The direct cause is a pituitary corticotroph adenoma driving autonomous ACTH secretion, which in turn stimulates adrenal cortisol overproduction. Somatic mutations in the USP8 gene, encoding ubiquitin-specific peptidase 8, have been identified in a subset of pituitary corticotroph adenomas and are catalogued as the associated known gene in the current dataset. The broader genetic basis of pituitary corticotroph adenoma formation is not fully established, and most cases arise sporadically.

Diagnosis involves biochemical confirmation of cortisol hypersecretion followed by source localization. Initial evaluation includes 24-hour urinary free cortisol measurement, late-night salivary cortisol testing, and low-dose dexamethasone suppression testing. Once autonomous cortisol production is confirmed, ACTH levels are measured to determine ACTH-dependence. Pituitary MRI is used to identify the corticotroph adenoma, which may be a microadenoma. Inferior petrosal sinus sampling may be employed when imaging is nonconfirmatory to distinguish pituitary from ectopic ACTH sources.

Three agents are FDA-approved for use in Cushing disease due to pituitary adenoma. Osilodrostat (ISTURISA), a steroidogenesis inhibitor, was approved by the FDA on March 6, 2020. Pasireotide (SIGNIFOR), a somatostatin receptor ligand, received FDA approval on December 14, 2012. Pasireotide long-acting release (SIGNIFOR LAR) received FDA approval on December 15, 2014. All three agents carry ACTIVE market status. Surgical resection of the pituitary adenoma (transsphenoidal surgery) is typically the primary treatment approach. Medical therapy with the above agents may be employed for patients who are not surgical candidates, have persistent disease following surgery, or are awaiting additional intervention. Radiation therapy and bilateral adrenalectomy may be considered in selected cases by a specialized multidisciplinary endocrine team.

Outcomes depend on tumor characteristics, completeness of surgical remission, and duration of cortisol exposure prior to treatment. Successful surgical remission significantly improves metabolic, cardiovascular, and musculoskeletal complications. Recurrence of disease following initial surgical remission can occur, necessitating long-term follow-up. Access to specialized pituitary tumor centers is associated with improved rates of surgical success.

Active clinical investigation is ongoing. ClinicalTrials.gov lists 10 active studies in the current dataset. Trial topics include novel steroidogenesis inhibitors, somatostatin analogs, and investigational approaches targeting ACTH secretion or pituitary tumor growth. Details including enrollment status, phase, and completion timelines are available through ClinicalTrials.gov.