Consensus on diagnosis and management of Cushing's disease: a guideline update
Open accessAbstract
Cushing’s disease (CD) requires accurate diagnosis, careful treatment selection, and long-term management to optimize patient outcomes. The Pituitary Society convened a Consensus Workshop comprising more than 50 academic researchers and clinical experts to discuss the application of recent evidence to clinical practice. In advance of the virtual meeting, recent data on screening and diagnosis; surgery, medical and radiation therapy; and disease- and treatment-related complications of CD were critically summarized in recorded lectures that were reviewed by all participants. During the meeting, concise summaries of the recorded lectures were presented, followed by small group breakout discussions. Consensus opinions from each group were collated into a draft document, which was reviewed and approved by all participants. Recommendations regarding use of laboratory tests, imaging, and treatment options are presented, along with algorithms for diagnosis of Cushing’s syndrome and management of CD. Topics considered most important to address in future research are also identified.
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Individually, none of the dynamic tests have 100% specificity because of high false-positive rates, and results can be discordant in up to 65% of patients.
“Individually, none of these tests have 100% specificity because if high false-positive rates, and results can be discordant in up to 65% of patients (2) because of a number of factors including differences in type of ectopic tumor, patient age, patient sex, and severity of hypercortisolism (9).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [9]
In “Distinguishing Between CD and Ectopic ACTH-dependent CS,” the guideline says that no diagnostic test reaches 100% specificity and notes potential false-positive results. But it says results may be discordant in up to one-third of patients, not up to 65%. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredMedical therapy rarely induces remission; instead, the goal is to achieve disease control using cortisol levels as a surrogate marker of treatment success.
“Medical therapy rarely induces remission; instead, the goal is to achieve disease control using cortisol levels as a surrogate marker of treatment success (37, 38).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [38]
The Medical Therapy: Clinical Considerations and Recommendations section says the goal in severe disease is to normalize cortisol levels and recommends monitoring cortisol alongside symptoms and comorbidities to assess treatment efficacy. The Targeting Adrenal Steroidogenesis section says these drugs control cortisol excess but do not directly target the pituitary adenoma. The copy does not establish that medical therapy rarely induces remission, and cortisol is not the sole measure of success; monitoring also includes clinical outcomes, with an exception for mifepristone. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn patients with CS, surgical resection of the causative lesion(s) is the first-line treatment option regardless of etiology.
“In patients with CS, surgical resection of the causative lesion(s) is the first-line treatment option regardless of etiology.”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [38]
The Pituitary Surgery background recommends transsphenoidal surgery as first-line therapy for Cushing’s disease, supporting the claim for that cause of Cushing’s syndrome. The guideline does not extend that recommendation to Cushing’s syndrome regardless of etiology; its discussion of ectopic ACTH-dependent disease concerns diagnosis rather than first-line treatment. Page numbers were not available in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredSteroidogenesis inhibitors work by inhibiting one or more enzymes involved in steroidogenesis, decreasing cortisol and other steroid hormone production.
“Steroidogenesis inhibitors work by inhibiting one or more enzymes involved in steroidogenesis, decreasing cortisol and other steroid hormone production (37, 38).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [38]
The ‘Medical Therapy: Targeting Adrenal Steroidogenesis’ background says these inhibitors block one or more adrenal enzymes and decrease glucocorticoid synthesis and/or adrenal androgen production. The claim captures the mechanism and cortisol reduction, but its unqualified ‘and other steroid hormone production’ implies both effects occur generally; the source says ‘and/or’ and notes that hormones upstream of a blockade can build up. (LLM, conf=0.86)
Experimental — accuracy not yet measuredWhile there is no laboratory test to diagnose glucocorticoid withdrawal syndrome, cortisol measurement provides utility in the diagnosis of adrenal insufficiency.
“While there is no laboratory test to diagnose glucocorticoid withdrawal syndrome, cortisol measurement provides utility in the diagnosis of adrenal insufficiency (38).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [38]
In “Medical Therapy: Clinical Considerations and Recommendations” (page not provided), the guideline says urinary free cortisol is not useful for diagnosing adrenal insufficiency and that morning cortisol may be used instead. Its mifepristone discussion also says low-cortisol measures typically help confirm adrenal insufficiency, except during mifepristone treatment. The passages do not state that no laboratory test can diagnose glucocorticoid withdrawal syndrome. (LLM, conf=0.84)
Experimental — accuracy not yet measured
In patients with CS, the possibility and impact of restoring a normal cortisol circadian rhythm on morbidity, mortality, and quality of life remains unclear.
