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What are adrenal insufficiency and Addison disease?

Adrenal insufficiency and Addison disease are hormonal or endocrine disorders caused by the body not producing enough of the adrenal hormones cortisol and aldosterone. This typically occurs when there is a malfunction in the system that maintains a close and timely balance of these hormones. This balance is achieved through a system of signaling and a feedback system. Signals sent and received among the hypothalamus in the brain, the pituitary gland in the brain, and the adrenal glands (located on top of each kidney) regulate adrenal hormone production. 

The adrenal glands are multi-layered:

  • The outer layer produces aldosterone, a salt-balancing hormone that has effects on blood pressure.
  • The middle layer produces cortisol, a hormone with effects on blood sugar, blood pressure and inflammatory responses.
  • The deepest layer produces hormones called androgens, which have effects on growth of sexual hair and acne, for example.

Normally, cortisol is produced and released by the adrenal cortex. Production of the hormone is regulated by the hypothalamus and the pituitary gland. When the blood cortisol level falls, the hypothalamus releases corticotropin-releasing hormone (CRH), which directs the pituitary gland to produce ACTH (adrenocorticotropic hormone). ACTH stimulates the adrenal glands to produce and release cortisol. In order for appropriate amounts of cortisol to be made, the hypothalamus and both the pituitary and adrenal glands must be functioning properly.

Without enough cortisol or aldosterone, people become weak and dehydrated, unable to maintain an adequate blood pressure or to respond properly to physical stress. Among its many roles, cortisol affects the metabolism of carbohydrates, proteins, and fats, affects glucose levels in the blood, acts as an anti-inflammatory agent, and helps the body react to stress such as infection or trauma. Aldosterone is produced by the adrenal cortex and manages the salt and potassium balance in the blood.

There are two different types of adrenal insufficiency and they depend on whether pituitary gland or adrenal dysfunction underlies hormone deficiencies:

  • Primary adrenal insufficiency (Addison disease)—caused by underactive or damaged adrenal glands, which affect cortisol and aldosterone levels in the blood.Addison disease is relatively rare. It affects about 1 person per 100,000 in the U.S. It is found in people of all ages and affects both males and females equally. Symptoms of insufficiency may not emerge until about 80% to 90% of the adrenal cortex has been destroyed.

    In the U.S., the most common cause (about 75%) of primary adrenal insufficiency in adults is an autoimmune process. It may occur with other autoimmune conditions that affect other glands, such as the thyroid. The rest of the time, Addison disease is due to other causes, such as tuberculosis, a common cause in areas of the world where tuberculosis is more prevalent, other chronic infections, especially fungal infections, bleeding into the adrenal glands (hemorrhage) and the spread of cancer into the adrenal glands. Rarely, it may be due to a genetic abnormality of the adrenal glands.

    In children, about 70% of cases are caused by a congenital disease termed congenital adrenal hyperplasia (CAH), while 30% of the time adrenal damage is due to autoimmune disease, the inherited disease adrenoleukodystrophy, or less common causes.

  • Secondary adrenal insufficiency—a decrease in the production of the pituitary hormone ACTH (adrenocorticotropic hormone) is at the root of secondary adrenal insufficiency. ACTH is a pituitary messenger; it tells the adrenal cortex to produce cortisol. If there is insufficient ACTH, due to pituitary damage, a pituitary tumor, or some other cause, then cortisol production is not stimulated. Secondary adrenal insufficiency can also arise when corticosteroid therapy (such as prednisone, which may be given to relieve inflammation in conditions such as rheumatoid arthritis or high dose inhaled steroids, which may be given to treat asthma ) is abruptly halted. These treatments suppress natural cortisol production and it can take several weeks or months for normal production to resume.


About Adrenal Insufficiency and Addison Disease

Signs and Symptoms

The signs and symptoms associated with adrenal insufficiency are often vague and nonspecific. They may emerge slowly, first appearing during times of physical stress such as an infection or trauma, then increase in intensity over a period of several months. Signs and symptoms may include a combination of the following:

  • Fatigue or extreme weakness
  • Unexplained weight loss
  • Muscle aches and weakness
  • Dizziness and fainting
  • Changes in blood pressure or heart rate
  • Abdominal pain
  • Nausea, vomiting
  • Diarrhea or constipation
  • Decreased body hair
  • Hyperpigmentation (with Addison disease, dark patches of skin, especially in the folds of the skin, and on the face, neck, and back of the hands)
  • Low blood sugar (hypoglycemia)
  • Salt craving (with Addison disease)
  • Dehydration (with Addison disease)

