker to predict long-term remission of cushing disease. J. Clin. Endocrinol. Metab. 106, e94–e102 (2021).

    Article  PubMed  Google Scholar 

  47. Lindsay, J. R., Oldfield, E. H., Stratakis, C. A. & Nieman, L. K. The postoperative basal cortisol and CRH tests for prediction of long-term remission from Cushing’s disease after transsphenoidal surgery. J. Clin. Endocrinol. Metab. 96, 2057–2064 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bou Khalil, R. et al. Sequential hormonal changes in 21 patients with recurrent Cushing’s disease after successful pituitary surgery. Eur. J. Endocrinol. 165, 729–737 (2011).

    Article  PubMed  Google Scholar 

  49. Amlashi, F. G. et al. Accuracy of late-night salivary cortisol in evaluating postoperative remission and recurrence in Cushing’s disease. J. Clin. Endocrinol. Metab. 100, 3770–3777 (2015).

    Article  CAS  PubMed  Google Scholar 

  50. Carroll, T. B., Javorsky, B. R. & Findling, J. W. Postsurgical recurrent Cushing disease: clinical benefit of early intervention in patients with normal urinary free cortisol. Endocr. Pract. 22, 1216–1223 (2016).

    Article  PubMed  Google Scholar 

  51. Braun, L. T. et al. Recurrence after pituitary surgery in adult Cushing’s disease: a systematic review on diagnosis and treatment. Endocrine 70, 218–231 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sandouk, Z. et al. Variability of late-night salivary cortisol in Cushing disease: a prospective study. J. Clin. Endocrinol. Metab. 103, 983–990 (2018).

    Article  PubMed  Google Scholar 

  53. Petersenn, S. et al. High variability in baseline urinary free cortisol values in patients with Cushing’s disease. Clin. Endocrinol. 80, 261–269 (2014).

    Article  CAS  Google Scholar 

  54. Cambos, S. et al. Persistent cortisol response to desmopressin predicts recurrence of Cushing’s disease in patients with post-operative corticotropic insufficiency. Eur. J. Endocrinol. 182, 489–498 (2020).

    Article  CAS  PubMed  Google Scholar 

  55. Abellan-Galiana, P. et al. Prognostic usefulness of ACTH in the postoperative period of Cushing’s disease. Endocr. Connect. 8, 1262–1272 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Albani, A. et al. Improved pasireotide response in USP8 mutant corticotroph tumours in vitro. Endocr. Relat. Cancer 29, 503–511 (2022).

    Article  CAS  PubMed  Google Scholar 

  57. Zoli, M. et al. Machine learning-based prediction of outcomes of the endoscopic endonasal approach in Cushing disease: is the future coming? Neurosurg. Focus 48, E5 (2020).

    Article  PubMed  Google Scholar 

  58. Nadezhdina, E. Y. et al. Prediction of recurrence and remission within 3 years in patients with Cushing disease after successful transnasal adenomectomy. Pituitary 22, 574–580 (2019).

    Article  PubMed  Google Scholar 

  59. Shahrestani, S. et al. Neural network modeling for prediction of recurrence, progression, and hormonal non-remission in patients following resection of functional pituitary adenomas. Pituitary 24, 523–529 (2021).

    Article  CAS  PubMed  Google Scholar 

  60. Nieman, L. K. 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 

  61. Melmed, S. Medical progress: acromegaly. N. Engl. J. Med. 355, 2558–2573 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Fleseriu, M. et al. Long-term outcomes of osilodrostat in Cushing’s disease: LINC 3 study extension. Eur. J. Endocrinol. 187, 531–541 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Fleseriu, M. et al. Long-term efficacy and safety of once-monthly pasireotide in Cushing’s disease: a Phase III extension study. Clin. Endocrinol. 91, 776–785 (2019).

    Article  CAS  Google Scholar 

  64. Fleseriu, M. et al. Levoketoconazole treatment in endogenous Cushing’s syndrome: extended evaluation of clinical, biochemical, and radiologic outcomes. Eur. J. Endocrinol. 187, 859–871 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Ferriere, A. et al. Cabergoline for Cushing’s disease: a large retrospective multicenter study. Eur. J. Endocrinol. 176, 305–314 (2017).

    Article  CAS  PubMed  Google Scholar 

  66. Simoes Correa Galendi, J., Correa Neto, A. N. S., Demetres, M., Boguszewski, C. L. & Nogueira, V. Effectiveness of medical treatment of Cushing’s disease: a systematic review and meta-analysis. Front. Endocrinol. 12, 732240 (2021).

    Article  Google Scholar 

  67. Pivonello, R., Pivonello, C., Simeoli, C., De Martino, M. C. & Colao, A. The dopaminergic control of Cushing’s syndrome. J. Endocrinol. Invest. 45, 1297–1315 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Varlamov, E. V., Han, A. J. & Fleseriu, M. Updates in adrenal steroidogenesis inhibitors for Cushing’s syndrome — a practical guide. Best Pract. Res. Clin. Endocrinol. Metab. 35, 101490 (2021).

    Article  CAS  PubMed  Google Scholar 

  69. Biller, B. M. et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J. Clin. Endocrinol. Metab. 93, 2454–2462 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Raverot, G. et al. European Society of Endocrinology clinical practice guidelines for the management of aggressive pituitary tumours and carcinomas. Eur. J. Endocrinol. 178, G1–G24 (2018).

    Article  CAS  PubMed  Google Scholar 

  71. Lasolle, H., Vasiljevic, A., Jouanneau, E., Ilie, M. D. & Raverot, G. Aggressive corticotroph tumors and carcinomas. J. Neuroendocrinol. 34, e13169 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Colao, A. 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 

  73. Lacroix, A. et al. Efficacy and safety of once-monthly pasireotide in Cushing’s disease: a 12 month clinical trial. Lancet Diabetes Endocrinol. 6, 17–26 (2018).

    Article  CAS  PubMed  Google Scholar 

  74. Manetti, L. et al. Long-term safety and efficacy of subcutaneous pasireotide in patients with Cushing’s disease: Interim results from a long-term real-world evidence study. Pituitary 22, 542–551 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lacroix, A. et al. Long-acting pasireotide improves clinical signs and quality of life in Cushing’s disease: Results from a phase III study. J. Endocrinol. Invest. 43, 1613–1622 (2020).

    Article  CAS  PubMed  Google Scholar 

  76. Pivonello, R. et al. Pasireotide treatment significantly improves clinical signs and symptoms in patients with Cushing’s disease: results from a phase III study. Clin. Endocrinol. 81, 408–417 (2014).

    Article  CAS  Google Scholar 

  77. Newell-Price, J. et al. Use of late-night salivary cortisol to monitor response to medical treatment in Cushing’s disease. Eur. J. Endocrinol. 182, 207–217 (2020).

    Article  CAS  PubMed  Google Scholar 

  78. Mondin, A. et al. Pasireotide-induced shrinkage in GH and ACTH secreting pituitary adenoma: a systematic review and meta-analysis. Front. Endocrinol. 13, 935759 (2022).

    Article  Google Scholar 

  79. Samson, S. L. et al. Managing pasireotide-associated hyperglycemia: a randomized, open-label, phase IV study. Pituitary 24, 887–903 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Pivonello, R., Simeoli, C., Di Paola, N. & Colao, A. Cushing’s disease: adrenal steroidogenesis inhibitors. Pituitary 25, 726–732 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Castinetti, F. et al. Ketoconazole in Cushing’s disease: is it worth a try? J. Clin. Endocrinol. Metab. 99, 1623–1630 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Viecceli, C. et al. Evaluation of ketoconazole as a treatment for Cushing’s disease in a retrospective cohort. Front. Endocrinol. 13, 1017331 (2022).

    Article  Google Scholar 

  83. Ollivier, M., Haissaguerre, M., Ferriere, A. & Tabarin, A. Should we avoid using ketoconazole in patients with severe Cushing’s syndrome and increased levels of liver enzymes? Eur. J. Endocrinol. 179, L1–L2 (2018).

