What causes hypocortisolism?

Causes of Hypocortisolism (Adrenal Insufficiency)

Hypocortisolism results from three main mechanisms: primary adrenal gland destruction or dysfunction, secondary pituitary ACTH deficiency, or tertiary hypothalamic-pituitary-adrenal axis suppression from exogenous glucocorticoid administration—with iatrogenic causes being by far the most common, affecting approximately 100 times more patients than intrinsic adrenal or pituitary disease. 1

Primary Adrenal Insufficiency (Addison's Disease)

Primary adrenal insufficiency occurs when the adrenal gland itself is destroyed or dysfunctional, resulting in deficiency of both cortisol and aldosterone. 1, 2

Autoimmune Causes

• Autoimmune adrenal destruction (Addison's disease) is the most common cause of primary adrenal insufficiency in Western populations, accounting for approximately 85% of cases. 3
• Characterized by the presence of 21-hydroxylase autoantibodies in most patients 3

Congenital Causes

• Congenital adrenal hyperplasia, particularly 21-hydroxylase deficiency, is the most common inherited cause, occurring in 1 in 15,000 live births. 1, 4
• Adrenal hypoplasia congenita and other genetic mutations affecting adrenal development 4

Infectious Causes

• Tuberculosis and fungal infections can cause adrenal destruction, particularly in endemic areas. 2
• HIV-related opportunistic infections 2

Infiltrative and Structural Causes

• Adrenal hemorrhage or infarction (Waterhouse-Friderichsen syndrome) 4
• Metastatic malignancy infiltrating the adrenal glands 2
• Sarcoidosis, hemochromatosis, and amyloidosis 2

Pharmacological Causes

• High-dose azole antifungal therapy can pharmacologically inhibit cortisol synthesis. 2
• Surgical removal of adrenal tissue (bilateral adrenalectomy) 2

Secondary Adrenal Insufficiency

Secondary adrenal insufficiency results from pituitary ACTH deficiency, with cortisol deficiency but preserved aldosterone production since the renin-angiotensin system remains intact. 1

Pituitary Pathology

• Pituitary tumors (adenomas, craniopharyngiomas) causing mass effect and ACTH cell destruction 2
• Pituitary surgery or radiation therapy 2
• Pituitary apoplexy (hemorrhage or infarction) 2

Inflammatory and Infiltrative Conditions

• Hypophysitis (autoimmune inflammation of the pituitary) 2
• Sarcoidosis, hemochromatosis, and histiocytosis X 2

Congenital Causes in Children

• Developmental disorders of the hypothalamus and pituitary, including mutations in essential transcription factors causing combined pituitary hormone deficiencies 1, 4
• Isolated ACTH deficiency due to genetic mutations 4
• Brain tumors and their treatment affecting approximately 1 in 10,000 children 1

Medication-Induced

• Chronic opioid therapy can suppress corticotropin production at the pituitary level. 2

Tertiary Adrenal Insufficiency (Iatrogenic/Glucocorticoid-Induced)

This is by far the most common cause of adrenal insufficiency in clinical practice, affecting approximately 7 in 1,000 people—roughly 100 times more prevalent than intrinsic adrenal or pituitary disease. 1

Exogenous Glucocorticoid Administration

• Any route of glucocorticoid administration can suppress the hypothalamic-pituitary-adrenal axis: oral, inhaled, topical, intranasal, and intra-articular. 1
• Inhaled corticosteroids, despite previous claims of safety within recommended doses, commonly cause HPA axis suppression in a dose-dependent manner. 1
• Prolonged supraphysiological doses of glucocorticoids for conditions such as asthma, inflammatory bowel disease, rheumatologic disorders, and renal disease 1, 2

High-Risk Pediatric Populations

• Children receiving glucocorticoid treatment for asthma, juvenile chronic arthritis, inflammatory bowel disease, renal disease, and Duchenne muscular dystrophy represent a significant proportion of adrenal insufficiency cases. 1

Rare Hypothalamic Causes

• Isolated CRH deficiency is a highly unusual cause of adrenal insufficiency with poorly understood pathogenesis. 5
• Hypothalamic tumors or infiltrative disease affecting CRH production 1

Clinical Significance and Mortality Risk

Patients with adrenal insufficiency face significantly elevated mortality risk, with risk ratios of 2.19 for men and 2.86 for women, primarily from cardiovascular, infectious, and malignant diseases. 1

Adrenal crises occur at a rate of 6-8 episodes per 100 patient-years and carry substantial mortality risk if untreated, with 8.6% of patients reporting previous crises caused by inadequate glucocorticoid coverage during hospitalization or surgery. 1