“In patients with CS, the possibility and impact of restoring a normal cortisol circadian rhythm on morbidity, mortality, and quality of life remains unclear, highlighting a critical area for future research (20, 38).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [38]
In “Medical Therapy: Clinical Considerations and Recommendations” (page unavailable), the guideline says it is unclear whether targeting diurnal cortisol secretion is meaningful and that there is no rigorous evidence for bedtime dosing to restore circadian patterns. It does not specifically assess the effects of restoring a normal rhythm on mortality or quality of life; it discusses clinical outcomes only more generally. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe risk of myocardial infarction is approximately 4.5 times higher in patients with Cushing syndrome compared with the general population.
“The risk of myocardial infarction is approximately 4.5 times higher in patients with CS compared with the general population (8, 9).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [9]
The Cardiovascular Disease section (page unavailable) identifies myocardial infarction as a contributor to increased mortality in patients with active or persistent Cushing’s disease. Its 4.1–16 figure is a standardized mortality ratio, not a 4.5-fold myocardial infarction risk for all patients with Cushing syndrome compared with the general population. (LLM, conf=0.88)
Experimental — accuracy not yet measuredHypercortisolism is associated with 3.5 to 5 times increased mortality risk compared with the general population.
“Hypercortisolism is associated with an increase in cardiovascular events (myocardial infarction), cerebrovascular events (stroke), sepsis, and thromboembolism with 3.5 to 5 times increased mortality risk compared with the general population (7-11).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [9]
The Cardiovascular Disease section reports increased mortality in patients with active or persistent Cushing’s disease, but gives a standardized mortality ratio of 4.1–16, not 3.5–5. It also says mortality is lower after remission, so its estimate does not apply to hypercortisolism without that disease-status qualifier. No page number is available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredPatients with EAS are typically unresponsive to CRH, although some tumors, in particular bronchial carcinoids, can express CRH receptors.
“Patients with EAS are typically unresponsive although some tumors, in particular bronchial carcinoids can express CRH receptors (9, 74, 81, 82).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [9]
The section “Distinguishing Between CD and Ectopic ACTH-dependent CS” (page not supplied) says most ectopic ACTH-secreting tumors lack these receptors and that a response to CRH usually indicates Cushing’s disease. It also says well-differentiated neuroendocrine tumors may express the receptors, but does not identify bronchial carcinoids in particular. (LLM, conf=0.85)
Experimental — accuracy not yet measuredFunctional imaging using 68Ga-PET/CT or 18FDG PET/CT can detect occult tumors, reinforce tumors seen on CT scan as being neuroendocrine, or contribute to the workup of metastatic tumors.
“Second-line tests include functional imaging using 68Ga-PET/CT or 18FDG PET/CT scans, which can be used to detect occult tumors, reinforce tumors seen on CT scan as being neuroendocrine, or contribute to the workup of metastatic tumors (9, 81).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [9]
In “Distinguishing Between CD and Ectopic ACTH-dependent CS” (page unavailable), the guideline says 68Ga-DOTATATE PET can localize ectopic ACTH-secreting neuroendocrine tumors, including tumors not seen or not definitively identified on cross-sectional imaging. Its discussion of 18F-FDG PET/CT concerns pituitary lesions instead. The cited passages do not establish a role for either scan in confirming that a CT-visible tumor is neuroendocrine or in working up metastatic tumors. (LLM, conf=0.85)
Experimental — accuracy not yet measuredMost but not all patients with Cushing disease will have an increase in plasma ACTH by more than 50% and cortisol concentrations by more than 20% after CRH stimulation.
“Therefore, most but not all patients with Cushing disease will have an increase in plasma ACTH by more than 50% and cortisol concentrations by more than 20% after CRH stimulation.”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [9]
The section “Distinguishing Between CD and Ectopic ACTH-dependent CS” says that ACTH and cortisol increases after CRH administration usually indicate Cushing disease, and that diagnostic tests are not perfectly accurate. It does not give the claimed thresholds of more than 50% for ACTH and more than 20% for cortisol, or state that most patients exceed both thresholds. (LLM, conf=0.80)
Experimental — accuracy not yet measuredIn Cushing disease, glucocorticoid receptors at the pituitary retain the ability to inhibit ACTH secretion in the presence of high dexamethasone doses (8 mg).
