What are the causes of primary adrenal insufficiency?

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Last updated: October 25, 2026 • View editorial policy

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Causes of Primary Adrenal Insufficiency

In adults, autoimmune adrenalitis (Addison's disease) is the most common cause of primary adrenal insufficiency, while in children, congenital adrenal hyperplasia—particularly 21-hydroxylase deficiency—accounts for approximately 80% of cases. 1

Major Etiologic Categories

Autoimmune Causes

Autoimmune destruction of the adrenal cortex represents the predominant etiology in Western countries 2. This can present as:

  • Isolated autoimmune adrenalitis - occurs without other autoimmune conditions
  • Autoimmune Polyglandular Syndrome (APS) Type 1 - associated with chronic mucocutaneous candidiasis and hypoparathyroidism
  • APS Type 2 - occurs alongside autoimmune thyroid disease and/or type 1 diabetes

Up to 50% of patients with autoimmune PAI will develop another autoimmune disorder during their lifetime, necessitating lifelong surveillance 3.

Genetic/Congenital Disorders

Congenital adrenal hyperplasia (CAH) is the leading cause in pediatric populations, with 21-hydroxylase deficiency being the most common subtype 1. Other genetic causes include:

  • Adrenoleukodystrophy - X-linked disorder affecting males; ABCD1 gene mutations account for 37.5% of non-CAH pediatric PAI 4
  • Adrenal hypoplasia congenita - X-linked NR0B1 mutations, SF-1 mutations
  • ACTH insensitivity syndromes - familial glucocorticoid deficiency (MC2R, MRAP, NNT, MCM4 mutations)
  • Triple A (Allgrove's) syndrome - achalasia, Addison's disease, alacrima
  • Other rare CAH forms: 11β-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase deficiency

Infiltrative/Destructive Processes

Infectious causes remain important globally, particularly:

  • Tuberculosis - historically the most common cause worldwide
  • HIV/AIDS-related infections - CMV, candidiasis, histoplasmosis
  • Other infections: syphilis, African trypanosomiasis, paracoccidioidomycosis

Adrenal hemorrhage occurs with:

  • Sepsis (Waterhouse-Friderichsen syndrome)
  • Anticoagulant therapy
  • Antiphospholipid syndrome

Malignant infiltration from:

  • Lung, breast, colon cancers
  • Melanoma
  • Lymphoma

Other infiltrative diseases: hemochromatosis, primary amyloidosis

Iatrogenic Causes

  • Bilateral adrenalectomy - performed for intractable Cushing's syndrome or bilateral pheochromocytoma
  • Drug-induced adrenal suppression 1:
    • Adrenal enzyme inhibitors: mitotane, ketoconazole, metyrapone, etomidate, aminoglutethimide
    • CTLA-4 inhibitors and immune checkpoint inhibitors - increasingly recognized cause due to enhanced autoimmunity 2
    • Drugs accelerating cortisol metabolism (including levothyroxine via 11β-HSD2 stimulation)

Metabolic Disorders

  • Mitochondrial diseases (rare)
  • Wolman's disease
  • Various inborn errors of metabolism - emerging recognition of PAI association with IEM 5

Clinical Pitfalls

The diagnosis of PAI is frequently delayed due to nonspecific presentation 6. Key features to recognize include hyperpigmentation, fatigue, anorexia, orthostatic hypotension, nausea, muscle/joint pain, and salt craving 3.

In pediatric populations, genetic testing via next-generation sequencing achieves diagnostic yield of 87.5% in non-CAH cases 4, making it an essential tool when CAH is excluded. The male predominance in pediatric non-CAH PAI (87.5% in one series) reflects the X-linked nature of common genetic causes like adrenoleukodystrophy and adrenal hypoplasia congenita 4.

Mortality in rare pediatric PAI causes reaches 10%, with acute adrenal crisis occurring in 45% of patients, typically from poor treatment adherence 7. This underscores the life-threatening nature of delayed diagnosis and suboptimal management.

References

6
Research

Autoimmune Primary Adrenal Insufficiency: Understanding the Past, Present, and Future.

Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 2025

7
Research

Rare Causes of Pediatric Primary Adrenal Insufficiency: An Observational Cohort Study.

Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists, 2026

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