What are the causes of low serum cortisol?

Causes of Low Serum Cortisol

Low serum cortisol results from either primary adrenal insufficiency (adrenal gland failure), secondary adrenal insufficiency (pituitary/hypothalamic dysfunction), or glucocorticoid-induced adrenal suppression, with important laboratory artifacts also capable of producing falsely low values.

Primary Adrenal Insufficiency (Addison's Disease)

Primary adrenal insufficiency occurs when the adrenal cortex cannot produce sufficient glucocorticoids and mineralocorticoids 1. The key distinguishing feature is elevated ACTH levels due to loss of negative feedback, along with elevated renin.

Common Etiologies:

• Autoimmune adrenalitis (most common in Western societies)
• Tuberculosis (historically common, still relevant in endemic areas) 2
• Adrenal hemorrhage or infarction
• Metastatic disease
• Genetic disorders (congenital adrenal hyperplasia, adrenoleukodystrophy)

Clinical presentation includes fatigue, weight loss, postural dizziness, anorexia, and the pathognomonic finding of hyperpigmentation of sun-exposed areas, skin creases, and mucosal membranes 1. Laboratory findings typically show hyponatremia and hyperkalemia 1.

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency results from insufficient ACTH production by the pituitary or hypothalamus. Both cortisol AND ACTH are low, distinguishing it from primary disease 2.

Common Etiologies:

• Pituitary tumors or masses (as demonstrated by sellar masses on MRI) 2
• Pituitary surgery or radiation
• Traumatic brain injury
• Infiltrative diseases (sarcoidosis, hemochromatosis)
• Sheehan syndrome (postpartum pituitary necrosis)

Key difference from primary disease: No hyperpigmentation occurs (ACTH is low, not elevated), and mineralocorticoid function remains intact since the renin-angiotensin-aldosterone system is preserved 1.

Glucocorticoid-Induced Adrenal Insufficiency

This is the most common cause of adrenal insufficiency in clinical practice 3. Exogenous glucocorticoid administration suppresses the hypothalamic-pituitary-adrenal axis through negative feedback, causing adrenal atrophy.

Key Features:

• Occurs with prolonged glucocorticoid therapy (typically >3 weeks at supraphysiologic doses)
• Both cortisol and ACTH are suppressed 3
• Recovery can take months to over a year after glucocorticoid discontinuation
• Morning cortisol >300 nmol/L (10 μg/dL) indicates HPA axis recovery 3
• Importantly, physiological doses (prednisolone ≤5 mg) still suppress the axis, and tapering these doses actually promotes recovery rather than following it 4

Laboratory Artifacts and False Low Values

Critical Pitfalls to Recognize:

Hypoalbuminemic states produce falsely low total cortisol due to decreased cortisol-binding globulin (CBG):

• Nephrotic syndrome (CBG lost in urine) 5
• Advanced cirrhosis
• Malnutrition
• Critical illness 3

In these situations, free cortisol (salivary cortisol) remains normal despite low serum total cortisol 5. This is not true adrenal insufficiency.

Elevated CBG states (pregnancy, oral estrogens) conversely elevate total cortisol, potentially masking insufficiency 3.

Heterophile antibody interference in immunoassays can produce spuriously low cortisol values 6. When clinical suspicion doesn't match laboratory results, test with a different assay or method (ideally liquid chromatography-tandem mass spectrometry).

Assay variability is substantial—different immunoassays can yield cortisol values varying by 170 nmol/L for the same sample 3. Know your laboratory's specific cut-offs and methodology.

Stress-Related Hypocortisolism

A distinct entity exists where chronic stress paradoxically produces low cortisol through increased glucocorticoid receptor sensitivity and enhanced negative feedback 7, 8. This occurs in:

• Post-traumatic stress disorder
• Chronic fatigue syndrome
• Fibromyalgia

This represents functional hypocortisolism without true adrenal or pituitary failure—the axis can respond to stimulation but operates at a lower set point 7.

Diagnostic Algorithm

When encountering low serum cortisol:

1. Verify the result isn't artifactual: Check for hypoalbuminemia, nephrotic syndrome, or assay interference. Consider salivary free cortisol if CBG abnormalities suspected 3, 5.

2. Measure ACTH simultaneously:

   • High ACTH → Primary adrenal insufficiency
   • Low/normal ACTH → Secondary or glucocorticoid-induced insufficiency

3. Assess for exogenous glucocorticoid exposure: Any glucocorticoid use in the past 6-12 months, including inhaled, topical, or intra-articular preparations 3.

4. Look for clinical clues:

   • Hyperpigmentation → Primary disease 1
   • Headaches, visual changes → Pituitary mass 2
   • Electrolyte abnormalities (hyponatremia, hyperkalemia) → Primary disease 1

5. Consider dynamic testing if morning cortisol is 150-300 nmol/L (5-10 μg/dL) and diagnosis remains uncertain 3.

**Morning cortisol <150 nmol/L strongly suggests adrenal insufficiency requiring treatment**, though newer second-generation assays suggest even lower thresholds may be appropriate 9. Values >300 nmol/L generally exclude clinically significant insufficiency 3.