Central Hypocortisolism Management

Introduction to Central Hypocortisolism

Central hypocortisolism (secondary adrenal insufficiency) is characterized by low morning cortisol with inappropriately low ACTH levels, caused by pituitary or hypothalamic disorders affecting ACTH production, and typically does not require mineralocorticoid replacement 1

The preferred glucocorticoid replacement is hydrocortisone (HC) with a total daily dose of 15-20 mg, typically divided into 2-3 doses, with a standard dosing schedule of 2/3 in the morning and 1/3 in the early afternoon to mimic physiological cortisol rhythm, as recommended by the Endocrine Society 1, 2, 3
Cortisone acetate (CA) is an alternative that requires activation to hydrocortisone by hepatic 11β-hydroxysteroid dehydrogenase type 1, available in 25 mg and 5 mg tablets, with a slightly delayed onset of action compared to hydrocortisone 1

Clinical assessment is the primary method for monitoring adequacy of replacement, with signs of over-replacement including weight gain, insomnia, and peripheral edema, and signs of under-replacement including fatigue, nausea, hypotension, and hyponatremia 1
Plasma ACTH and serum cortisol are not useful parameters for dose adjustment, but the American College of Endocrinology recommends adjusting hydrocortisone doses based on clinical symptoms, avoiding both over-replacement (iatrogenic Cushing's) and under-replacement (adrenal insufficiency) 1, 3
The target range for mean daily serum cortisol should be 150-300 nmol/L to approximate normal cortisol production rates, although this value may vary depending on individual patient factors and laboratory assays 2

Patients should be educated to increase their dose 2-3 times during minor illness or stress, and parenteral hydrocortisone is required for severe illness or surgery, with delays in hydrocortisone administration during emergencies potentially being fatal 1
Patients should wear medical identification and have an emergency injectable hydrocortisone kit, with training for patients and family members on administration, as recommended by the Endocrine Society 1, 3

When both cortisol and thyroid hormones are deficient, always replace cortisol first to prevent precipitating an adrenal crisis, as recommended by the Endocrine Society 3
Replacing thyroid hormone before cortisol in patients with multiple pituitary deficiencies can precipitate adrenal crisis, and careful monitoring is required when using steroidogenesis inhibitors or mifepristone (a glucocorticoid receptor blocker) 3, 2

Annual clinical assessment for adequacy of replacement, monitoring for symptoms of under- or over-replacement, and assessing for development of other pituitary hormone deficiencies are necessary, with bone health monitoring may be warranted with long-term therapy 1
Patients who undergo bilateral adrenalectomy, have post-surgical adrenal insufficiency, or have received radiation therapy may require lifelong glucocorticoid replacement, typically with hydrocortisone, to maintain normal cortisol levels and prevent adrenal crisis 2, 1, 4
Children with Cushing's disease may require temporary medical therapies like metyrapone or ketoconazole, but long-term use is limited due to adverse effects, and hydrocortisone replacement may be needed following successful treatment 4