“In patients with Cushing disease, glucocorticoid receptors at the pituitary level retain the ability to inhibit ACTH secretion in the presence of high dexamethasone doses (8 mg).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [9]
The Background subsection of “Distinguishing Between CD and Ectopic ACTH-dependent CS” says that glucocorticoid receptors in patients with Cushing disease typically retain the ability to inhibit ACTH secretion at high dexamethasone doses. It does not specify 8 mg, and “typically” qualifies the claim rather than making it true of every patient. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIf a pituitary adenoma >6 mm is found on MRI, the need for further testing with BIPSS is not necessary.
“If a pituitary adenoma > 6 mm is found on MRI, the need for further testing with bilateral inferior petrosal sinus sampling (BIPSS) is not necessary (1, 9, 74, 75).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [9]
In “Distinguishing Between CD and Ectopic ACTH-dependent CS” (page not provided), the guideline says IPSS is unnecessary for tumors ≥10 mm when dynamic testing is consistent with Cushing’s disease. It notes that some studies use a >6 mm cutoff, but expert opinions differ for 6–9 mm tumors and the majority recommend IPSS. The claim therefore overstates when BIPSS can be omitted. (LLM, conf=0.90)
Experimental — accuracy not yet measuredWhen glucocorticoid receptor antagonists are used, improvements in clinical signs, symptoms, and CS-induced comorbidities serve as an indicator of treatment efficiency, since biochemical measures are not reliable.
“However, when glucocorticoid receptor antagonists are used, improvements in clinical signs, symptoms, and CS-induced comorbidities serve as an indicator of treatment efficiency, since biochemical measures are not reliable (37, 38).”
From Measuring cortisol in Cushing syndrome: diagnosis, monitoring, and cortisol circadian rhythm improvement. (2026) · cites this paper as [38]
Most ectopic ACTH-secreting tumors do not respond to high-dose dexamethasone.
“In contrast, most ectopic ACTH-secreting tumors do not respond to high-dose dexamethasone (9).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [9]
Using dynamic tests in combination with pituitary MRI can improve clinical accuracy, decreasing the need for BIPSS.
“However, using these dynamic tests in combination with pituitary MRI can improve clinical accuracy, decreasing the need for BIPSS (9, 75).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [9]
An absence of both ACTH and cortisol response is expected in patients with EAS, although false-positive results can be seen as EAS tumors may express type 3 vasopressin receptors.
“On the other hand, an absence of both ACTH and cortisol is expected in patients with EAS, although false-positive results can be seen as EAS tumors may express type 3 vasopressin receptors (9, 74, 81).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [9]
Dynamic testing with high-dose DST, CRH test, and desmopressin testing can help differentiate between Cushing disease and EAS.
“Dynamic testing with high-dose DST, CRH test, and desmopressin testing can also be used to help differentiate between Cushing disease and EAS (9, 81).”
From Approach to the Patient: Diagnosis of Cushing Syndrome (2022) · cites this paper as [9]
There is no international consensus on how ACS in patients with adrenal incidentalomas should be diagnosed, and different recommendations have been provided.
“Currently, there is no international consensus on how ACS in patients with adrenal incidentalomas should be diagnosed, and different recommendations have been provided (1–5, 21–23).”
From The diagnostic value of salivary cortisol and salivary cortisone in patients with suspected hypercortisolism (2022) · cites this paper as [22]
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References 272 · Cited by 953
Research works printed but not linked: 2
- [1]Cushing H The basophil adenomas of the pituitary body and their clinical manifestation. Bull Johns Hopkins Hosp 1932; 50: 137– 95.
- [100]Fleseriu M, Biller B, Grossman A, Swearingen B, Melmed S, on behalf of the Pituitary Society International Cushing Disease Workshop Task Force. Hypercoagulability in Cushing disease: a risk awareness and prophylaxis survey on behalf of the Pituitary Society. 15th International Pituitary Congress; March 29–31, 2017; Orlando, Florida. Abstract P7.
