This review article summarizes our current understanding of this rare disorder and includes definitions, pathology, and treatment options, together with a subset of tumors undergoing malignant transformation.
Fountas A, Karavitaki N. Nelson's Syndrome: An Update. Endocrinol Metab Clin North Am. 2020 Sep;49(3):413-432.
A total of 12 pregnant women who underwent adrenalectomy over a 15-year period were identified from a prospectively maintained database. Results show that while maternal outcome is acceptable, fetal outcome is influenced by several factors and is variable.
Gaujoux S, et al. Adrenalectomy during pregnancy: A 15-year experience at a tertiary referral center. Surgery. 2020 Aug;168(2):335-339
This is a retrospective case record analysis of 42 patients with Cushing’s Disease who underwent conventional fractionated radiotherapy (CFR) with at least 12 months follow-up. Results show that peri-CRT use of cabergoline is significantly associated with increased recurrence rates of disease.
Thakkar K, et al. Cabergoline may act as a radioprotective agent in Cushing's disease. Clin Endocrinol (Oxf). 2020 Jan;92(1):55-62.
This study pooled data from 255 patients across 10 institutions participating in the International Radiosurgery Research Foundation. Are endocrine remission rates most improved following early or late stereotactic radiosurgery?
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. 2020 Feb 21:1-9.
This multicentre retrospective study of 95 patients with Cushing’s Disease, responding preoperatively to desmopressin test (DT) and with early post-operative corticotropic insufficiency (COI), underwent a DT within 3 months post-surgery. Results may help stratify patients with COI and refine their follow-up according to the risk of recurrence.
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. 2020 May;182(5):489-498.
This study aimed to establish robust reference intervals for, and compare the diagnostic accuracy of, salivary cortisol and cortisone in late-night samples and after a low-dose dexamethasone suppression test. Will the results confirm the accuracy of late-night cortisol and cortisone testing?
Bäcklund N, et al. Reference intervals of salivary cortisol and cortisone and their diagnostic accuracy in Cushing's syndrome. Eur J Endocrinol. 2020 Jun;182(6):569-582.
This tertiary care center study, which looked at 43 patients over a 35-year period, analyzed clinical symptomatology, cortisol, ACTH, and radiology following total bilateral adrenalectomy. Could the findings lead to improved patient care, including a reduction in the need for frequent imaging?
Das L, et al. ACTH increment post total bilateral adrenalectomy for Cushing's disease: a consistent biosignature for predicting Nelson's syndrome. Pituitary. 2020 Oct;23(5):488-497.
This study of fourteen patients − with severe and complicated Cushing’s syndrome related to adrenal carcinoma or ectopic ACTH secretion − compared data from those treated with high starting doses of etomidate in ICU or with lower starting doses in non-ICU medical wards. Results suggest that low doses of etomidate in medical wards should be considered.
Constantinescu SM, et al. Etomidate infusion at low doses is an effective and safe treatment for severe Cushing's syndrome outside intensive care. Eur J Endocrinol. 2020 Aug;183(2):161-167.
Primary pigmented nodular adrenocortical disease (PPNAD) and primary bilateral macronodular adrenocortical hyperplasia are linked to respective gene mutations. This study aims to determine the potential influence of ARMC5 genes – which have many non-pathological variants in the general population – on PRKAR1A mutations, the defect that causes PPNAD. What was shown?
Maria AG, et al. ARMC5 variants in PRKAR1A-mutated patients modify cortisol levels and Cushing's syndrome. Endocr Relat Cancer. 2020 Sep;27(9):509-517.
This review identified 91 articles, which included original articles, case reports and case series, reporting on 99 cases of ectopic adrenocorticotropic hormone and/or corticotrophin-releasing-hormone secreting pheochromocytomas. What do we currently know about disease characteristics, management, and outcomes in these patients?
Elliott PF, et al. Ectopic ACTH- and/or CRH-producing pheochromocytomas. J Clin Endocrinol Metab. 2021 Jan 23;106(2):598-608.
Read the findings of the prospective, multicentre, open-label, double-blind randomized withdrawal period phase III study (LINC 3).
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. 2020 Sep;8(9):748-761.
