From the Guidelines
Low ACTH with high cortisol levels typically indicates a condition called Cushing's syndrome, specifically the ACTH-independent form, and the most recent guideline recommends imaging of the adrenal glands, typically starting with an adrenal CT scan with contrast, and treatment depends on the underlying cause but often involves surgical removal of the affected adrenal gland(s) or medical therapy with cortisol-lowering medications 1. This pattern suggests that the excess cortisol is being produced autonomously by the adrenal glands rather than being driven by pituitary ACTH stimulation. The most common cause is an adrenal tumor (adenoma or carcinoma) or bilateral adrenal hyperplasia.
Key Points
- The condition is characterized by a negative feedback loop where high cortisol suppresses pituitary ACTH production, which is why ACTH levels are low despite elevated cortisol.
- Prompt diagnosis and treatment are essential as chronic hypercortisolism can lead to serious complications including diabetes, hypertension, osteoporosis, and increased cardiovascular risk.
- For adrenal adenomas, laparoscopic adrenalectomy is the standard approach, and for bilateral disease, medical therapy with cortisol-lowering medications like ketoconazole (400-800 mg daily), metyrapone (500-750 mg every 4 hours), or mitotane (2-6 g daily in divided doses) may be necessary 1.
Diagnosis and Treatment
- The diagnosis of Cushing's syndrome is supported by a 24-hour urine free cortisol excretion of >193 nmol/24 h (>70 μg/m2) or a late-night salivary cortisol based on local assay cut-off 1.
- The treatment of choice for ACTH-independent Cushing's syndrome is surgical removal of the affected adrenal gland(s) or medical therapy with cortisol-lowering medications.
Medical Therapy
- Medical management of hypercortisolism is achieved with adrenostatic agents, including ketoconazole, metyrapone, mitotane, and osilodrostat, which block one or more adrenal enzymes, decreasing GC synthesis and/or adrenal androgen production and secretion 1.
- The choice of medical therapy depends on the underlying cause, the severity of the disease, and the patient's overall health status.
- It is essential to monitor patients closely for signs of adrenal insufficiency and adjust the treatment regimen as needed.
From the Research
Low ACTH with High Cortisol
- The combination of low adrenocorticotropic hormone (ACTH) and high cortisol levels can be indicative of Cushing's syndrome, a condition caused by excess cortisol production 2.
- In Cushing's syndrome, the high cortisol levels can be due to an ACTH-independent source, such as an adrenal tumor, or an ACTH-dependent source, such as a pituitary tumor 2.
- The diagnosis of Cushing's syndrome can be made using various tests, including the dexamethasone suppression test (DST) and the measurement of 24-hour urine free cortisol (UFC) levels 2, 3.
- The DST involves administering a low dose of dexamethasone, a synthetic glucocorticoid, and measuring the subsequent decrease in cortisol production 3.
- The 24-hour UFC test measures the amount of cortisol excreted in the urine over a 24-hour period, which can be elevated in Cushing's syndrome 2, 3.
- The combination of low ACTH and high cortisol levels can also be seen in other conditions, such as adrenal insufficiency, where the adrenal glands do not produce enough cortisol 4, 5.
- In adrenal insufficiency, the low ACTH levels can be due to a lack of stimulation from the pituitary gland, while the high cortisol levels can be due to exogenous steroid use or other factors 4, 5.
- The diagnosis of adrenal insufficiency can be made using various tests, including the ACTH stimulation test, which measures the increase in cortisol production in response to ACTH administration 4, 5.
- Newer cortisol assays, such as the Elecsys II and LC-MS/MS, have lower thresholds for a normal response to ACTH stimulation, which can affect the diagnosis of adrenal insufficiency 5.