What is the recommended diagnosis, treatment, and follow‑up for secondary adrenal insufficiency?

Secondary Adrenal Insufficiency: Diagnosis, Treatment, and Follow-Up

Diagnosis

Secondary adrenal insufficiency (SAI) is characterized by low cortisol with low or inappropriately normal ACTH, distinguishing it from primary adrenal insufficiency where ACTH is markedly elevated. 1

Initial Diagnostic Testing

• Measure early morning (8 AM) serum cortisol and plasma ACTH simultaneously as the first-line diagnostic approach. 1, 2 This timing is critical because cortisol follows a circadian rhythm with peak levels in the morning.

• Morning cortisol <5 µg/dL (<140 nmol/L) with low or inappropriately normal ACTH is diagnostic of secondary adrenal insufficiency. 1, 2

• Morning cortisol 5-10 µg/dL (140-275 nmol/L) with low or inappropriately normal ACTH raises strong suspicion and requires confirmatory testing. 1, 2

• Morning cortisol >18-20 µg/dL (>500-550 nmol/L) effectively excludes adrenal insufficiency. 1

• Obtain a basic metabolic panel to assess for hyponatremia, which occurs in 90% of newly diagnosed cases, though hyperkalemia is typically absent in SAI (unlike primary adrenal insufficiency where it occurs in ~50% of cases). 1, 3

Confirmatory Testing: ACTH Stimulation Test

When morning cortisol is indeterminate (5-18 µg/dL), perform the cosyntropin stimulation test to definitively confirm or exclude adrenal insufficiency. 1, 4

Test Protocol

• Administer 0.25 mg (250 µg) cosyntropin (tetracosactide) intramuscularly or intravenously. 1, 4

• Obtain baseline serum cortisol before administration. 1

• Measure serum cortisol at 30 and/or 60 minutes post-administration. 1, 4

• Peak cortisol <500 nmol/L (<18 µg/dL) is diagnostic of adrenal insufficiency. 1, 4

• Peak cortisol >550 nmol/L (>18-20 µg/dL) is normal and excludes adrenal insufficiency. 1, 4

• The high-dose (250 µg) test is preferred over low-dose (1 µg) testing due to easier practical administration, comparable diagnostic accuracy, and FDA approval. 1

Critical Diagnostic Pitfalls

• Never delay treatment of suspected acute adrenal crisis for diagnostic procedures—if the patient is clinically unstable with hypotension, altered mental status, or severe symptoms, give hydrocortisone 100 mg IV immediately plus 0.9% saline infusion. 1, 3, 4

• Do not attempt diagnostic testing in patients actively taking exogenous corticosteroids (prednisone, prednisolone, dexamethasone, inhaled fluticasone), as these suppress the HPA axis and cause iatrogenic secondary adrenal insufficiency, confounding all test results. 1, 5, 2 Wait until the patient has been weaned off corticosteroids before performing definitive testing.

• If you must treat suspected adrenal crisis but still want to preserve the ability to perform diagnostic testing later, use dexamethasone 4 mg IV instead of hydrocortisone, as dexamethasone does not interfere with cortisol assays. 1

• The absence of hyperkalemia does not exclude adrenal insufficiency—hyperkalemia is present in only ~50% of primary adrenal insufficiency cases and is typically absent in secondary adrenal insufficiency. 1, 3

Etiologic Workup for Secondary Adrenal Insufficiency

Once SAI is confirmed biochemically, determine the underlying cause:

• The most common endogenous cause is a pituitary or hypothalamic tumor, often associated with other pituitary hormone deficiencies (panhypopituitarism). 6, 7 Obtain MRI of the pituitary/hypothalamus to evaluate for tumors, hemorrhage, infiltrative lesions, or structural abnormalities.

• The most common overall cause is iatrogenic—long-term glucocorticoid therapy suppressing the HPA axis. 5, 6, 2 Any patient taking ≥20 mg/day prednisone or equivalent for ≥3 weeks is at risk.