    Article  CAS  PubMed  Google Scholar 

  84. Young, J. et al. Hepatic safety of ketoconazole in Cushing’s syndrome: results of a compassionate use programme in france. Eur. J. Endocrinol. 178, 447–458 (2018).

    Article  PubMed  Google Scholar 

  85. Creemers, S. G. et al. Levoketoconazole, the 2S,4R enantiomer of ketoconazole, a new steroidogenesis inhibitor for Cushing’s syndrome treatment. J. Clin. Endocrinol. Metab. 106, e1618–e1630 (2021).

    Article  PubMed  Google Scholar 

  86. Pivonello, R. et al. Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS). Pituitary 25, 911–926 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Fleseriu, M. et al. Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing’s syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial. Lancet Diabetes Endocrinol. 7, 855–865 (2019).

    Article  CAS  PubMed  Google Scholar 

  88. Pivonello, R. et al. Levoketoconazole in the treatment of patients with Cushing’s syndrome and diabetes mellitus: results from the SONICS phase 3 study. Front. Endocrinol. 12, 595894 (2021).

    Article  Google Scholar 

  89. Pivonello, R. et al. Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 8, 748–761 (2020).

    Article  CAS  PubMed  Google Scholar 

  90. Gadelha, M. et al. Randomized trial of osilodrostat for the treatment of cushing disease. J. Clin. Endocrinol. Metab. 107, e2882–e2895 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  91. Fleseriu, M. et al. Long-term efficacy and safety of osilodrostat in Cushing’s disease: final results from a Phase II study with an optional extension phase (LINC 2). Pituitary 25, 959–970 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. He, X., Findling, J. W. & Auchus, R. J. Glucocorticoid withdrawal syndrome following treatment of endogenous Cushing syndrome. Pituitary 25, 393–403 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Fontaine-Sylvestre, C., Letourneau-Guillon, L., Moumdjian, R. A., Berthelet, F. & Lacroix, A. Corticotroph tumor progression during long-term therapy with osilodrostat in a patient with persistent Cushing’s disease. Pituitary 24, 207–215 (2021).

    Article  CAS  PubMed  Google Scholar 

  94. Nowotny, H. F. et al. 11-Oxygenated C19 steroids are the predominant androgens responsible for hyperandrogenemia in Cushing’s disease. Eur. J. Endocrinol. 187, 663–673 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bonnet-Serrano, F. et al. Differences in the spectrum of steroidogenic enzyme inhibition between osilodrostat and metyrapone in ACTH-dependent Cushing syndrome patients. Eur. J. Endocrinol. 187, 315–322 (2022).

    Article  CAS  PubMed  Google Scholar 

  96. Daniel, E. et al. Effectiveness of metyrapone in treating Cushing’s syndrome: a retrospective multicenter study in 195 patients. J. Clin. Endocrinol. Metab. 100, 4146–4154 (2015).

    Article  CAS  PubMed  Google Scholar 

  97. Nieman, L. K. et al. Metyrapone treatment in endogenous Cushing’s syndrome: results at week 12 from PROMPT, a prospective international multicenter, open-label, phase III/IV study. J. Endocr. Soc. 5, A515 (2021).

    Article  PubMed Central  Google Scholar 

  98. Constantinescu, S. M. et al. Etomidate infusion at low doses is an effective and safe treatment for severe Cushing’s syndrome outside intensive care. Eur. J. Endocrinol. 183, 161–167 (2020).

    Article  CAS  PubMed  Google Scholar 

  99. Baudry, C. et al. Efficiency and tolerance of mitotane in Cushing’s disease in 76 patients from a single center. Eur. J. Endocrinol. 167, 473–481 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Fleseriu, M. 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 

  101. Fleseriu, M. et al. Changes in plasma ACTH levels and corticotroph tumor size in patients with Cushing’s disease during long-term treatment with the glucocorticoid receptor antagonist mifepristone. J. Clin. Endocrinol. Metab. 99, 3718–3727 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kamenicky, P. et al. Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent Cushing’s syndrome. J. Clin. Endocrinol. Metab. 96, 2796–2804 (2011).

