What is the significance of elevated Adrenocorticotropic hormone (ACTH) and cortisol levels in a symptomatic female with a positive Dexamethasone suppression test (DST) and low cortisol levels?

From the Guidelines

The clinical picture of elevated Adrenocorticotropic hormone (ACTH) and cortisol levels in a symptomatic female with a positive Dexamethasone suppression test (DST) and low cortisol levels is most consistent with Cushing's disease (pituitary-dependent hypercortisolism), and management should include referral to an endocrinologist for confirmation with additional testing and consideration of transsphenoidal surgery or medical therapy. This condition is typically caused by an ACTH-secreting pituitary adenoma that drives excessive cortisol production from the adrenal glands. The positive DST indicates failure to suppress cortisol with dexamethasone administration, which is characteristic of Cushing's syndrome 1.

Key Points to Consider

• Elevated levels of ACTH indicate that excessive cortisol secretion is not coming from the adrenal gland, but rather from a pituitary or ectopic source 1.
• The positive DST and elevated cortisol levels are consistent with Cushing's syndrome, and the low cortisol levels may represent a lab error or timing issue 1.
• Management should include referral to an endocrinologist for confirmation with additional testing such as 24-hour urinary free cortisol, late-night salivary cortisol, and pituitary MRI.
• If Cushing's disease is confirmed, transsphenoidal surgery to remove the pituitary adenoma would be the first-line treatment, with medical therapy with medications like ketoconazole, metyrapone, or pasireotide used temporarily or in cases where surgery is contraindicated 1.
• Early diagnosis and treatment are crucial as chronic hypercortisolism can lead to serious complications including diabetes, hypertension, osteoporosis, and increased cardiovascular risk 1.

Additional Testing and Considerations

• Additional testing such as 24-hour urinary free cortisol, late-night salivary cortisol, and pituitary MRI should be performed to confirm the diagnosis and rule out other causes of Cushing's syndrome 1.
• The patient's clinical features, such as weight, glycemia, and blood pressure, should be closely monitored, and quality of life should be taken into account, preferably through patient-reported outcomes 1.
• Combination therapy may be considered if cortisol levels are persistently elevated after 2-3 months on maximum tolerated doses, and monitoring for potential overlapping toxicities and drug-drug interactions is important 1.

From the Research

Significance of Elevated ACTH and Cortisol Levels

• Elevated Adrenocorticotropic hormone (ACTH) and cortisol levels in a symptomatic female with a positive Dexamethasone suppression test (DST) and low cortisol levels may indicate Cushing's syndrome, a condition caused by excess glucocorticoids 2, 3, 4.
• The combination of elevated ACTH and cortisol levels suggests an ACTH-dependent form of Cushing's syndrome, which can be caused by a pituitary adenoma (Cushing's disease) or ectopic tumors secreting ACTH or corticotropin-releasing hormone (CRH) 2.
• A positive DST, which measures the suppression of cortisol production after administration of dexamethasone, can help diagnose Cushing's syndrome, but low cortisol levels may indicate a false-negative result or another underlying condition 4, 5.

Diagnostic Considerations

• Further diagnostic testing, such as 24-hour urinary free cortisol, salivary cortisol, or night-time plasma cortisol values, may be necessary to confirm the diagnosis of Cushing's syndrome 2, 4.
• Imaging studies, such as pituitary magnetic resonance imaging or adrenal computed tomography scan, may be used to localize the source of excess ACTH or cortisol production 2, 6.
• Inferior petrosal sinus sampling can help distinguish between Cushing's disease and ectopic ACTH tumors 2, 3.

Treatment Implications

• The treatment of Cushing's syndrome depends on the underlying cause and may involve surgical removal of the tumor, medication to control cortisol production, or radiation therapy 2, 6.
• In cases of ACTH-dependent Cushing's syndrome, transsphenoidal surgery to remove the pituitary tumor may be the initial treatment of choice, while bilateral adrenalectomy may be considered in cases of adrenal Cushing's syndrome 2, 6.