2016 Endocrine Society Guidelines: CENTRAL Adrenal Insufficiency

Adrenal Insufficiency (AI) is defined by low cortisol production.  It could be due to failure, infection, injury, bleeding or inflammation of the adrenal glands, or from limited production of ACTH hormone by the pituitary.  

Adrenal Insufficiency as a result of low ACTH is called “central” or “secondary”. These guidelines were developed by Endocrine Society to address specifically Central AI. They were released in November 2016.

Please find below excerpts with slightly modified wording for easier and succinct reading.



Also see:

Adrenal insufficiency





J C E M, Endocrine Society Guidelines

Central Adrenal Insufficiency

November 2016



  • We suggest measuring serum cortisol levels at 8–9 am as the first-line test for diagnosing central adrenal insufficiency.

  • We recommend against using a random cortisol level to diagnose AI.

  • We suggest that a cortisol level <3 μg/dL is indicative of adrenal insufficiency and a cortisol level >15 μg/dL likely excludes an AI diagnosis.

  • We suggest performing a corticotropin stimulation test when morning cortisol values are between 3-15 μg/dL to diagnose AI. Peak cortisol levels <18.1 μg/dL at 30 or 60 minutes indicate AI.

  • We suggest that clinicians perform biochemical testing for the hypothalamic-pituitary-adrenal (HPA) axis at least 18–24 hours after the last hydrocortisone (HC) dose or longer for synthetic glucocorticoids (GC).



  • We recommend using hydrocortisone, usually 15–20 mg total daily dose in single or divided doses. Patients using divided doses should take the highest dose in the morning at awakening and the second in the afternoon (two-dose regime) or the second and third at lunch and late afternoon, respectively (three-dose regime).

  • We suggest using longer-acting glucocorticoids in selected cases (eg, non-availability, poor compliance, convenience).

  • We recommend that clinicians teach all patients with adrenal insufficiency regarding stress-dose and emergency GC administration and instruct them to obtain an emergency card/bracelet/necklace regarding AI and an emergency kit containing injectable high-dose GC.

  • We recommend against using fludrocortisone in patients with central adrenal insufficiency.

  • We recommend that clinicians treat patients with suspected adrenal crisis (AC) due to secondary AI with an immediate parenteral injection of 50–100 mg hydrocortisone.


Hormone Interactions

  • We suggest evaluating central hypothyroid patients for adrenal insufficiency before starting LT4 therapy. If this is not feasible, clinicians should prescribe empiric glucocorticoid therapy in patients with central hypothyroidism who are starting LT4 therapy until there is a definitive evaluation for adrenal insufficiency.

  • We suggest that when clinicians assess adrenal reserve or the adequacy of hydrocortisone replacement, they take into consideration that total serum cortisol level can be elevated due to the effects of estrogen on corticosteroid-binding globulin (CBG).

  • Because adrenal insufficiency [relative hypovolemia] may mask the presence of partial diabetes insipidus, we suggest monitoring for the development of DI after starting GC replacement.



  • Clinicians should individually assess glucocorticoid replacement and avoid over-replacement to reduce the risk of osteoporosis. We suggest low-dose hydrocortisone replacement because this approach might be associated with increased bone formation and a positive bone-remodeling balance.

  • In men with hypopituitarism over-replaced with GC and at risk for fractures, we suggest vertebral fracture assessment (baseline plain spinal x-rays or DEXA) to identify patients with unsuspected vertebral fractures.

  • In patients with central adrenal insufficiency, we recommend using the lowest tolerable dose of HC replacement to potentially decrease the risks of metabolic and cardiovascular disease.


Non-pituitary surgery

  • On the day of surgery, we recommend adjusting glucocorticoid dose according to the severity of illness and magnitude of the stressor.

  • In cases of minor to moderate surgical stress, we suggest HC 25–75 mg/day (usually for 1–2 days).

  • In cases of major surgical stress, we suggest a HC 100 mg IV injection followed by a continuous iv infusion of 200 mg HC per 24 hours (alternatively 50 mg every 6 hours iv or im).



  • We suggest using hydrocortisone as the preferred GC in pregnancy and increasing the dose based on the individual clinical course; higher doses may be required, in particular during the third trimester.

  • We suggest that pregnant patients with central AI be closely monitored for clinical symptoms and signs of GC over- and under-replacement (eg, normal weight gain, fatigue, postural hypotension or hypertension, hyperglycemia).

  • We recommend against using dexamethasone in pregnancy because it is not inactivated in the placenta.

  • We recommend HC stress dosing during the active phase of labor, similar to that used in major surgical stress.

More from the Publication:

Central AI represents inadequate cortisol secretion due to ACTH deficiency. It can be secondary, when pituitary disease impairs the release of ACTH, or tertiary from inadequate hypothalamic CRH.

The prevalence of central AI (excluding exogenous steroid use) is 150–280 per million inhabitants; almost one-third of the patients with pituitary failure may have AI. The reported prevalence after pituitary surgery varies, with up to 90% after craniopharyngioma surgery.

Patients who have undergone cranial radiation for non-pituitary tumors have a high prevalence of hypopituitarism. The timing of the onset of new pituitary deficiencies after radiation varies, but in most cases it may take a few years to develop. A high index of suspicion is required for diagnosing AI because delaying treatment can result in adrenal crisis and death. Mild ACTH deficiency may manifest as clinically important AI with stress.