What are the causes of low cortisol levels?

Causes of Low Cortisol Levels

Low cortisol levels are primarily caused by primary adrenal insufficiency, secondary adrenal insufficiency, or glucocorticoid-induced adrenal insufficiency, with autoimmune destruction of the adrenal glands being the most common etiology of primary adrenal insufficiency. 1, 2

Primary Adrenal Insufficiency

Primary adrenal insufficiency results from direct failure of the adrenal glands and is characterized by:

• Autoimmune destruction - The most common cause in developed countries 3, 1
• Congenital adrenal hyperplasia 2
• Infections:
  • Tuberculosis
  • Fungal infections 2
• Pharmacological inhibition:
  • High doses of azole antifungal therapy 2
• Surgical removal of adrenal cortical tissue 2

In primary adrenal insufficiency, laboratory findings typically show:

• Low morning cortisol (<5 μg/dL)
• High ACTH levels
• Low DHEAS (dehydroepiandrosterone sulfate) levels 2

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency occurs due to disorders affecting the pituitary gland or hypothalamus, resulting in inadequate ACTH production:

• Pituitary tumors
• Pituitary hemorrhage
• Inflammatory or infiltrative conditions:
  • Hypophysitis
  • Sarcoidosis
  • Hemochromatosis
• Pituitary surgery or radiation therapy
• Medications that suppress corticotropin production (e.g., opioids) 2

Laboratory findings typically show:

• Low or intermediate morning cortisol (5-10 μg/dL)
• Low or low-normal ACTH levels
• Low DHEAS levels 2

Glucocorticoid-Induced Adrenal Insufficiency

This is the most common form of adrenal insufficiency and is caused by:

• Administration of supraphysiological doses of glucocorticoids 2
• Abrupt discontinuation of glucocorticoid therapy 4

The FDA warns that drug-induced secondary adrenocortical insufficiency may occur after discontinuation of therapy and can persist for months, requiring gradual reduction of dosage when discontinuing treatment 4.

Clinical Presentation

Patients with low cortisol typically present with:

• Fatigue (50%-95% of cases)
• Nausea and vomiting (20%-62%)
• Anorexia and weight loss (43%-73%)
• Hypotension
• Hyperpigmentation (in primary adrenal insufficiency)
• Electrolyte abnormalities:
  • Hyponatremia
  • Hyperkalemia (in approximately 50% of primary adrenal insufficiency cases) 3, 2

Diagnostic Approach

The diagnostic workup for suspected low cortisol includes:

1. Morning cortisol and ACTH measurement:

   • S-cortisol <250 nmol/L with increased ACTH during acute illness is diagnostic of primary adrenal insufficiency
   • S-cortisol <400 nmol/L with increased ACTH during acute illness raises strong suspicion 3

2. ACTH stimulation test (gold standard):

   • Baseline blood samples for cortisol and ACTH
   • Administration of synthetic ACTH (cosyntropin)
   • Measurement of post-stimulation cortisol at 30 and 60 minutes
   • Peak serum cortisol <500 nmol/L is diagnostic of adrenal insufficiency 3, 1

3. Etiological investigation:

   • Measurement of 21-hydroxylase (anti-adrenal) autoantibodies
   • If antibodies are negative, CT imaging is recommended
   • In male patients, very long-chain fatty acids should be assayed to check for adrenoleukodystrophy 3

Common Pitfalls in Diagnosis

• Failing to recognize the impact of oral contraceptives on cortisol levels
• Overlooking the need for dose adjustments during pregnancy
• Not considering adrenal insufficiency in patients who have recently tapered or discontinued glucocorticoids 1, 4
• Delaying treatment of suspected acute adrenal insufficiency for diagnostic procedures (treatment should never be delayed) 3

Remember that adrenal crisis is a life-threatening emergency requiring immediate treatment with fluids and corticosteroids if there is strong clinical suspicion 5.