    Article  CAS  PubMed  Google Scholar 

  103. Valassi, E., Crespo, I., Gich, I., Rodriguez, J. & Webb, S. M. A reappraisal of the medical therapy with steroidogenesis inhibitors in Cushing’s syndrome. Clin. Endocrinol. 77, 735–742 (2012).

    Article  CAS  Google Scholar 

  104. Feelders, R. A. 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 

  105. Vilar, L. et al. Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease. Pituitary 13, 123–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Barbot, M. et al. Combination therapy for Cushing’s disease: effectiveness of two schedules of treatment: should we start with cabergoline or ketoconazole? Pituitary 17, 109–117 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. Feelders, R. et al. Prospective phase ii study (CAPACITY) of pasireotide monotherapy or in combination with cabergoline in patients with Cushing’s disease (Poster). Endocr. Rev. 38 (Suppl. 1), i1–i1431 (2017).

    Google Scholar 

  108. Broersen, L. H. A., Jha, M., Biermasz, N. R., Pereira, A. M. & Dekkers, O. M. Effectiveness of medical treatment for Cushing’s syndrome: a systematic review and meta-analysis. Pituitary 21, 631–641 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Gadelha, M. R., Wildemberg, L. E. & Shimon, I. Pituitary acting drugs: cabergoline and pasireotide. Pituitary 25, 722–725 (2022).

    Article  CAS  PubMed  Google Scholar 

  110. Gatto, F., Arvigo, M. & Ferone, D. Somatostatin receptor expression and patients’ response to targeted medical treatment in pituitary tumors: evidences and controversies. J. Endocrinol. Invest. 43, 1543–1553 (2020).

    Article  CAS  PubMed  Google Scholar 

  111. Greenblatt, H. K. & Greenblatt, D. J. Liver injury associated with ketoconazole: review of the published evidence. J. Clin. Pharmacol. 54, 1321–1329 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Findling, J. W. et al. Late-night salivary cortisol may be valuable for assessing treatment response in patients with Cushing’s disease: 12-month, phase III pasireotide study. Endocrine 54, 516–523 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Dormoy, A. et al. Efficacy and safety of osilodrostat in paraneoplastic Cushing’s syndrome: a real-world multicenter study in France. J. Clin. Endocrinol. Metab. 108, 1475–1487 (2023).

    Article  PubMed  Google Scholar 

  114. Bessiene, L. et al. Rapid control of severe ectopic Cushing’s syndrome by oral osilodrostat monotherapy. Eur. J. Endocrinol. 184, L13–L15 (2021).

    Article  CAS  PubMed  Google Scholar 

  115. Valassi, E. et al. Preoperative medical treatment in Cushing’s syndrome: frequency of use and its impact on postoperative assessment: data from ERCUSYN. Eur. J. Endocrinol. 178, 399–409 (2018).

    Article  CAS  PubMed  Google Scholar 

  116. Liu, N. A. et al. Treatment of Cushing’s disease with pituitary-targeting seliciclib. J. Clin. Endocrinol. Metab. 108, 726–735 (2023).

    Article  PubMed  Google Scholar 

  117. Krasner, A. et al. Inhibition of Basal and ACTH-Stimulated Cortisol Secretion in Humans Using an Oral, Nonpeptide ACTH Antagonist (CRN04894) ENDO 2022. Poster presentation (2022).

  118. Feldhaus, A. L. et al. ALD1613, a novel long-acting monoclonal antibody to control ACTH-driven pharmacology. Endocrinology 158, 1–8 (2017).

    CAS  PubMed  Google Scholar 

  119. Ben-Shlomo, A. & Cooper, O. Role of tyrosine kinase inhibitors in the treatment of pituitary tumours: From bench to bedside. Curr. Opin. Endocrinol. Diabetes Obes. 24, 301–305 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Sugiyama, A. et al. Inhibition of heat shock protein 90 decreases ACTH production and cell proliferation in AtT-20 cells. Pituitary 18, 542–553 (2015).

