What causes a low Adrenocorticotropic Hormone (ACTH) level?

Causes of Low ACTH Levels

Low ACTH levels indicate either secondary (central) adrenal insufficiency from pituitary or hypothalamic dysfunction, or ACTH-independent Cushing's syndrome from autonomous adrenal cortisol production. 1

Primary Diagnostic Framework

The interpretation of low ACTH depends critically on the concurrent cortisol level, as this relationship determines the underlying pathophysiology and clinical significance 1:

Low ACTH with Low Cortisol: Secondary Adrenal Insufficiency

This combination indicates central (secondary) adrenal insufficiency, where the pituitary fails to produce adequate ACTH. 1

Common Causes:

• Hypophysitis - Inflammation of the pituitary gland, most commonly presenting with central adrenal insufficiency, and may also cause central hypothyroidism, diabetes insipidus, and hypogonadism 1

• Iatrogenic suppression - Patients on exogenous corticosteroids (oral prednisolone, dexamethasone, or inhaled fluticasone) develop secondary adrenal insufficiency with suppressed ACTH due to negative feedback on the hypothalamic-pituitary axis 1

• Pituitary tumors or masses - Space-occupying lesions can compress or destroy ACTH-producing corticotroph cells 1

• Pituitary surgery or radiation - Prior treatment can damage the pituitary gland and impair ACTH production 1

• Hypothalamic dysfunction - Disorders affecting CRH production will secondarily reduce ACTH secretion 1

Diagnostic Workup for Secondary Adrenal Insufficiency:

• Evaluate morning (AM) ACTH and cortisol levels, TSH, free T4, and electrolytes 1

• Consider ACTH stimulation testing for indeterminate results (morning cortisol >3 mcg/dL and <15 mcg/dL) 1

• Evaluate LH, FSH, and testosterone in males or estrogen in premenopausal females with fatigue, loss of libido, and mood changes 1

• Obtain MRI of the brain with pituitary/sellar cuts in patients with multiple endocrine abnormalities, especially with new severe headaches or vision changes 1

Low ACTH with High Cortisol: ACTH-Independent Cushing's Syndrome

This combination indicates autonomous adrenal cortisol production that suppresses pituitary ACTH through negative feedback. 2, 3

Common Causes:

• Adrenal adenoma - Benign cortisol-secreting tumor is the most common cause of ACTH-independent Cushing's syndrome 2, 3

• Adrenal carcinoma - Malignant cortisol-producing tumor with more aggressive behavior 2, 3

• Bilateral adrenocortical adenomas - Rare cause with fewer than 40 cases reported in the literature 4

• Primary pigmented nodular adrenocortical disease (PPNAD) - Rare genetic disorder causing bilateral micronodular hyperplasia 5

• ACTH-independent macronodular adrenal hyperplasia (AIMAH) - Bilateral adrenal enlargement with autonomous cortisol production, sometimes under control of aberrant hormone receptors 3, 5

Diagnostic Workup for ACTH-Independent Cushing's:

• In ACTH-independent Cushing's syndrome, ACTH is always low and usually undetectable 6

• Morning plasma ACTH <5 ng/L (or undetectable) with elevated cortisol confirms ACTH-independent disease 2

• Perform adrenal CT or MRI to identify the adrenal lesion(s) - This is the definitive next step after confirming low ACTH with hypercortisolism 1, 2

• Evaluate for metastasis or hemorrhage as potential causes of primary adrenal pathology 1

Critical Clinical Pitfalls

Timing of ACTH Measurement

• Always measure ACTH in the morning (08:00-09:00h) for optimal interpretation, as ACTH follows a diurnal rhythm with highest levels in the morning 2

• Random ACTH measurements may be misleading and should be avoided for diagnostic purposes 2

Medication Interference

• Stop drugs affecting pituitary or adrenocortical function before ACTH testing - Consider at least 5 half-lives to avoid interference 7

• Exogenous corticosteroids will artificially suppress ACTH and confound interpretation 1

• Anticonvulsants, psychotropic drugs, hormone preparations, antithyroid agents, and cyproheptadine may affect test results 7

Distinguishing Primary from Secondary Adrenal Insufficiency

The ACTH-cortisol relationship is the definitive distinguishing feature: 1

• Primary adrenal insufficiency: High ACTH (>5 ng/L) with low cortisol - The adrenal glands fail, so the pituitary appropriately increases ACTH production 1

• Secondary adrenal insufficiency: Low ACTH with low cortisol - The pituitary fails to produce ACTH, so the adrenals atrophy from lack of stimulation 1

Special Diagnostic Considerations

• In patients with suspected adrenal insufficiency based on low cortisol, assess the adrenal glands' ability to respond to exogenous ACTH before employing metyrapone testing 7

• For patients with cyclical Cushing's disease, hypercortisolemia must be confirmed immediately prior to diagnostic procedures to ensure the patient is in an active disease phase 2

• Bilateral adrenal vein sampling (AVS) can provide critical information about the functional state of bilateral adrenal lesions before surgery 4