Cushing Disease

First exclude exogenous corticosteroid exposure, the most common cause of Cushing syndrome. In patients with a phenotype concerning for endogenous disease, use late-night salivary cortisol, a 1-mg overnight dexamethasone suppression test, and/or 24-hour urinary free cortisol (UFC) as initial biochemical tests. BMJBMJCushing syndrome - Symptoms, diagnosis and treatment | BMJ Best Practice US

For the 1-mg overnight dexamethasone suppression test, administer dexamethasone at midnight and measure serum cortisol at approximately 09:00; suppression to less than 1.8 micrograms/dL (50 nmol/L) is the cited normal result. A 48-hour low-dose dexamethasone protocol uses 0.5 mg every 6 hours, with the same post-test cortisol threshold of less than 1.8 micrograms/dL. PubMedPubMedFlorid Cushing’s Syndrome - Endotext - NCBI Bookshelf

When clinical suspicion remains high despite intermittently normal testing, obtain repeated late-night salivary cortisol and UFC measurements rather than localizing a single equivocal biochemical result. Cyclic Cushing syndrome can produce spontaneous remissions and requires demonstration of active hypercortisolism before ACTH-source testing or invasive sampling. PubMed+2PubMedAn individualized approach to the management of Cushing disease - PubMedThe LancetDiagnostic challenges in cyclic Cushing's syndromecellAnnexin A1 as a diagnostic biomarker for cyclic Cushing ...

Measure plasma ACTH after confirming endogenous hypercortisolism. ACTH above 20 ng/L establishes ACTH dependence and requires discrimination between a pituitary corticotroph tumor and ectopic ACTH secretion; ACTH below 10 ng/L directs the workup toward ACTH-independent adrenal cortisol production. Intermediate values are a diagnostic gray zone because they may occur with either Cushing disease or adrenal pathology. PubMedPubMedFlorid Cushing’s Syndrome - Endotext - NCBI Bookshelf

Obtain contrast-enhanced pituitary MRI for ACTH-dependent disease, but do not equate a detected lesion with causality. MRI identifies an adenoma in only about 60% to 75% of patients in one contemporary review, and historical estimates cited detection of approximately 40% to 52% of corticotroph tumors. PubMed+1PubMedAn individualized approach to the management of Cushing disease - PubMedScienceDirectEvaluation and treatment of Cushing’s syndrome - ScienceDirect

Use bilateral inferior petrosal sinus sampling (BIPSS), usually with corticotropin-releasing hormone stimulation, when ACTH-dependent hypercortisolism is established but MRI is negative, equivocal, or discordant with biochemical and dynamic testing. BIPSS is regarded as the gold-standard procedure for distinguishing central from ectopic ACTH secretion, but it should be performed in an experienced center. ScienceDirect+2ScienceDirectInferior petrosal sinus sampling and stimulation with CRH: 15 years of experience in a tertiary hospital - ScienceDirectScienceDirectInferior Petrosal Sinus Sampling - an overviewPubMedAn individualized approach to the management of Cushing disease - PubMed

A central-to-peripheral ACTH gradient supports Cushing disease. A post-stimulation ratio greater than 3.0 is cited as diagnostic of a central source, although one tertiary-center series reported optimized cutoffs of 2.06 at baseline and 2.49 after corticotropin-releasing hormone stimulation; interpret thresholds in the context of the local protocol and documented technical adequacy. ScienceDirect+1ScienceDirectPetrosal Sinus Sampling - an overviewScienceDirectInferior petrosal sinus sampling and stimulation with CRH: 15 years of experience in a tertiary hospital - ScienceDirect

Refer patients with localized Cushing disease for transsphenoidal pituitary adenoma resection as first-line treatment. The Endocrine Society recommends tumor removal as initial treatment for endogenous Cushing syndrome unless surgery is not possible or is unlikely to correct cortisol excess. endocrineendocrineTreatment of Cushing's Syndrome Guideline Resources | Endocrine Society

