From the Guidelines
Elevated cortisol with normal Adrenocorticotropic Hormone (ACTH) levels is typically caused by an adrenal tumor, either benign (adrenal adenoma) or malignant (adrenal carcinoma), which autonomously produces excess cortisol without requiring stimulation from pituitary ACTH. This condition is known as ACTH-independent hypercortisolism. The study by 1 highlights that Cushing syndrome can be caused by a benign adrenal tumor or a malignant adrenal tumor, neither of which produce ACTH.
Possible Causes
- Adrenal tumors (benign or malignant)
- Bilateral adrenal hyperplasia
- Exogenous glucocorticoid use
- Ectopic cortisol production from non-adrenal tumors (extremely rare)
- Certain medications that interfere with cortisol metabolism or testing
- Pseudo-Cushing's states like alcoholism, depression, obesity, and poorly controlled diabetes
Diagnostic Workup
The diagnostic workup for elevated cortisol with normal ACTH levels typically includes:
- A dexamethasone suppression test
- Adrenal imaging (CT or MRI)
- Potentially adrenal vein sampling to localize the source
Treatment
Treatment depends on the underlying cause, with:
- Surgical removal being the standard approach for adrenal tumors
- Medication adjustment or lifestyle changes may be appropriate for other causes As noted in the study by 1, medical management of hypercortisolism is achieved with adrenostatic agents, including ketoconazole and mitotane, and bilateral adrenalectomy is recommended in certain cases.
From the Research
Causes of Elevated Cortisol with Normal Adrenocorticotropic Hormone (ACTH) Levels
- Primary adrenal causes of Cushing's syndrome can lead to elevated cortisol levels with normal or undetectable ACTH levels, as seen in a study of 11 consecutive patients with primary adrenal causes of hypercortisolism 2.
- Adrenal adenomas or carcinomas can cause autonomous cortisol secretion, leading to elevated cortisol levels with normal ACTH levels, as demonstrated by a study of 68 consecutive patients with clinically inapparent adrenal adenomas 3.
- The cortisol/ACTH ratio (CAR) can be a useful diagnostic tool for Cushing's syndrome, with high CAR indicating increased cortisol secretion from the adrenal glands, as shown in a study of 44 subjects with subclinical Cushing's syndrome and 14 with ACTH-independent Cushing's syndrome 4.
- Chronic ACTH excess can lead to chronic cortisol excess, but this is typically associated with elevated ACTH levels, whereas normal ACTH levels with elevated cortisol may indicate an adrenal cause of Cushing's syndrome, as discussed in a study on the effects of chronic ACTH excess on the human adrenal cortex 5.
- Various factors can influence the adrenocorticotropin test, including contemporary cortisol assays, body composition, and oral contraceptive agents, which can affect the interpretation of cortisol and ACTH levels, as demonstrated by a study of 100 unmedicated subjects and 13 women taking oral contraception 6.