    Article  CAS  PubMed  Google Scholar 

  121. Pivonello, R. et al. Relacorilant, a selective glucocorticoid receptor modulator, induces clinical improvements in patients with Cushing syndrome: results from a prospective, open-label phase 2 study. Front. Endocrinol. 12, 662865 (2021).

    Article  Google Scholar 

  122. Oda, S. et al. An open-label phase I/IIA clinical trial of 11BETA-HSD1 inhibitor for Cushing’s syndrome and autonomous cortisol secretion. J. Clin. Endocrinol. Metab. 106, e3865–e3880 (2021).

    Article  PubMed  Google Scholar 

  123. Katznelson, L. Role of radiation in the treatment of Cushing disease. Pituitary 25, 740–742 (2022).

    Article  CAS  PubMed  Google Scholar 

  124. Gheorghiu, M. L. Updates in the outcomes of radiation therapy for Cushing’s disease. Best Pract. Res. Clin. Endocrinol. Metab. 35, 101514 (2021).

    Article  CAS  PubMed  Google Scholar 

  125. Sherry, A. D. et al. Outcomes of stereotactic radiosurgery and hypofractionated stereotactic radiotherapy for refractory Cushing’s disease. Pituitary 22, 607–613 (2019).

    Article  CAS  PubMed  Google Scholar 

  126. Mehta, G. U. et al. Stereotactic radiosurgery for Cushing disease: results of an international, multicenter study. J. Clin. Endocrinol. Metab. 102, 4284–4291 (2017).

    Article  PubMed  Google Scholar 

  127. Mathieu, D. et al. Stereotactic radiosurgery for secretory pituitary adenomas: systematic review and international stereotactic radiosurgery society practice recommendations. J. Neurosurg. 136, 801–812 (2022).

    Article  CAS  PubMed  Google Scholar 

  128. Bunevicius, A. et al. Early versus late Gamma Knife radiosurgery for Cushing’s disease after prior resection: results of an international, multicenter study. J. Neurosurg. 134, 807–815 (2020).

    Article  PubMed  Google Scholar 

  129. Lee, C. C. et al. Whole-sellar stereotactic radiosurgery for functioning pituitary adenomas. Neurosurgery 75, 227–237 (2014).

    Article  PubMed  Google Scholar 

  130. Shepard, M. J. et al. Technique of whole-sellar stereotactic radiosurgery for cushing disease: results from a multicenter. Int. Cohort Study World Neurosurg. 116, e670–e679 (2018).

    Article  Google Scholar 

  131. Ironside, N. et al. Effects of neuroanatomic structural distances on pituitary function after stereotactic radiosurgery: a multicenter study. Neurosurgery 92, 1035–1042 (2023).

    Article  PubMed  Google Scholar 

  132. Burman, P., van Beek, A. P., Biller, B. M., Camacho-Hubner, C. & Mattsson, A. F. Radiotherapy, especially at young age, increases the risk for de novo brain tumors in patients treated for pituitary/sellar lesions. J. Clin. Endocrinol. Metab. 102, 1051–1058 (2017).

    Article  PubMed  Google Scholar 

  133. van Varsseveld, N. C. et al. Cerebrovascular events, secondary intracranial tumors, and mortality after radiotherapy for nonfunctioning pituitary adenomas: a subanalysis from the Dutch National Registry of Growth Hormone Treatment in Adults. J. Clin. Endocrinol. Metab. 100, 1104–1112 (2015).

    Article  PubMed  Google Scholar 

  134. Hamblin, R. et al. Risk of second brain tumour after radiotherapy for pituitary adenoma or craniopharyngioma: a retrospective, multicentre, cohort study of 3679 patients with long-term imaging surveillance. Lancet Diabetes Endocrinol. 10, 581–588 (2022).

    Article  PubMed  Google Scholar 

  135. Wolf, A. et al. Risk of radiation-associated intracranial malignancy after stereotactic radiosurgery: a retrospective, multicentre, cohort study. Lancet Oncol. 20, 159–164 (2019).

