What are the causes and treatment options for low cortisol levels, or adrenal insufficiency, in a patient?

Causes of Low Cortisol (Adrenal Insufficiency)

Primary Causes (Adrenal Gland Failure)

Low cortisol with high ACTH indicates primary adrenal insufficiency, where the adrenal glands themselves have failed. 1

Autoimmune Destruction

• Autoimmune adrenalitis accounts for approximately 85% of primary adrenal insufficiency cases in Western populations 1
• Measure 21-hydroxylase autoantibodies as the first-line etiologic test—positive results confirm autoimmune etiology 1
• Often associated with other autoimmune endocrinopathies requiring annual screening for thyroid disease, diabetes, pernicious anemia, and celiac disease 1

Infectious Causes

• Tuberculosis remains a significant cause, particularly in endemic regions 2
• Fungal infections can destroy adrenal tissue, especially in immunocompromised patients 2
• HIV-related opportunistic infections may cause adrenal destruction 2

Structural and Infiltrative Causes

• Adrenal hemorrhage (bilateral) from trauma, anticoagulation, or sepsis 1
• Metastatic disease to both adrenal glands 1
• Congenital adrenal hyperplasia (21-hydroxylase deficiency most common) 2
• Adrenoleukodystrophy—check very long-chain fatty acids (VLCFA) in males with negative autoantibodies 1

Pharmacological Causes

• High-dose azole antifungal therapy (ketoconazole, fluconazole) directly inhibits cortisol synthesis 2
• Etomidate suppresses adrenal steroidogenesis 1
• Mitotane and other adrenolytic agents 2

Surgical

• Bilateral adrenalectomy for any indication results in permanent primary adrenal insufficiency 2

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Secondary Causes (Pituitary/Hypothalamic Dysfunction)

Low cortisol with low or inappropriately normal ACTH indicates secondary adrenal insufficiency from inadequate ACTH stimulation. 1, 3

Pituitary Tumors and Masses

• Pituitary adenomas (functioning or non-functioning) can compress normal corticotroph cells 1
• Craniopharyngiomas and other sellar/parasellar masses 4
• Pituitary microadenomas may cause isolated ACTH deficiency 1

Pituitary Damage

• Pituitary surgery or radiation therapy causes progressive HPA axis dysfunction 2
• Pituitary apoplexy (hemorrhage or infarction) 4
• Sheehan syndrome (postpartum pituitary necrosis) 4
• Traumatic brain injury affecting the pituitary stalk 4

Inflammatory and Infiltrative Conditions

• Hypophysitis (autoimmune, IgG4-related, or lymphocytic) 2
• Sarcoidosis infiltrating the hypothalamus or pituitary 2
• Hemochromatosis with iron deposition 2
• Histiocytosis X (Langerhans cell histiocytosis) 4

Medications Suppressing ACTH

• Chronic opioid therapy suppresses hypothalamic CRH and pituitary ACTH secretion 2
• Megestrol acetate and other progestins 4
• Checkpoint inhibitor immunotherapy causing hypophysitis 2

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Glucocorticoid-Induced Adrenal Insufficiency (Most Common)

This is the most prevalent form of adrenal insufficiency, caused by exogenous glucocorticoid administration suppressing the HPA axis. 2

Risk Factors for HPA Suppression

• Prednisone ≥20 mg daily (or equivalent) for ≥3 weeks causes predictable HPA suppression 1, 5
• Doses of 5-20 mg prednisone daily: approximately one-third to one-half of patients develop inadequate adrenal reserve 1
• Inhaled corticosteroids (especially fluticasone at high doses) can suppress the HPA axis 1
• Topical, intra-articular, and epidural steroid injections may cause suppression with repeated use 5

Duration of Suppression

• HPA axis suppression can persist for up to 12 months after discontinuation of prolonged glucocorticoid therapy 5
• Recovery is unpredictable and requires testing 3 months after stopping maintenance glucocorticoid therapy 1

Critical Clinical Pitfall

• Never abruptly discontinue glucocorticoids after prolonged use—taper gradually and provide stress-dose coverage during the recovery period 5
• Any unusual stress (illness, surgery, trauma) during the 12-month recovery period requires stress-dose glucocorticoid coverage 5