Set expectations using tumor size and surgical expertise. Initial surgical remission has been reported at 70% to 90% for pituitary microadenomas and 50% to 65% for macroadenomas; another review reported remission around 78%. accessdata fda+1accessdata fda[PDF] 202107Orig1s000 - accessdata.fda.govOxford AcademicTreatment of Cushing's Disease | Endocrine Reviews

Assess postoperative cortisol to document remission and guide follow-up. Postoperative plasma cortisol predicts long-term outcome and has been used to determine which patients should receive pituitary irradiation after surgery. WileyWileyCurrent management of Cushing's disease - Tritos - 2019

Plan glucocorticoid replacement and subsequent withdrawal after curative treatment, because successful correction of endogenous hypercortisolism may be followed by hypothalamic-pituitary-adrenal axis suppression. The treatment guideline specifically addresses replacement, discontinuation, and recovery of other pituitary hormonal deficits after therapy. endocrine+1endocrineTreatment of Cushing's Syndrome Guideline Resources | Endocrine SocietyNatureCushing syndrome | Nature Reviews Disease Primers

After failed initial pituitary surgery, consider repeat surgery, pituitary radiotherapy or radiosurgery, medical therapy, or bilateral adrenalectomy. The selection depends on whether a surgically accessible residual or recurrent pituitary lesion is present, whether rapid cortisol reduction is needed, and whether prior radiotherapy has been delivered. endocrine+1endocrineTreatment of Cushing's Syndrome Guideline Resources | Endocrine Societyaccessdata fda[PDF] 202107Orig1s000 - accessdata.fda.gov

Recurrence is clinically meaningful even after apparent remission. Reported long-term recurrence estimates include approximately 25% at 10 years in an FDA review and a range of 5% to 50% within 10 years across surgical series. Continue biochemical surveillance rather than discharging patients after early postoperative remission. accessdata fda+1accessdata fda200677Orig1s000 - accessdata.fda.govThe LancetRisk of recurrence after successful surgery for Cushing's ...

Use medical treatment when surgery is unsuccessful, contraindicated, delayed, or insufficiently rapid for the severity of cortisol excess. The guideline includes medical therapy among second-line options, and FDA review material identifies adrenal-directed agents such as metyrapone, etomidate, and ketoconazole as off-label therapies historically used to reduce cortisol secretion. endocrine+1endocrineTreatment of Cushing's Syndrome Guideline Resources | Endocrine Societyaccessdata fda[PDF] 202107Orig1s000 - accessdata.fda.gov

Pasireotide has been used for patients in whom medical therapy is appropriate; an EMA dosing example cited a starting dose of 0.6 mg twice daily, reduced to 0.3 mg twice daily with moderate liver impairment. Do not extrapolate this non-U.S. dosing statement to U.S. prescribing without checking current FDA labeling and formulation-specific instructions. accessdata fdaaccessdata fda200677Orig1s000 - accessdata.fda.gov

Follow patients after pituitary surgery with serial biochemical assessment for recurrent hypercortisolism, using tests that previously documented disease activity and accounting for possible cyclic secretion. Recurrence may occur years after surgery, with reported 10-year recurrence estimates ranging from 5% to 50%. The Lancet+2The LancetRisk of recurrence after successful surgery for Cushing's ...accessdata fda200677Orig1s000 - accessdata.fda.govPubMedAn individualized approach to the management of Cushing disease - PubMed

During postoperative recovery, assess for glucocorticoid requirement and recovery of the hypothalamic-pituitary-adrenal axis before discontinuing replacement. The treatment guideline includes specific recommendations on glucocorticoid replacement, discontinuation, and resolution of other hormonal deficiencies after treatment. endocrineendocrineTreatment of Cushing's Syndrome Guideline Resources | Endocrine Society

When symptoms recur but standard cortisol testing is intermittently normal, repeat late-night salivary cortisol and UFC collections during symptomatic periods before concluding that recurrence is absent. Cyclic Cushing syndrome can create spontaneous biochemical remissions and misleading single-time-point testing. PubMed+2PubMedAn individualized approach to the management of Cushing disease - PubMedThe LancetDiagnostic challenges in cyclic Cushing's syndromecellAnnexin A1 as a diagnostic biomarker for cyclic Cushing ...