    Article  PubMed  Google Scholar 

  136. Reincke, M. et al. A critical reappraisal of bilateral adrenalectomy for ACTH-dependent Cushing’s syndrome. Eur. J. Endocrinol. 173, M23–M32 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Ritzel, K. et al. Clinical review: outcome of bilateral adrenalectomy in Cushing’s syndrome: a systematic review. J. Clin. Endocrinol. Metab. 98, 3939–3948 (2013).

    Article  CAS  PubMed  Google Scholar 

  138. Bertherat, J. Cushing’s disease: role of bilateral adrenalectomy. Pituitary 25, 743–745 (2022).

    Article  PubMed  Google Scholar 

  139. Reibetanz, J. et al. Differences in morbidity and mortality between unilateral adrenalectomy for adrenal Cushing’s syndrome and bilateral adrenalectomy for therapy refractory extra-adrenal Cushing’s syndrome. Langenbecks Arch. Surg. 407, 2481–2488 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Papakokkinou, E. et al. Prevalence of Nelson’s syndrome after bilateral adrenalectomy in patients with cushing’s disease: a systematic review and meta-analysis. Pituitary 24, 797–809 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Das, L. et al. ACTH increment post total bilateral adrenalectomy for Cushing’s disease: a consistent biosignature for predicting Nelson’s syndrome. Pituitary 23, 488–497 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Reincke, M. et al. Corticotroph tumor progression after bilateral adrenalectomy (Nelson’s syndrome): systematic review and expert consensus recommendations. Eur. J. Endocrinol. 184, P1–P16 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Suarez, M. G. et al. Hypercoagulability in Cushing syndrome, prevalence of thrombotic events: a large, single-center, retrospective study. J. Endocr. Soc. 4, bvz033 (2020).

    Article  PubMed  Google Scholar 

  144. Varlamov, E. V., Langlois, F., Vila, G. & Fleseriu, M. Management of endocrine disease: cardiovascular risk assessment, thromboembolism, and infection prevention in Cushing’s syndrome: a practical approach. Eur. J. Endocrinol. 184, R207–R224 (2021).

    Article  CAS  PubMed  Google Scholar 

  145. Feelders, R. A. & Nieman, L. K. Hypercoagulability in Cushing’s syndrome: incidence, pathogenesis and need for thromboprophylaxis protocols. Pituitary 25, 746–749 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Bunevicius, A., Lavezzo, K., Smith, P. W., Vance, M. L. & Sheehan, J. Stereotactic radiosurgery before bilateral adrenalectomy is associated with lowered risk of Nelson’s syndrome in refractory Cushing’s disease patients. Acta Neurochir. 163, 1949–1956 (2021).

    Article  PubMed  Google Scholar 

  147. Losa, M. et al. Gamma knife radiosurgery in patients with Nelson’s syndrome. J. Endocrinol. Invest. 44, 2243–2251 (2021).

    Article  CAS  PubMed  Google Scholar 

  148. Amodru, V. et al. Cushing’s syndrome in the elderly: data from the european registry on Cushing’s syndrome. Eur. J. Endocrinol. 188, 395–406 (2023).

    Article  PubMed  Google Scholar 

  149. Qiao, N., Swearingen, B. & Tritos, N. A. Cushing’s disease in older patients: presentation and outcome. Clin. Endocrinol. 89, 444–453 (2018).

    Article  Google Scholar 

  150. van Haalen, F. M. et al. Current clinical practice for thromboprophylaxis management in patients with Cushing’s syndrome across reference centers of the European Reference Network on rare endocrine conditions (Endo-ERN). Orphanet J. Rare Dis. 17, 178 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  151. Boscaro, M. et al. Anticoagulant prophylaxis markedly reduces thromboembolic complications in Cushing’s syndrome. J. Clin. Endocrinol. Metab. 87, 3662–3666 (2002).

