What causes low cortisol levels?

Causes of Low Cortisol Levels

Low cortisol levels result from three main categories: primary adrenal insufficiency (adrenal gland destruction), secondary adrenal insufficiency (pituitary/hypothalamic dysfunction), and iatrogenic adrenal suppression from exogenous glucocorticoid therapy—with the latter being approximately 100 times more common than intrinsic causes. 1

Primary Adrenal Insufficiency (High ACTH, Low Cortisol)

Direct destruction or dysfunction of the adrenal glands themselves causes both cortisol and aldosterone deficiency. 1, 2

Autoimmune Causes

• Addison's disease (autoimmune adrenal insufficiency) accounts for approximately 85% of primary adrenal insufficiency cases in Western populations, characterized by 21-hydroxylase autoantibodies 3, 4
• Autoimmune destruction frequently occurs as part of autoimmune polyendocrine syndromes with associated thyroid disease, diabetes mellitus, pernicious anemia, vitiligo, or premature ovarian failure 5

Congenital Causes

• Congenital adrenal hyperplasia is the most common cause in children, occurring in 1 in 15,000 live births 1
• Developmental disorders of the adrenal glands 1

Infectious Causes

• Tuberculosis remains an important cause globally 4
• Fungal infections (histoplasmosis, coccidioidomycosis) 4
• HIV-related adrenal involvement 6

Other Causes

• Adrenal hemorrhage or infarction 3, 4
• Metastatic cancer or infiltrative disease 4
• Pharmacological inhibition from high-dose azole antifungal therapy 4
• Surgical removal of adrenal tissue 4

Secondary Adrenal Insufficiency (Low ACTH, Low Cortisol)

Pituitary or hypothalamic dysfunction results in inadequate ACTH production, causing isolated cortisol deficiency while aldosterone production remains intact. 1, 2

Pituitary/Hypothalamic Disorders

• Pituitary tumors and their surgical or radiation treatment 1, 4
• Pituitary hemorrhage (Sheehan's syndrome, apoplexy) 4
• Hypophysitis (inflammatory pituitary disease), including immune checkpoint inhibitor-induced hypophysitis 2, 4
• Infiltrative conditions: sarcoidosis, hemochromatosis, Langerhans cell histiocytosis 4
• Developmental disorders of the hypothalamus and pituitary 1

Autoimmune Causes

• Isolated ACTH deficiency can occur as an autoimmune phenomenon, sometimes associated with lymphocytic hypophysitis and other autoimmune conditions 5, 7
• Secondary adrenal insufficiency may coexist with autoimmune thyroid disease, though less commonly recognized than primary adrenal insufficiency 5

Medication-Induced

• Chronic opioid therapy suppresses corticotropin production 4
• Other medications that suppress the hypothalamic-pituitary axis 4

Iatrogenic (Tertiary) Adrenal Insufficiency

This is the most common cause of low cortisol, affecting approximately 7 in 1,000 people—roughly 100 times more prevalent than intrinsic adrenal insufficiency. 1

Exogenous Glucocorticoid Therapy

• Oral corticosteroids at supraphysiological doses cause hypothalamic-pituitary-adrenal axis suppression 1, 8, 4
• Inhaled corticosteroids can cause adrenal suppression even at commonly prescribed doses in a dose-dependent manner, contrary to previous assumptions 1
• Topical, intranasal, and intra-articular corticosteroid administration can all suppress the axis 1
• Drug-induced secondary adrenocortical insufficiency may persist for months after discontinuation of therapy 8

High-Risk Populations

• Patients with asthma on chronic inhaled steroids 1
• Patients with inflammatory bowel disease, rheumatologic conditions, or renal disease requiring chronic glucocorticoid therapy 1
• Children with Duchenne muscular dystrophy or juvenile chronic arthritis on long-term steroids 1

Special Clinical Contexts

Critical Illness

• Reduced cortisol metabolism during critical illness can paradoxically lead to both hypercortisolemia and impaired cortisol response, with more than 50% reduction in cortisol clearance 9
• This represents altered cortisol dynamics rather than true insufficiency, though functional insufficiency may still occur 9

Liver Disease

• Hepatitis C, cirrhosis, and prior orthotopic liver transplantation are associated with increased frequency of biochemical adrenal insufficiency 6
• Liver disease affects cortisol metabolism and binding protein production 6

Critical Diagnostic Distinction

The pattern of ACTH and cortisol distinguishes the causes: primary adrenal insufficiency shows high ACTH with low cortisol, while secondary/tertiary insufficiency shows low or inappropriately normal ACTH with low cortisol. 2, 3, 10, 4