This cross-sectional study of 200 patients took place in a referral University Hospital Center from 2010 to 2019. The human corticotropin-releasing hormone (CRH) test was performed mainly for the differential diagnosis of ACTH-dependent CS or adrenal lesions but what were the findings?
F Ceccato, et al. Human Corticotropin-Releasing Hormone Tests: 10 Years of Real-Life Experience in Pituitary and Adrenal Disease. J Clin Endocrinol Metab. 2020 Nov 1;105(11):dgaa564.
This study of 64 patients confirms earlier findings that tumor-to-liver standardized uptake value ratio (SUV)max (>1.5) is a useful biomarker for the diagnosis of malignancy in adrenal masses but was a predictive model also identified?
Salgues B, et al. Risk stratification of adrenal masses by [(18) F] FDG PET/CT: Changing tactics. Clin Endocrinol (Oxf) 2021 Feb;94(2):133-140.
This study was designed to identify predictive features of delayed post-operative disease remission using machine-based algorithms. Findings, which were based on 201 patients, identified a model with predictive ability that was significantly better than using Knosp grading and postoperative immediate morning serum cortisol alone. Could this effective approach lead to better patient care?
Yanghua Fan, et al. Development of Machine Learning Models for Predicting Postoperative Delayed Remission in Patients with Cushing's Disease. J Clin Endocrinol Metab. 2021 Jan 1;106(1):e217-e231.
This case study highlights the importance of monitoring ACTH and corticotroph tumor size in patients with persistent Cushing’s syndrome, either under effective treatment with steroidogenesis inhibitors or after bilateral adrenalectomy.
Fontaine-Sylvestre C, et al. Corticotroph tumor progression during long-term therapy with osilodrostat in a patient with persistent Cushing's disease. Clin. Endocrinol. 2020 Sep 25.
This retrospective cohort study identified 1199 new adrenal Cushing’s syndrome patients presenting between 2002 and 2017. Results show a high risk of pre- and post-operative comorbidities. The major types of glucocorticoids prescribed are given.
Ahn CH, et al. Epidemiology and Comorbidity of Adrenal Cushing's Syndrome: A Nationwide Cohort Study. J Clin Endocrinol Metab. 2020 Oct 19:dgaa752.
Patients with ACTH-dependent Cushing's syndrome (n = 27) underwent 68-Ga CRH PET-CT. Information provided by medical imaging provided surgeons with valuable information for intraoperative tumor navigation, and helped in differentiating pituitary from extra-pituitary sources of ACTH-dependent CS.
Walia R, et al. Molecular Imaging Targeting Corticotropin Releasing Hormone Receptor for Corticotropinoma: A Changing Paradigm. J Clin Endocrinol Metab. 2020 Oct 20:dgaa755.
Postoperative day 1 morning serum cortisol value is shown to be a helpful predictor of long-term disease recurrence in the statistical analysis of 260 patients with Cushing’s disease.
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. 2021 Jan 1;106:e94-e102.
This longitudinal cohort study of patients with Cushing’s disease (1979−2018) identified the main predictors for mortality, which is mainly linked to cardiovascular disease.
Roldán-Sarmiento P, et al. Diabetes, Active Disease, and Afternoon Serum Cortisol Levels Predict Cushing's Disease Mortality: A Cohort Study. J Clin Endocrinol Metab. 2021 Jan 1;106:e103-e111.
This retrospective cohort study of 73 pediatric patients with Cushing’s disease analyzed BMI after long-term remission and determined predictive factors for those at risk of remaining overweight or obese following successful treatment.
Valdés N, et al. Pediatric Cushing's syndrome: greater risk of being overweight or obese after long-term remission and its predictive factors. Eur J Endocrinol. 2021 Jan;184:179-187.
This review article examines the use of adrenally acting medical therapies, including ketoconazole, metyrapone, osilodrostat, mitotane, and etomidate. Use of these drugs mandates adequate patient instruction and close monitoring to that ensure treatment goals are met while untoward adverse effects are minimized.
Tritos NA. Adrenally Directed Medical Therapies for Cushing Syndrome. J Clin Endocrinol Metab. 2021 Jan 1;106:16-25.
This cross-sectional study at a tertiary referral center examines 36 women in disease remission. The study aims to quantify the degree of fatty infiltration in thigh muscle and evaluate the relationship between these changes and physical performance.