    CAS  PubMed  Google Scholar 

  152. Dekkers, A. J. et al. Long-term effects of glucocorticoid excess on the brain. J. Neuroendocrinol. 34, e13142 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Braun, L. T. et al. Whom should we screen for cushing syndrome? the endocrine society practice guideline recommendations 2008 revisited. J. Clin. Endocrinol. Metab. 107, e3723–e3730 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  154. Vogel, F. et al. Persisting muscle dysfunction in Cushing’s syndrome despite biochemical remission. J. Clin. Endocrinol. Metab. 105, e4490–e4498 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Webb, S. M. & Valassi, E. Quality of life impairment after a diagnosis of Cushing’s syndrome. Pituitary 25, 768–771 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  156. Gumaste, N., Shah, L., Cheesman, K. C. & Geer, E. B. Evaluating patient-reported outcomes in Cushing’s syndrome. Endocrinol. Metab. Clin. North Am. 51, 691–707 (2022).

    Article  PubMed  Google Scholar 

  157. Pupier, E. et al. Impaired quality of life, but not cognition, is linked to a history of chronic hypercortisolism in patients with Cushing’s disease in remission. Front. Endocrinol. 13, 934347 (2022).

    Article  Google Scholar 

  158. Schernthaner-Reiter, M. H. et al. Acute and life-threatening complications in cushing syndrome: prevalence, predictors, and mortality. J. Clin. Endocrinol. Metab. 106, e2035–e2046 (2021).

    Article  PubMed  Google Scholar 

  159. Ebbehoj, A. et al. The socioeconomic consequences of Cushing’s syndrome: a nationwide cohort study. J. Clin. Endocrinol. Metab. 107, e2921–e2929 (2022).

    Article  PubMed  Google Scholar 

  160. Santos, A. et al. Quality of life in patients with Cushing’s disease. Front. Endocrinol. 10, 862 (2019).

    Article  Google Scholar 

  161. van Aken, M. O. 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 

  162. Hamblin, R., Coulden, A., Fountas, A. & Karavitaki, N. The diagnosis and management of Cushing’s syndrome in pregnancy. J. Neuroendocrinol. 34, e13118 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Sridharan, K. et al. Diagnosis and treatment outcomes of Cushing’s disease during pregnancy. Pituitary 24, 670–680 (2021).

    Article  CAS  PubMed  Google Scholar 

  164. Hochman, C. et al. Pre-term birth in women exposed to Cushing’s disease: the baby-cush study. Eur. J. Endocrinol. 184, 469–476 (2021).

    Article  PubMed  Google Scholar 

  165. Luger, A. et al. ESE clinical practice guideline on functioning and nonfunctioning pituitary adenomas in pregnancy. Eur. J. Endocrinol. 185, G1–G33 (2021).

    Article  CAS  PubMed  Google Scholar 

  166. Valassi, E. et al. Worse health-related quality of life at long-term follow-up in patients with Cushing’s disease than patients with cortisol producing adenoma. Data from the ERCUSYN. Clin. Endocrinol. 88, 787–798 (2018).

    Article  CAS  Google Scholar 

  167. Valassi, E. et al. High mortality within 90 days of diagnosis in patients with Cushing’s syndrome: results from the ERCUSYN registry. Eur. J. Endocrinol. 181, 461–472 (2019).

    Article  CAS  PubMed  Google Scholar 

  168. Lambert, J. K. 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 

  169. Boscaro, M. et al. Extended treatment of Cushing’s disease with pasireotide: results from a 2-year, phase II study. Pituitary 17, 320–326 (2014).

    Article  CAS  PubMed  Google Scholar 

  170. Schopohl, J. et al. Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing’s disease: results from an open-ended, open-label extension trial. Pituitary 18, 604–612 (2015).

    Article  CAS  PubMed  Google Scholar 

  171. Trementino, L. et al. A single-center 10-year experience with pasireotide in Cushing’s disease: patients’ characteristics and outcome. Horm. Metab. Res. 48, 290–298 (2016).

