Causes of Adrenal Insufficiency
Adrenal insufficiency has three main categories: primary (autoimmune disease accounts for up to 90% in Western countries), secondary (pituitary disorders), and glucocorticoid-induced (the most common form overall from exogenous steroid use). 1, 2
Primary Adrenal Insufficiency (PAI)
The adrenal glands themselves fail to produce cortisol, aldosterone, and androgens. The causes include:
Most Common in Developed Countries
- Autoimmune destruction (Addison's disease): Accounts for up to 90% of PAI cases in Western countries 1. Approximately 58% of patients with autoimmune adrenal insufficiency have associated autoimmune thyroid disorders 3.
Infectious Causes
- Tuberculosis: The leading cause in developing countries and historically the most common cause worldwide 1
- Fungal infections 2
- HIV-associated adrenal disease 3
Genetic/Congenital Causes (More Common in Children)
- Congenital adrenal hyperplasia (particularly 21-hydroxylase deficiency, affecting 1 in 10,000-15,000 births) 1, 4
- Adrenal hypoplasia congenita 5
- Congenital lipoid adrenal hyperplasia 5
- P450-oxidoreductase deficiency 5
Iatrogenic/Pharmacological
- Bilateral adrenalectomy 1
- Pharmacological inhibition of cortisol synthesis: High-dose azole antifungals, etomidate, aminoglutethimide 1, 2
- Adrenal hemorrhage: Related to anticoagulant therapy 1
- Accelerated cortisol metabolism: Anticonvulsants (phenytoin, phenobarbital), rifampicin 1
Infiltrative/Neoplastic
Secondary Adrenal Insufficiency (SAI)
The pituitary gland fails to produce adequate ACTH, resulting in cortisol deficiency but preserved aldosterone production (since aldosterone is primarily regulated by the renin-angiotensin system, not ACTH).
Structural Pituitary Lesions
- Pituitary macroadenomas: Account for 64.5% of SAI cases 3
- Pituitary surgery or radiation therapy 2
- Pituitary hemorrhage (apoplexy) 2
Inflammatory/Infiltrative
- Hypophysitis (including checkpoint inhibitor-induced, such as pembrolizumab) 2, 3
- Sarcoidosis 2
- Hemochromatosis 2
Genetic Causes
- Isolated ACTH deficiency 4
- Combined pituitary hormone deficiencies (mutations in transcription factors) 4
Pharmacological
- Opioid medications: Suppress corticotropin production 2
Glucocorticoid-Induced Adrenal Insufficiency
This is the most common form of adrenal insufficiency overall 2, though often underrecognized. It results from:
- Prolonged supraphysiological doses of exogenous glucocorticoids used for anti-inflammatory therapy 2, 6, 7
- Suppression occurs at the hypothalamic level (tertiary adrenal insufficiency)
- Should be suspected in any patient who has recently tapered or discontinued glucocorticoid therapy 2
Clinical Context and Pitfalls
A critical pitfall is the growing number of iatrogenic causes in chronically ill patients requiring intensive care with multiple pharmacological therapies 1. The combination of anticoagulants, steroid synthesis inhibitors, and drugs that accelerate cortisol metabolism increasingly contributes to PAI manifestation.
The prevalence of checkpoint inhibitor therapy (like pembrolizumab) for cancer treatment has introduced a new cohort of patients at risk for hypophysitis-induced SAI 3. Screening protocols should be implemented for high-risk groups including HIV-positive patients and those receiving checkpoint inhibitors 3.
Approximately 5% of patients with SAI may not show typical symptoms of hypocortisolism 3, making biochemical screening essential in at-risk populations rather than relying solely on clinical presentation.