An individualized approach to the management of Cushing disease

Nature Reviews Endocrinology (2023)Cite this article

120 Accesses

24 Altmetric

Metrics details

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.

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 Nature and 54 other Nature Portfolio journals

Get Nature+, our best-value online-access subscription

$29.99 / 30 days

cancel any time

Subscribe to this journal

Receive 12 print issues and online access

$189.00 per year

only $15.75 per issue

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

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

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

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

Article CAS PubMed Google Scholar

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

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

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

Article PubMed PubMed Central Google Scholar

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

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

Article PubMed Google Scholar

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

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

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

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

Article CAS PubMed Google Scholar

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

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

Article PubMed Google Scholar

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

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

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

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

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

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

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

Article PubMed Google Scholar

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

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

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

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

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

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

Article PubMed Google Scholar

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

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

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

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

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

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

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

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

Article CAS PubMed PubMed Central Google Scholar

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Article CAS PubMed Google Scholar

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Article CAS PubMed Google Scholar

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

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

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

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

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

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

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

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).

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

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

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

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

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

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

Article CAS PubMed Google Scholar

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

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

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

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

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

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

Article PubMed Google Scholar

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

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

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

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

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

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

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

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

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

Article PubMed Google Scholar

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Article Google Scholar

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

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

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

Article CAS PubMed Google Scholar

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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).

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

Maria Fleseriu & Elena V. Varlamov

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

Maria Fleseriu

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

Maria Fleseriu

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

Jose M. Hinojosa-Amaya

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

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

Shlomo Melmed

You can also search for this author in PubMed Google Scholar

The authors contributed equally to all aspects of the article.

Correspondence to Maria Fleseriu.

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.

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.

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

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.

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

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

Download citation

Accepted: 22 June 2023

Published: 03 August 2023

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

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative