Why does pituitary adenoma-induced Cushing's syndrome (Cushing's) exhibit resistance to a low-dose dexamethasone (Dexamethasone) suppression test but not to a high-dose test, differing from other causes of Cushing's syndrome?

From the Guidelines

Pituitary adenoma-induced Cushing's disease shows resistance to low-dose dexamethasone suppression testing but responds to high-dose testing due to the partial autonomy of the tumor. In pituitary adenomas, ACTH-producing cells retain some sensitivity to negative feedback, but require higher cortisol levels to suppress ACTH production. When given low-dose dexamethasone (1 mg), the adenoma continues producing ACTH despite levels that would suppress a normal pituitary. However, high-dose dexamethasone (8 mg) provides enough glucocorticoid activity to overcome this partial resistance and suppress ACTH production, as seen in the latest guidelines 1.

This pattern differs from other causes of Cushing's syndrome:

• Adrenal tumors produce cortisol independently of ACTH and show no suppression with either test
• Ectopic ACTH-producing tumors (like small cell lung cancer) completely lack feedback mechanisms and resist both low and high-dose tests. This differential response pattern helps clinicians distinguish the source of hypercortisolism, which is crucial for determining appropriate treatment, whether it's transsphenoidal surgery for pituitary adenomas, adrenalectomy for adrenal causes, or treatment of the primary tumor for ectopic ACTH production, as recommended by recent consensus guidelines 1.

The diagnosis of Cushing's disease is supported by a >20% increase in cortisol from baseline during a corticotrophin-releasing hormone (CRH) test, with a sensitivity of 74-100% and specificity of 100% 1. The use of bilateral inferior petrosal sinus sampling for ACTH is also recommended to confirm a central source of ACTH excess, with a central-to-peripheral ACTH ratio of ≥3 after CRH or desmopressin stimulation 1.

In contrast, adrenal incidentalomas are managed differently, with a low threshold for multidisciplinary review and consideration of adrenalectomy for patients with autonomous cortisol secretion or other hormone excess 1. The management of cortisol-secreting adenomas involves screening with a 1 mg dexamethasone suppression test, with additional testing and consideration of adrenalectomy on an individual patient basis 1.

Overall, the diagnosis and management of Cushing's syndrome require a comprehensive approach, taking into account the underlying cause and the patient's individual needs, with the goal of improving morbidity, mortality, and quality of life.

From the Research

Pituitary Adenoma Induced Cushing's Syndrome

• Pituitary adenoma induced Cushing's syndrome presents with resistance to a low dose dexamethasone test but no resistance to a high level dexamethasone test due to the partial suppression of adrenocorticotropic hormone (ACTH) secretion by high doses of dexamethasone 2, 3, 4.
• This is different from other causes of Cushing's syndrome, such as ectopic ACTH-producing tumors, which do not suppress ACTH secretion even with high doses of dexamethasone 3, 4.

Dexamethasone Suppression Test

• The low dose dexamethasone suppression test is used to diagnose Cushing's syndrome, while the high dose test is used to distinguish between pituitary and ectopic ACTH-dependent Cushing's syndrome 3, 5, 4.
• The high dose dexamethasone test can suppress ACTH secretion in pituitary adenoma induced Cushing's syndrome, but not in ectopic ACTH-producing tumors 3, 4.

Diagnosis and Treatment

• The diagnosis of Cushing's syndrome involves a combination of clinical evaluation, laboratory tests, and imaging studies 2, 3, 5, 4, 6.
• Treatment of pituitary adenoma induced Cushing's syndrome typically involves transsphenoidal surgery to remove the adenoma, followed by medical therapy to control any residual disease 2, 3, 4, 6.