• Other causes include pituitary surgery, radiation therapy, traumatic brain injury, lymphocytic hypophysitis, infiltrative diseases (sarcoidosis, hemochromatosis), and medications that suppress ACTH production (opioids). 6, 2

• Assess for other pituitary hormone deficiencies by measuring TSH, free T4, LH, FSH, testosterone (men) or estradiol (women), prolactin, and IGF-1. 6

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Treatment

Maintenance Glucocorticoid Replacement

All patients with confirmed secondary adrenal insufficiency require lifelong glucocorticoid replacement therapy. 8, 1, 2

Standard Dosing Regimens

• Hydrocortisone 15-25 mg daily in 2-3 divided doses is the preferred glucocorticoid replacement. 8, 1, 2 Typical regimens include:

  • 10 mg at 7:00 AM, 5 mg at 12:00 PM, 2.5-5 mg at 4:00 PM 1
  • Alternative: 15 mg + 5 mg, or 10 mg + 10 mg, or 10 mg + 5 mg + 5 mg 1

• Alternative: Cortisone acetate 25-37.5 mg daily in divided doses. 8, 1 Cortisone acetate requires hepatic conversion to hydrocortisone and has slightly delayed onset of action.

• Alternative: Prednisone 3-5 mg daily (or prednisolone 4-5 mg daily). 1, 2 Consider this in select patients with marked energy fluctuations throughout the day or when hydrocortisone is not tolerated.

• Avoid dexamethasone for chronic replacement therapy. 1 It has a long half-life that prevents recreation of the diurnal cortisol rhythm.

Key Differences from Primary Adrenal Insufficiency

• Mineralocorticoid replacement (fludrocortisone) is NOT required in secondary adrenal insufficiency because the renin-angiotensin-aldosterone system remains intact—aldosterone production is preserved. 1, 9 This is a critical distinction from primary adrenal insufficiency, which requires both glucocorticoid and mineralocorticoid replacement.

• Unrestricted sodium salt intake is generally not necessary in SAI (unlike primary AI). 1

Monitoring Glucocorticoid Replacement

Monitoring relies predominantly on clinical assessment, not laboratory parameters—plasma ACTH and serum cortisol are not useful for dose adjustment. 8

Signs of Over-Replacement

• Weight gain 8
• Insomnia 8
• Peripheral edema 8
• Cushingoid features developing over time

Signs of Under-Replacement

• Lethargy, fatigue 8, 1
• Nausea, poor appetite 8, 1
• Weight loss 8
• Morning nausea or lack of appetite (consider having the patient wake earlier to take the first dose, then return to sleep) 8, 1

Fine-Tuning Dosage

• Question patients about daily energy levels, "get up and go," mental concentration, daytime somnolence, and timing of energy dips during the day. 8

• Adjust timing of doses based on when symptoms occur—the goal is to approximate physiological cortisol secretion with higher doses in the morning and lower doses in the afternoon/evening. 8, 1

• In cases where malabsorption is suspected, serum or salivary cortisol day curve monitoring (morning postdose peak and trough predose levels) may guide dosing adjustments. 8

Drug Interactions Affecting Hydrocortisone Requirements

CYP3A4 inducers increase hydrocortisone clearance and may require higher replacement doses: 8, 1

• Anti-epileptics (phenytoin, carbamazepine, phenobarbital)
• Rifampin and other antituberculosis drugs
• Barbiturates

CYP3A4 inhibitors decrease hydrocortisone clearance and may require lower doses: 8, 1

• Grapefruit juice (avoid)
• Liquorice (avoid)

Stress Dosing ("Sick Day Rules")

All patients must be educated on increasing glucocorticoid doses during illness, fever, injury, or physical stress to prevent adrenal crisis. 1, 3, 2

Minor Stress (mild illness, fever <38.5°C)

• Double the usual daily hydrocortisone dose for 1-2 days. 1

Moderate Stress (fever >38.5°C, moderate illness, dental procedures)

• Hydrocortisone 30-50 mg total daily dose (or prednisone 20 mg daily) for 2-3 days. 1

Major Stress (severe illness, major surgery, trauma)

• Hydrocortisone 100-150 mg daily in divided doses or as continuous IV infusion. 1

Inability to Take Oral Medications (vomiting, diarrhea)

• Patients must use parenteral hydrocortisone 100 mg IM immediately and seek emergency care. 1, 3, 2 All patients should be prescribed an emergency injectable hydrocortisone kit with self-injection training.