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Diagnostic Approach

Initial Testing

• Obtain early morning (8 AM) serum cortisol and plasma ACTH simultaneously 1, 2
• Check basic metabolic panel for hyponatremia (present in 90% of cases) and hyperkalemia (only 50% of primary AI) 1
• Measure DHEAS—low levels support adrenal insufficiency 2

Interpretation of Initial Results

• Morning cortisol <250 nmol/L (<9 μg/dL) with high ACTH is diagnostic of primary adrenal insufficiency 1
• Morning cortisol <250 nmol/L with low/normal ACTH indicates secondary adrenal insufficiency 3
• Morning cortisol 140-275 nmol/L (5-10 μg/dL) requires confirmatory cosyntropin stimulation testing 1, 2
• Morning cortisol >500 nmol/L (>18 μg/dL) effectively rules out adrenal insufficiency 1

Confirmatory Testing

• Cosyntropin stimulation test: administer 0.25 mg (250 mcg) IV or IM, measure cortisol at 30 and 60 minutes 1
• Peak cortisol <500 nmol/L (<18 μg/dL) confirms adrenal insufficiency 1
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes adrenal insufficiency 1

Important Testing Caveats

• Do not attempt diagnostic testing in patients currently taking glucocorticoids—cortisol assays measure both endogenous and exogenous steroids 1
• Hydrocortisone must be held for 24 hours before testing; other steroids require longer washout periods 1
• If testing must be performed while treating suspected adrenal crisis, use dexamethasone 4 mg IV instead of hydrocortisone, as it does not interfere with cortisol assays 1
• Never delay treatment of suspected adrenal crisis for diagnostic testing—treat immediately and obtain samples before giving hydrocortisone if possible 1, 6

Etiologic Workup After Diagnosis

• For primary AI: measure 21-hydroxylase autoantibodies first 1
• If autoantibodies negative: obtain adrenal CT to evaluate for hemorrhage, tumor, tuberculosis, or infiltration 1
• In males with negative antibodies: check very long-chain fatty acids for adrenoleukodystrophy 1
• For secondary AI: obtain pituitary MRI and test other pituitary hormones (TSH, LH, FSH, prolactin, IGF-1) 4

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Treatment Principles

Glucocorticoid Replacement

• Hydrocortisone 15-25 mg daily in divided doses (typically 10 mg at 7 AM, 5 mg at noon, 2.5-5 mg at 4 PM) mimics physiological cortisol secretion 1, 2
• Alternative: prednisone 3-5 mg daily as a single morning dose 1, 2
• Avoid dexamethasone for chronic replacement therapy 1

Mineralocorticoid Replacement (Primary AI Only)

• Fludrocortisone 0.05-0.2 mg daily (up to 0.3 mg may be needed in younger adults) 1, 2
• Titrate based on blood pressure (supine and standing), salt cravings, plasma renin activity, and serum potassium 1
• Secondary AI does not require mineralocorticoid replacement—the renin-angiotensin-aldosterone system remains intact 1, 3

Stress Dosing

• Minor stress (mild illness): double the usual daily dose for 1-2 days 1
• Moderate stress (fever, gastroenteritis): hydrocortisone 50-75 mg daily or prednisone 20 mg daily 1
• Major stress (surgery, severe illness): hydrocortisone 100-150 mg daily IV in divided doses 1
• Adrenal crisis: hydrocortisone 100 mg IV bolus immediately, then 50-100 mg IV every 6-8 hours plus 0.9% saline at 1 L/hour 1, 2

Mandatory Patient Education

• All patients must receive education on stress dosing and self-management 1, 2
• Prescribe emergency injectable hydrocortisone 100 mg IM kit with self-injection training 1
• Patients must wear medical alert bracelet or necklace indicating adrenal insufficiency 1, 2
• Provide written sick-day rules for doubling or tripling doses during illness 1

Critical Management Pitfall

• When treating concurrent hypothyroidism and adrenal insufficiency, always start glucocorticoids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis 1, 7