Martel-Duguech L, et al. Thigh Muscle Fat Infiltration Is Associated With Impaired Physical Performance Despite Remission in Cushing's Syndrome. J Clin Endocrinol Metab. 2020 May 1;105:dgz329.
This cross-sectional study with prospective enrolment (2014− 2019), involved 213 patients with adrenal adenomas, with and without Cushing’s syndrome. Bone turnover markers within three patient subgroups are discussed, together with the impact of adrenalectomy.
Athimulam S, et al. The Impact of Mild Autonomous Cortisol Secretion on Bone Turnover Markers. J Clin Endocrinol Metab. 2020 May 1;105:1469-77.
The aim of this meta-analysis, based on 5367 patients in different populations, is to assess the time span between first symptoms and diagnosis to identify what factors, if any, are associated with earlier rates of detection.
Rubinstein G, et al. Time to Diagnosis in Cushing's Syndrome: A Meta-Analysis Based on 5367 Patients. J Clin Endocrinol Metab. 2020 Mar 1;105:dgz136.
This is a retrospective study of 632 non-Cushing’s patients evaluated for adrenal incidentalomas. Results show that affected patients are at risk of atrial fibrillation. Do these findings have implications for Cushing’s disease?
Di Dalmazi G, et al. Prevalence and Incidence of Atrial Fibrillation in a Large Cohort of Adrenal Incidentalomas: A Long-Term Study. J Clin Endocrinol Metab. 2020 Aug 1;105:dgaa270.
This retrospective, nationwide study explored outcomes in 502 patients with confirmed Cushing’s disease identified in the Swedish National Patient Register between 1987 and 2013.
Papakokkinou E, et al. Excess Morbidity Persists in Patients With Cushing's Disease During Long-term Remission: A Swedish Nationwide Study. J Clin Endocrinol Metab. 2020;105:dgaa291.
This retrospective study involving 194 patients at two centers tested a non-invasive diagnostic strategy associated with 100% positive predictive value for Cushing’s disease. Will this diagnostic algorithm eventually replace the highly invasive IPSS?
Frete C, et al. Non-invasive Diagnostic Strategy in ACTH-dependent Cushing's Syndrome. J Clin Endocrinol Metab. 2020 Oct 1;105(10):dgaa409.
This retrospective cohort study of 123 adult patients at a clinical research center explores the prevalence of abnormal thyroid function in Cushing's syndrome and whether it is reversible after cure.
Shekhar S, et al. The Hypothalamic-Pituitary-Thyroid Axis in Cushing Syndrome before and after Curative Surgery. J Clin Endocrinol Metab. 2020 Nov 25:dgaa858.
This follow-up study looks at the impact of surgery on bone mineral density and fracture rates in patients with confirmed Cushing's syndrome at the time of diagnosis and 2 years after successful tumor resection. Could successful surgery reduce the rate of Cushing’s-linked osteoporosis?
Braun LT, et al. The Effect of Biochemical Remission on Bone Metabolism in Cushing's Syndrome: A 2-Year Follow-Up Study. J Bone Miner Res. 2020;35:1711-1717. Open access.
This review examines the potential role, and limitations, of the desmopressin test as an early and reliable predictive marker of long-term disease remission in surgical patients.
Vassiliadi DA, Tsagarakis S. Cushing's disease: the desmopressin test as a compelling predictive marker of long-term remission after transsphenoidal surgery. Eur J Endocrinol. 2020 Jun;182(6):C17-C19. Open access.
This review explains the recent advances in our understanding of hypothalamic-pituitary-adrenal axis regulation and the resulting emergence of a promising novel chronotherapy.
Lightman SL, et al. Dynamics of ACTH and Cortisol Secretion and Implications for Disease. Endocr Rev. 2020;41:470-490. Open access.
This single-center retrospective cohort study examined the records of 242 patients with Cushing’s syndrome highlighting the range of acute and life-threatening complications and their high prevalence, even before diagnosis and after successful surgery.
Schernthaner-Reiter MH, et al. Acute and life-threatening complications in Cushing’s syndrome: prevalence, predictors and mortality. J Clin Endocrinol Metab. 2021. Jan 31;dgab058.