Patient Education and Safety Measures

Every patient with secondary adrenal insufficiency must: 1, 3, 2

• Wear a medical alert bracelet or necklace indicating adrenal insufficiency to trigger stress-dose corticosteroids by emergency medical personnel

• Carry a steroid emergency card at all times

• Be prescribed an emergency injectable hydrocortisone 100 mg IM kit with training on self-administration

• Receive detailed education on stress dosing and warning signs of impending adrenal crisis (severe weakness, confusion, persistent vomiting, severe hypotension)

• Understand that even mild gastrointestinal upset may precipitate adrenal crisis if oral medications cannot be absorbed

Special Situations

Concurrent Hypothyroidism

When treating both adrenal insufficiency and hypothyroidism, start corticosteroids several days before initiating thyroid hormone replacement to prevent precipitating adrenal crisis. 1 Thyroid hormone increases cortisol metabolism and can unmask or worsen adrenal insufficiency.

Perioperative Management

• Minor surgery: Double the usual daily dose for 1-2 days 1
• Moderate surgery: Hydrocortisone 50-75 mg daily 1
• Major surgery: Hydrocortisone 100 mg IV at induction, then 100-150 mg daily as continuous infusion or divided doses 1
• Mandatory endocrinology consultation before surgery for stress-dose planning 1

Recovery from Iatrogenic SAI

• For patients with glucocorticoid-induced adrenal insufficiency, the HPA axis typically recovers 6-12 months after cessation of exogenous glucocorticoids, though timing is variable. 5

• Test for HPA axis recovery after 3 months of maintenance therapy with hydrocortisone in patients with isolated central adrenal insufficiency from steroid use. 1

• Until recovery is confirmed, continue glucocorticoid replacement and stress-dosing precautions.

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Follow-Up

Routine Monitoring Schedule

Patients with secondary adrenal insufficiency should be reviewed at least annually. 1

Annual Assessment Should Include:

• Clinical evaluation of overall health, well-being, and quality of life 1

• Weight monitoring (to detect over- or under-replacement) 1

• Blood pressure measurement (supine and standing to detect orthostatic changes) 1

• Serum electrolytes (sodium, potassium) 1

• Assessment for signs of glucocorticoid over-replacement (weight gain, cushingoid features, bone loss) or under-replacement (fatigue, weight loss, hypotension)

• Bone mineral density every 3-5 years to assess for glucocorticoid-induced osteoporosis 1

Screening for Associated Conditions

In patients with pituitary/hypothalamic disease causing SAI, screen annually for: 1

• Thyroid function (TSH, free T4)—hypothyroidism frequently coexists with pituitary disease

• Diabetes mellitus (fasting glucose or HbA1c)

• Other pituitary hormone deficiencies (growth hormone, gonadotropins, prolactin)

• Vitamin B12 deficiency (if pernicious anemia is suspected)

Endocrinology Consultation

Mandatory endocrinology consultation is recommended for: 1

• Newly diagnosed secondary adrenal insufficiency (for initial education and management planning)

• Pre-operative planning before any surgery

• Recovery protocols after prolonged steroid use

• Any patient with recurrent adrenal crises

• Difficulty achieving adequate symptom control on standard replacement doses

Preventing Recurrent Crises

Evaluate patients with recurrent adrenal crises for: 3

• Chronic under-replacement with glucocorticoids (inadequate maintenance dose)

• Poor medication adherence

• Underlying psychiatric disorders affecting compliance

• Inadequate patient education on stress dosing

• Medications that accelerate cortisol clearance (CYP3A4 inducers) without dose adjustment

• Failure to increase doses during intercurrent illness despite education