- Authors
- Fleseriu, M., Auchus, R., Bancos, I., Ben-Shlomo, A., Bertherat, J., Biermasz, N. R., Boguszewski, C. L., Bronstein, M. D., Buchfelder, M., Carmichael, J. D., Casanueva, F. F., Castinetti, F., Chanson, P., Findling, J., Gadelha, M., Geer, E. B., Giustina, A., Grossman, A., Gurnell, M., Ho, K., Ioachimescu, A. G., Kaiser, U. B., Karavitaki, N., Katznelson, L., Kelly, D. F., Lacroix, A., McCormack, A., Melmed, S., Molitch, M., Mortini, P., Newell-Price, J., Nieman, L., Pereira, A. M., Petersenn, S., Pivonello, R., Raff, H., Reincke, M., Salvatori, R., Scaroni, C., Shimon, I., Stratakis, C. A., Swearingen, B., Tabarin, A., Takahashi, Y., Theodoropoulou, M., Tsagarakis, S., Valassi, E., Varlamov, E. V., Vila, G., Wass, J., Webb, S. M., Zatelli, M. C., & Biller, B. M. K.
- Affiliations
- Oregon Health & Science University (US)
- University of Michigan (US)
- Mayo Clinic (US)
- Cedars-Sinai Medical Center (US)
- Université Paris Cité (FR)
- Leiden University Medical Center (NL)
- Universidade de São Paulo (BR)
- Universitätsklinikum Erlangen (DE)
- University of Southern California (US)
- Universidade de Santiago de Compostela (ES)
- Université Paris-Saclay (FR)
- Medical College of Wisconsin (US)
- Universidade Federal do Rio de Janeiro (BR)
- Memorial Sloan Kettering Cancer Center (US)
- Vita-Salute San Raffaele University (IT)
- University of London (GB)
- University of Cambridge (GB)
- Garvan Institute of Medical Research (AU)
- Emory University (US)
- Brigham and Women's Hospital (US)
- University Hospitals Birmingham NHS Foundation Trust (GB)
- Stanford University (US)
- Centre Hospitalier de l’Université de Montréal (CA)
- Northwestern University (US)
- University of Sheffield (GB)
- National Institutes of Health (US)
- University of Duisburg-Essen (DE)
- University of Naples Federico II (IT)
- Johns Hopkins University (US)
- University of Padua (IT)
- Rabin Medical Center (IL)
- Massachusetts General Hospital (US)
- Université de Bordeaux (FR)
- Nara Medical University (JP)
- LMU Klinikum (DE)
- Evangelismos Hospital (GR)
- Hospital de Sant Pau (ES)
- Medical University of Vienna (AT)
- Churchill Hospital (GB)
- Universitat Autònoma de Barcelona (ES)
- University of Ferrara (IT)
- Corresponding author
- Fleseriu, Maria
- ORCID
- Bertherat, Jerome
- Buchfelder, Michael
- Chanson, Philippe
- Gadelha, Mônica
- Grossman, Ashley
- Ho, Ken
- Kaiser, Ursula B
- Katznelson, Laurence
- Lacroix, André
- McCormack, Ann
- Mortini, Pietro
- Newell-Price, John
- Nieman, Lynnette
- Pereira, Alberto M
- Petersenn, Stephan
- Tabarin, Antoine
- Takahashi, Yutaka
- Valassi, Elena
- Vila, Greisa
- Webb, Susan M
- Venue
- The Lancet Diabetes & Endocrinology
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 9
- Issue
- 12
- Pages
- 847-875
- ISSN
- 2213-8587 (ISSN-L)
- PMC
- PMC8743006
- OpenAlex
- W3204188022
- Semantic Scholar
- 1deeb67dd743e287bdb1754d2392c6e406dc6a12
- Cited by
- 953
- References
- 272
- Citations by year
- 2026: 205 · 2025: 223 · 2024: 208 · 2023: 181 · 2022: 133 · 2021: 1
- FWCI
- 97.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 166 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- The Lancet Diabetes & Endocrinology (acceptedVersion)
- PubMed (publishedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by-nc-nd)
- Institutional Research Information System University of Ferrara (University of Ferrara) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- U.S. Food and Drug Administration
- Pfizer
- Ipsen Biopharmaceuticals
- National Institutes of Health (GPR101, PDE11A)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
- Health Sciences › Medicine › Epidemiology › Neuroendocrine Tumor Research Advances
- Keywords
- Cushing's disease, Cushing's syndrome, diagnosis, surgical treatment, medical therapy, radiotherapy, treatment complications, screening, diagnostic algorithm, pituitary adenoma
- MeSH terms
- Cushing Syndrome, Humans, Pituitary Gland, Consensus, Pituitary ACTH Hypersecretion
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