This review examines the complexity of clinical steroidogenesis inhibition from the establishment of initial dosage and drug scheduling to the monitoring of efficacy and side effects. Four agents are considered − ketoconazole, levoketoconazole, metyrapone and osilodrostat − in mono- and combination therapy.
Castinetti F, et al. Approach to the Patient Treated with Steroidogenesis Inhibitors. J Clin Endocrinol Metab. 2021 Mar 2:dgab122.
This phase 2 trial analyzes whether metformin can improve metabolic profiles and clinical outcomes for glucocorticoid-treated patients with inflammatory disease.
Pernicova I, et al. Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial. Lancet Diabetes Endocrinol. 2020;8:278-91.
This meta-analysis looks at remission and recurrence rates after trans-sphenoidal surgery, with a focus on factors predictive of remission.
Stroud A, et al. Outcomes of pituitary surgery for Cushing's disease: a systematic review and meta-analysis. Pituitary. 2020;23:595-609.
An exploratory analysis looking at the use of late-night salivary cortisol (LNSC) to monitor pharmacological response to medical treatment in Cushing’s disease.
Newell-Price J, et al. Use of late-night salivary cortisol to monitor response to medical treatment in Cushing's disease. Eur J Endocrinol. 2020;182:207-17. Open access.
Expert review of diagnostic and therapeutic strategies surrounding ectopic ACTH syndrome, including currently available tools and comment on effectiveness of operational care via a multidisciplinary team.
Young J, et al. Management of endocrine disease: Cushing's syndrome due to ectopic ACTH secretion: an expert operational opinion. Eur J Endocrinol. 2020;182:R29-58. Open access.
A systematic review and associated guidance from the European Society of Endocrinology providing a rational approach to endocrine testing and treatment in people with obesity. Could this help optimize the diagnosis of Cushing syndrome?
Wilding JPH. Endocrine testing in obesity. Eur J Endocrinol. 2020;182:C13-5. Commentary. Open access.
This retrospective, single-center, longitudinal study looks at the prevalence of thrombotic events in patients with Cushing’s syndrome after surgical and medical treatment.
Suarez MG, et al. Hypercoagulability in Cushing syndrome, prevalence of thrombotic events: a large, single-center, retrospective study. J Endocr Soc. 2019;4:bvz033. Open access.
An observational study focusing on long-term muscle function, exploring how glucocorticoid-induced myopathy resolves following remission of endogenous Cushing’s syndrome.
Vogel F, et al. Persisting muscle dysfunction in Cushing's syndrome despite biochemical remission. J Clin Endocrinol Metab. 2020;105:e4490–8. Open access.
Current medical therapies for Cushing’s disease do not generally have an action on tumor growth. High throughput screening using a novel ‘gain of signal’ adrenocorticotropic hormone (ACTH) assay is helping identify drugs that inhibit corticotroph tumor ACTH secretion and growth, which may be of promise in Cushing’s syndrome.
Zhang D et al. Targeting Corticotroph HDAC and PI3-Kinase in Cushing Disease. J Clin Endocrinol Metab. 2021;106:e232-e246. Open Access.
Patients with active Cushing's syndrome may be immunocompromised, and so require strict adherence to barrier methods to prevent infection with COVID-19. Clinical practice guidelines lay out the key principles of care of these patients during the pandemic, including algorithms for investigations and management of the syndrome.
See also the Publication Highlight
Newell-Price J et al. Endocrinology in the time of COVID-19: Management of Cushing's syndrome. Eur J Endocrinol. 2020;1831:G1-7. Open access
Fountas A et al. Outcomes of Patients with Nelson’s Syndrome after Primary Treatment: A Multicenter Study from 13 UK Pituitary Centers. J Clin Endocrinol Metab. 2020;105:1527–37. Open access.
Ketoconazole is indicated in the European Union for the treatment of endogenous Cushing’s syndrome in adults and adolescents aged over 12.
Shirley M. Ketoconazole in Cushing’s syndrome: a profile of its use. Drugs Ther Perspect. 2021; doi.org/10.1007/s40267-020-00799-7. Open access.
Systematic review of 40 years of research in Cushing’s syndrome underlines the importance of annual clinical and biochemical follow-up.
Braun LT et al. Recurrence after pituitary surgery in adult Cushing's disease: a systematic review on diagnosis and treatment. Endocrine. 2020;70:218-31. Open access.