Glucocorticoid Replacement Therapy

Glucocorticoid replacement gives hydrocortisone, or a longer-acting steroid, to replace the cortisol that is lost in adrenal insufficiency. It is needed for life in primary adrenal insufficiency (Addison disease, tuberculous or autoimmune adrenalitis, adrenal haemorrhage, congenital adrenal hyperplasia) and in secondary adrenal insufficiency from pituitary disease or from prolonged exogenous steroids. The aim is the lowest dose that relieves symptoms, because over-replacement causes weight gain, diabetes, hypertension and bone loss.

Shape of the dose. Normal cortisol is highest on waking and lowest at midnight. Dosing should copy this, with the largest dose on waking and the last dose no later than mid-afternoon.

Mineralocorticoid. Primary disease also needs fludrocortisone. Secondary disease does not, because aldosterone is preserved.

Before starting thyroid replacement. Start hydrocortisone first when both deficiencies exist, because thyroid hormone speeds cortisol clearance and can trigger a crisis.

First choice. Hydrocortisone tablets 5 mg, 10 mg and 20 mg, taken in 2 to 3 divided doses.

Alternatives. Prednisolone 3 to 5 mg once daily when adherence to divided doses is poor. Dexamethasone 0.25 to 0.5 mg once daily is used rarely, because dose titration is difficult and over-replacement is common.

Emergency supply. Hydrocortisone sodium succinate 100 mg for intramuscular or intravenous injection, kept at home with a trained family member.

Congenital adrenal hyperplasia. Specialist-led, with higher doses in childhood to suppress adrenal androgens.

Adults. Hydrocortisone 15 to 25 mg orally daily in total, with a maximum of 30 mg daily in routine use. Typical schedules: - Three doses: 10 mg on waking, 5 mg at noon and 5 mg in the mid-afternoon. - Two doses: 15 mg on waking and 5 mg at 14:00 to 16:00.

Secondary adrenal insufficiency. Use the lower end, 15 to 20 mg daily, because some cortisol production remains.

Prednisolone option. 3 to 5 mg orally once daily in the morning.

Children. Hydrocortisone 8 to 10 mg/m2/day in 3 divided doses for adrenal insufficiency, and 10 to 15 mg/m2/day in 3 divided doses for congenital adrenal hyperplasia. Use hydrocortisone granules or crushed tablets, never a long-acting steroid, because growth is suppressed.

Titration. Change the dose by 2.5 to 5 mg at a time. Judge by symptoms, weight, blood pressure with a lying and standing reading, sodium and potassium. Cortisol day curves are not routinely needed.

Interactions that raise the dose. Rifampicin, phenytoin, carbamazepine, phenobarbital and efavirenz speed cortisol breakdown, so the daily dose should be doubled, usually by adding an extra 10 mg dose, and reduced again when the interacting drug stops. Oestrogen-containing contraception and pregnancy raise cortisol-binding globulin and may raise the dose needed.

Interactions that lower the dose. Itraconazole, ritonavir and cobicistat slow cortisol breakdown, so watch for over-replacement.

Pregnancy. Continue the usual dose in the first and second trimesters. In the third trimester increase the dose by 20 to 40% if symptoms or low blood pressure appear. In labour, give hydrocortisone 100 mg intravenously at onset, then 200 mg over 24 hours by infusion or 50 mg every 6 hours, and return to the usual dose over 2 to 3 days after delivery.

Special groups. - Kidney impairment: no adjustment; watch potassium if fludrocortisone is also taken. - Liver disease: cortisol clearance and binding are reduced, so use the lower end of the range and avoid over-replacement. - Older adults: use 15 mg daily in total where possible, because bone and glucose effects are greater. - Breastfeeding: compatible at replacement doses. - Diabetes: replacement may raise glucose, so review insulin or sulphonylurea doses. - Weight: dose by response in adults and by body surface area in children.

Monitoring. Review at least yearly: energy, appetite, weight, postural blood pressure, sodium, potassium, glucose and HbA1c. Check bone density every 2 to 3 years in long-term treatment. Teach every patient about sick day rules and give a steroid card and medical alert.

Over-replacement. Weight gain, rounded face, hypertension, glucose intolerance and bone loss. Reduce the dose by 2.5 to 5 mg.

Under-replacement. Fatigue, nausea, weight loss, hyperpigmentation, postural dizziness and hyponatraemia. Increase the dose by 2.5 to 5 mg and check for missed doses or an interacting drug.

Stopping. Replacement is lifelong in primary disease. In secondary disease caused by exogenous steroids, recovery is tested by a morning cortisol before the dose after the dose has been held for 24 hours, and replacement is withdrawn only after specialist review.

Referral and escalation. Refer every new diagnosis to endocrinology. Escalate to the emergency dose of hydrocortisone for vomiting, collapse, fever with drowsiness or severe illness, and admit the patient.