    Article  CAS  PubMed  Google Scholar 

  172. Petersenn, S. et al. Long-term treatment of Cushing’s disease with pasireotide: 5-year results from an open-label extension study of a phase III trial. Endocrine 57, 156–165 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Fleseriu, M. et al. Safety and efficacy of subcutaneous pasireotide in patients with Cushing’s disease: results from an open-label, multicenter, single-arm, multinational, expanded-access study. Front. Endocrinol. 10, 436 (2019).

    Article  Google Scholar 

  174. Pivonello, R. et al. The medical treatment with pasireotide in Cushing’s disease: an Italian multicentre experience based on “real-world evidence”. Endocrine 64, 657–672 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Godbout, A. et al. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur. J. Endocrinol. 163, 709–716 (2010).

    Article  CAS  PubMed  Google Scholar 

  176. Pivonello, R. 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 

  177. Fleseriu, M. et al. Osilodrostat, a potent oral 11beta-hydroxylase inhibitor: 22-week, prospective, phase II study in Cushing’s disease. Pituitary 19, 138–148 (2016).

    Article  CAS  PubMed  Google Scholar 

  178. Bunevicius, A., Laws, E. R., Vance, M. L., Iuliano, S. & Sheehan, J. Surgical and radiosurgical treatment strategies for Cushing’s disease. J. Neurooncol. 145, 403–413 (2019).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Shira Berman from Cedars-Sinai Medical Center for editorial assistance. Images of staining patterns (Fig. 3Ac–Af) are courtesy of Matthew Wood (Department of Pathology, Oregon Health & Science University).

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health & Science University, Portland, OR, USA

    Maria Fleseriu & Elena V. Varlamov

  2. Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, USA

    Maria Fleseriu

  3. Pituitary Center, Oregon Health & Science University, Portland, OR, USA

    Maria Fleseriu

  4. Division of Endocrinology, Department of Medicine, Hospital Universitario “Dr. José E. González”, Autonomous University of Nuevo León, Monterrey, Mexico

    Jose M. Hinojosa-Amaya

  5. Division of Endocrinology, Department of Medicine, Centre intégré universitaire de santé et de services sociaux de l’Estrie — Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec, Canada

    Fabienne Langlois

  6. Department of Medicine and Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Shlomo Melmed

Authors
  1. Maria Fleseriu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elena V. Varlamov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jose M. Hinojosa-Amaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fabienne Langlois
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shlomo Melmed
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Maria Fleseriu.

Ethics declarations

Competing interests

M.F. has received grants to the institution from Crinetics, Novartis, Recordati, Sparrow, and Xeris (formerly Strongbridge), consulting fees from Crinetics, HRA Pharma, Novartis, Recordati, Sparrow, and Xeris (formerly Strongbridge), and serves as a member of the Board of Directors (non-compensated) for the Pituitary Society. E.V.V. has received grants to the institution from Recordati. F.L. has served as an adviser to Novartis and Recordati, and has served as a member of the Continuing Medical Education Committee for AMEQ (Association des Médecins Endocrinologues du Québec). S.M. has received grants to the institution from the US Food and Drug Administration and Recordati and non-financial support from Cyclacel, and serves as Secretary (non-compensated) for the Pituitary Society. J.M.H.-A. declares no competing interests.

Peer review

Peer review information

Nature Reviews Endocrinology thanks Irina Bancos, who co-reviewed with Rashi Sandooja; Prashant Chittiboina; and Constantine Stratakis for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Review criteria

We searched PubMed for full-text articles published in English, French and Spanish from January 2000 through January 2023 using the terms “Cushing’s disease”, “ACTH-secreting adenoma”, “hypercortisolism”, “hypercortisolemia”, and “pituitary adenoma”, in combination with the terms “treatment”, “surgery” and “radiation therapy”. Inclusion preference was for articles published within the past 5 years. Some articles were not included in the review due to space limitations or low patient numbers.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fleseriu, M., Varlamov, E.V., Hinojosa-Amaya, J.M. et al. An individualized approach to the management of Cushing disease. Nat Rev Endocrinol 19, 581–599 (2023). https://doi.org/10.1038/s41574-023-00868-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-023-00868-7

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing