Current diagnosis

• Initial diagnosis of adrenocortical insufficiency (AI) is based in most cases on a morning cortisol level, measured at 8 to 9 am in patients with a normal circadian rhythm.

• A morning cortisol level less than 5 µg/dL supports diagnosis, and a value greater than 15 µg/dL effectively rules out AI.

• To confirm diagnosis, especially in cases with intermediate cortisol values, a high-dose (250 µg) cosyntropin (Cortrosyn) stimulation test is suggested with a normal cut-off peak cortisol greater than 18 to 20 µg/dL at 30 or 60 minutes.

• Primary AI is characterized by elevated endogenous adrenocorticotropic hormone (ACTH) levels and absence of mineralocorticoid hormones in addition to glucocorticoid deficiency; antibody screening and/or adrenal imaging is indicated.

• Secondary AI is characterized by an inappropriately normal or low endogenous ACTH level and low cortisol with preserved mineralocorticoid hormones. If exogenous glucocorticoid use is ruled out, magnetic resonance imaging (MRI) of the pituitary sella is appropriate.

Current Therapy

• Oral hydrocortisone (Cortef) is the preferred form of steroid to attain physiologic replacement. Doses are usually 15 to 25 mg divided into two or three daily doses, with the highest dose in the morning. However, recent studies based on cortisol production rates suggest that most patients are overreplaced if taking more than 20 mg daily.

• In case of physiologic stress, such as fever, severe infection, or minor surgery, doses should be doubled or tripled (depending on the type of stress or procedure) for the duration of the event.

• In patients with primary AI, fludrocortisone (Florinef), a mineralocorticoid, should be added to the treatment regimen, with a typical dose between 0.05 and 0.1 mg daily.

• For adrenal crisis in patients with known AI, administer hydrocortisone injection (Solu-Cortef) 50 to 100 mg IV every 6 to 8 hours along with generous volumes of saline.

• Patients should wear a medical alert bracelet or necklace and have extensive education regarding AI and treatment and prevention of adrenal crisis.


Primary AI, also known as Addison disease when of autoimmune cause, has a prevalence of 100 to 140 cases per million persons. More than 90% of Addison disease in the developed world is secondary to autoimmune adrenalitis, and it is more common in women. Secondary AI caused by therapeutic glucocorticoid administration is the most prevalent; pituitary tumors and surgeries are other common etiologies.

Risk Factors

Primary Adrenocortical Insufficiency

A personal or family history of autoimmune disease (e.g., type 1 diabetes, Hashimoto disease, vitiligo, pernicious anemia) is a risk factor for autoimmune adrenalitis. Especially in the context of acute AI in the hospital, thrombosis and secondary hemorrhage must be ruled out and the possibility of heparin-induced thrombocytopenia (HIT) must be elicited if the patient is on heparin. Miliary tuberculosis is the most frequent cause of primary AI in developed countries.

Infiltration in the context of malignancy is often due to a known plurimetastatic cancer; other infiltrative diseases are rare.

Secondary Adrenocortical Insufficiency

The most prevailing risk factor for secondary AI is prolonged use of exogenous glucocorticoids. Patients taking more than 5 mg of prednisone or equivalent for longer than 3 weeks are at risk for secondary AI. In some patients with glucocorticoid receptor hypersensitivity, even smaller doses of glucocorticoid other than oral (topical, injected, or inhaled) can also suppress the hypothalamopituitary-adrenal axis. Chronic opioid use can also suppress central ACTH and induce AI.

Patients with a tumor of the hypothalamic–pituitary region or history of treatment of such tumors with surgery and/or radiation are at significant risk. Other causes such as autoimmune lymphocytic hypophysitis are most frequent peripartum, either in the third trimester or postpartum. Sheehan syndrome is rare and characterized by pituitary apoplexy secondary to shock due to severe blood loss during parturition.


Primary AI is characterized by a complete destruction of the adrenal cortex, with deficits in glucocorticoid, mineralocorticoid, and androgens. With loss of cortisol feedback inhibition, ACTH will be markedly elevated. Secondary AI is the result of isolated low glucocorticoid production due a defect at the pituitary or hypothalamus level resulting in low ACTH. Mineralocorticoid activity is maintained in secondary AI as it is controlled by the renin- angiotensin-aldosterone system.


No clinically practical strategy for preventing primary AI exists. Glucocorticoid-associated secondary AI may be prevented through judicious use of systemic glucocorticoids, with efforts made to limit administration of glucocorticoids to the lowest effective dose for the shortest possible time.

Clinical Manifestations

Primary Adrenocortical Insufficiency

The presentation of primary AI is sometimes dramatic, with a constellation of weakness, fatigue, anorexia, weight loss, nausea, abdominal pain, salt craving, and orthostatic hypotension. Earlier symptoms are more subtle and nonspecific. The skin and buccal mucosa are often hyperpigmented, owing to the effect of excess ACTH on cutaneous melanocortin receptors. Hyponatremia and hyperkalemia (as a result of mineralocorticoid deficiency) are often present.

Secondary Adrenocortical Insufficiency

The presentation of secondary AI is more insidious, with weight loss, fatigue, and malaise as presenting features. This often leads to a delay in diagnosis. Because production of mineralocorticoid is relatively intact in secondary AI, electrolyte abnormalities and hypotension are rarer. Hyperpigmentation is not present, reflecting normal or low ACTH levels. Laboratory abnormalities are less common, but hypoglycemia is occasionally seen, especially with concomitant growth hormone deficiency. Because isolated ACTH deficiency is rare, signs and symptoms of other pituitary hormone abnormalities, such as hyperprolactinemia, central hypogonadism, growth hormone deficiency, or central hypothyroidism, may be present.


Morning cortisol (within 2 hours of waking up) of 5 µg/dL or less has a relatively high predictive value for AI, and a morning cortisol level greater than 15 µg/dL effectively rules out AI. To confirm the diagnosis of AI, a cortisol stimulation test is performed. Insulin tolerance testing has largely been replaced by stimulation testing with synthetic cosyntropin (Cortrosyn, Synacthen). ACTH stimulation testing of cortisol is a reliable method of evaluating the adrenal reserve. In high-dose testing, a cortisol level is checked before and 30 and 60 minutes after 250 µg of IV cosyntropin is administered. A peak cortisol level greater than 18 to 20 µg/dL defines a normal response.

Cosyntropin testing should not be used in cases of short-term secondary insufficiency, such as after recent pituitary surgery, because adrenal atrophy must have occurred for the adrenal response to cosyntropin to be blunted. The low-dose (1 µg) test measures cortisol 20 to 30 minutes after cosyntropin administration and may be more sensitive for diagnosis of secondary AI. However, the high-dose (250 µg) test remains the standard. One must consider the total serum cortisol as affected by its binding protein, which is elevated by high estrogen levels and could be low in hypoalbuminemia. If the clinical picture is not concordant with the investigation, an endocrinology consult should be sought.

Once diagnosis is confirmed, a low or normal plasma ACTH level indicates secondary AI, although care must be taken with the methodology of the test as some immunoassays for ACTH can give falsely low results if preanalytic precautions are not respected. An elevated ACTH level (more than twofold the upper limit of normal) typically indicates primary AI, and high plasma renin and simultaneously low aldosterone levels will confirm associated mineralocorticoid deficiency. After the diagnosis of primary versus secondary AI has been established, an etiology should be sought (Boxes 1 and 2). Serology for antiadrenal (21-hydroxylase) antibodies or evidence of other autoimmune diseases is useful in primary AI, given the very large fraction of these patients with autoimmune adrenalitis. Enlarged adrenal glands with high-density areas or calcification on computed tomography can suggest granulomatous disease or neoplasm. Acute hematoma or fluid collections around the adrenals during an acute adrenal crisis can indicate adrenal hemorrhage. Secondary AI is most often associated with chronic glucocorticoid therapy but may be caused by a number of other diseases (see Box 2). If exogenous steroids have been excluded, MRI and testing of the other hypothalamic–pituitary axes are appropriate.

Box 1
Causes of Primary Adrenocortical Insufficiency


Autoimmune polyglandular syndromes 1 and 2






Human immunodeficiency virus




Rarely bacterial

Bilateral Adrenal Infarction

Hemorrhage Anticoagulation

Sepsis (e.g., meningococcemia)



Thrombophilic condition (e.g., antiphospholipid antibody syndrome)

Heparin-induced thrombocytopenia


Metastatic cancer





Non–small cell lung cancer


Ketoconazole (Nizoral)

Mitotane (Lysodren)

Etomidate perfusion (Amidate)

Infiltrative Diseases


Primary amyloidosis


Postbilateral Adrenalectomy

For bilateral tumors or intractable Cushing syndrome

Familial or Genetic

Classical congenital adrenal hyperplasia


Familial glucocorticoid deficiency

Adrenocorticotropic hormone insensitivity syndromes

Box 2
Etiologies of Secondary Adrenocortical Insufficiency

Chronic steroid therapy, most often oral or parenteral, but could also be inhaled, topical, or injected

Chronic opioid therapy

Pituitary Injury

Post-transsphenoidal or transcranial surgery

Radiation to the sella

Infarction (e.g., Sheehan)

Head trauma: closed head injury with concussion

Tumors of the Sella

Pituitary adenoma



Rathke cleft cyst

Metastatic cancer

Infiltrative Diseases

Sarcoidosis, tuberculosis, or other granulomatous diseases

Lymphocytic hypophysitis

Idiopathic adrenocorticotropic hormone deficiency

Differential Diagnosis

Because the presentation of AI can be subtle (especially in secondary AI), the differential diagnosis is broad and includes a number of illnesses associated with fatigue, weight loss, and malaise, including occult malignancies, renal or hepatic dysfunction, and electrolyte disturbances. In acute AI crisis, differential diagnosis includes other systemic illnesses associated with orthostatic hypotension and electrolyte abnormalities, including dehydration and distributive and septic shock. Fever can be part of an AI crisis, but one must rule out an infectious process as the precipitating cause.


Glucocorticoid replacement is recommended with oral hydrocortisone two or three times daily. One half to two thirds of the daily dose is given upon waking, and the dosage is roughly 15 to 25 mg per day (or 10–12 mg/m2 body surface area per day), typically 10 or 15 mg in the morning and 5 mg in the afternoon. Once-daily hydrocortisone is frequently used in secondary AI.

Patients should be instructed to increase this dosage according to physiologic stress, as doses should be doubled or tripled for 3 or more days in case of fever or intercurrent systemic illness. Day-to-day emotional stress does not require an increment in dosing. For surgery, parenteral glucocorticoid doses should be administered according to the level of surgical stress, such as 25 mg for minor stress (e.g., cataract surgery), 50 to 75 mg for moderate stress (e.g., cholecystectomy), and 100 to 150 mg daily in divided doses for major stress (e.g., heart surgery).

Patients should wear a medical alert bracelet or necklace and should be dispensed hydrocortisone or dexamethasone injection with instructions for home self-administration in case of vomiting and inability to take oral doses. If symptoms do not improve within hours after injection, patients should seek an urgent medical evaluation.

Mineralocorticoid replacement is indicated in patients with primary AI, and fludrocortisone (Florinef) is the available drug with a typical dose between 0.05 and 0.2 mg once daily. Most patients require 0.1 mg daily.

If a patient with known AI presents in adrenal crisis, hydrocortisone (Solu-Cortef) 50 to 100 mg IV every 6 to 8 hours is an appropriate initial therapy, with the dose tapered to an appropriate oral dose as the patient’s condition improves. Aggressive hydration with a saline solute will help to increase the intravascular volume, and high-dose glucocorticoids have some mineralocorticoid activity; thus mineralocorticoids are not required in the treatment of acute adrenal crisis.

In critical illness, treatment of AI should not be delayed if diagnosis cannot be established and the patient is unstable. Baseline cortisol and ACTH levels should preferably be drawn prior to initiation of treatment and should be interpreted as a stress value (i.e., should be> 18 µg/dL). If in doubt, high-dose stress steroids are administered until testing is complete, and cosyntropin stimulation testing may be delayed until the patient’s condition improves because hydrocortisone has to be suspended at least 24 hours before testing.

Dehydroepiandrosterone (DHEA) use is controversial and not recommended by present guidelines. However, a trial may be warranted in selected cases of women with persistent symptoms, including low libido and low energy. DHEA is only available as a dietary supplement.


Patients should be interviewed and examined routinely for indicators of excess glucocorticoid replacement, such as weight gain, striae, facial plethora, osteoporosis, or glucose intolerance, or under replacement if symptoms of AI persist. Cortisol levels and ACTH are not helpful in monitoring glucocorticoid doses. Monitoring of mineralocorticoid status should include volume status, electrolytes, blood pressure, and occasionally serum renin levels. Development of hypertension, edema, or hypokalemia could mandate a dose reduction.


Adrenal crisis in patients with known AI occurs at a rate of approximately 6 cases per 100 patient-years. Precipitating causes of adrenal crisis are mainly gastrointestinal infection and other infections, with other stressful events (pain, surgery, severe emotional distress, and pregnancy) occurring less commonly. Iatrogenic Cushing syndrome can develop if the dose of glucocorticoid replacement is supraphysiologic over the long term.


The authors thank Justin Moore, MD, the author of the previous chapter version, and Shirley McCartney, PhD, for editorial assistance.


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