Tertiary Adrenal Insufficiency

Tertiary adrenal insufficiency is cortisol deficiency caused by suppression or loss of hypothalamic corticotrophin releasing hormone, with low ACTH. The commonest cause by far is prolonged exogenous glucocorticoid use.

Glucocorticoid induced suppression follows treatment with prednisolone 5 mg daily or more (or equivalent) for over 3 to 4 weeks, and can follow inhaled, topical, intra-articular, ocular and injected steroids at high doses. Roughly half of long term oral steroid users have biochemical suppression.

Other causes are hypothalamic tumours (craniopharyngioma), radiotherapy, head injury, megestrol and opioids. Recovery takes weeks to over a year after stopping.

Pathophysiology.

Exogenous or endogenous glucocorticoid exposure suppresses corticotrophin releasing hormone and ACTH, causing adrenal atrophy. Suppression depends on dose, duration, potency and timing, and varies widely between patients.

Mineralocorticoid production is preserved.

• Fatigue, weakness, nausea, anorexia, arthralgia, low mood and postural dizziness, particularly during steroid taper.
• Crisis with intercurrent illness, surgery or abrupt stopping.
• Cushingoid features may persist from earlier steroid exposure.

Red flags.

• Hypotension, vomiting, hyponatraemia or collapse (adrenal crisis).
• Intercurrent illness or surgery in a patient taking steroids.

• Documented steroid exposure including topical, inhaled and injected forms. Ask about supplements and traditional preparations that contain glucocorticoid.
• 8 to 9 am cortisol, taken 24 hours after the last hydrocortisone dose (and after the last prednisolone dose, whose assay cross-reaction can mislead): under 100 nmol/L (3.6 micrograms/dL) confirms deficiency, and over 400 nmol/L (about 14.5 micrograms/dL) excludes it.
• Intermediate values: short tetracosactide test (250 micrograms); peak cortisol under about 450 nmol/L (assay dependent) indicates deficiency.
• ACTH low. Potassium and renin normal. Pituitary imaging if no steroid exposure is found.

Differential diagnosis.

• Secondary adrenal insufficiency from pituitary disease.
• Primary adrenal insufficiency, and relapse of the underlying disease during taper.
• Steroid withdrawal syndrome (symptoms with normal cortisol).

• Do not stop long term glucocorticoid suddenly. Taper as the underlying disease allows.
• When the dose is at physiological replacement (prednisolone 5 mg daily), change to hydrocortisone 15 to 20 mg daily in two or three divided doses and reduce by 2.5 to 5 mg every 1 to 2 weeks to 10 mg daily or less.
• Test morning cortisol, 24 hours after the last hydrocortisone dose. Over 400 nmol/L: stop. 100 to 400 nmol/L: continue and retest in 4 to 12 weeks. Under 100 nmol/L: continue replacement and retest every 3 to 6 months.
• Sick day rules: double the dose for fever and illness, and give hydrocortisone 100 mg intramuscularly or intravenously for vomiting or collapse. Provide a steroid alert card.
• Surgery or major illness: hydrocortisone 100 mg intravenously at induction, then 200 mg over 24 hours.
• Adrenal crisis: hydrocortisone 100 mg intravenously at once, then 200 mg over 24 hours, with intravenous 0.9% sodium chloride 1000 mL over the first hour.

Special groups. Patients on high dose inhaled or topical steroids, particularly children, can have suppression. Pregnancy: increase hydrocortisone in the third trimester and give 100 mg intravenously at labour.

Monitoring. Symptoms, weight and blood pressure at each visit. Morning cortisol every 4 to 12 weeks during recovery, and bone density with prolonged steroid exposure.

Referral and escalation. Endocrinology if cortisol has not recovered at 12 months, or for diagnostic doubt. Same day review for adrenal crisis.