Since the signs and symptoms of adrenal insufficiency are gradual and non-specific, people may ignore them until they suddenly worsen into a severe condition called an adrenal crisis. About 25% of the time, adrenal insufficiency is diagnosed during an adrenal crisis (also called an Addisonian crisis). This crisis may be caused by a period of increased physical stress, such as illness, trauma, surgery, or infection. If left untreated, it can be fatal. In an adrenal crisis, the signs and symptoms may include:

  • Abdominal pain
  • Difficulty breathing
  • Kidney failure
  • Loss of consciousness
  • Low blood pressure
  • Severe pain in the lower back, abdomen or legs
  • Severe vomiting and diarrhea, leading to dehydration
  • Shock


Signs and symptoms such as darkened patches of skin on the face, neck, and back of the hands (hyperpigmentation), weakness, low blood pressure, and salt cravings may lead a healthcare practitioner to suspect adrenal insufficiency, especially if these appear to worsen during periods of physical stress, such as an illness or trauma. Laboratory tests can determine if adrenal insufficiency is present, distinguish between primary and secondary insufficiencies, and help determine the underlying cause of the condition.

Laboratory Tests

  • Cortisol. Levels normally vary in the blood, peaking in the early morning. If the adrenal gland is either not functioning normally or not being stimulated by ACTH, then cortisol levels will be consistently low. Cortisol tests, with blood samples usually collected in the morning, may be used in combination with morning ACTH tests and/or ACTH stimulation tests, to help diagnose adrenal insufficiency.
  • ACTH. ACTH is a pituitary hormone that signals the adrenal glands to produce cortisol. This test is primarily ordered as a baseline test to evaluate if the pituitary is producing appropriate amounts of ACTH. In someone with adrenal insufficiency, low ACTH levels indicate secondary adrenal insufficiency, while high levels indicate primary adrenal insufficiency (Addison disease).
  • ACTH stimulation test. This is the optimal test for diagnosing primary adrenal insufficiency, according to guidelines from the Endocrine Society. It involves measuring the level of cortisol in a person’s blood before and after an injection of synthetic ACTH. If the adrenal glands are functional, cortisol blood levels will rise in response to the ACTH stimulation. If they are damaged or non-functional, then their response to ACTH will be minimal. This rapid screening test may be ordered along with a baseline ACTH test and, if abnormal, may be followed with a 1 to 3 day prolonged ACTH stimulation test to help differentiate between primary and secondary adrenal insufficiency.
  • Aldosterone. Levels are measured to help diagnose Addison disease, to determine whether the adrenal gland is producing aldosterone. If the levels are low, it is another indication that an individual may have a primary adrenal insufficiency.
  • Renin. Renin activity is elevated in primary adrenal insufficiency because a lack of aldosterone causes increased renal sodium losses. This lowers blood sodium levels and decreases the amount of fluid in the blood (which lowers blood volume and pressure), which in turn stimulates renin production by the kidney.
  • Electrolytes. Sodium, potassium, chloride and carbon dioxide are measured to help detect and evaluate the severity of an existing electrolyte imbalance and to monitor the effectiveness of treatment. Electrolytes may be affected by many conditions. With Addison disease, the sodium, chloride, and carbon dioxide levels are often low, while the potassium level may be very high.
  • BUN and Creatinine are tests done to monitor kidney function.
  • Glucose levels may be very low during an adrenal crisis. Glucose testing may be used in order to help monitor an individual during a crisis.
  • Corticotropin-releasing hormone (CRH) stimulation test. Currently, this test is not available in the United States. In other countries, it may be used when the ACTH test is abnormal to help determine the cause of adrenal insufficiency. CRH is a hormone released by the hypothalamus that stimulates ACTH production by the pituitary gland, which in turn stimulates cortisol production by the adrenal glands. For this test, synthetic CRH is injected intravenously and blood cortisol and ACTH levels are measured at timed intervals after the injection, for example, at 30 and 60 minutes. The normal response is a peak in ACTH levels followed by a peak in cortisol levels.
    • People with Addison disease (underactive or damaged adrenal glands) produce a high level of ACTH but no cortisol.
    • People with secondary adrenal insufficiency have absent or delayed ACTH responses. If someone has a damaged pituitary, CRH will not stimulate ACTH secretion and an absent ACTH response indicates the pituitary is the cause. If ACTH response is delayed, that indicates the hypothalamus is the cause.

Examples of tests to identify the underlying cause

  • Insulin-induced hypoglycemia test. Occasionally, a healthcare practitioner will order this test to learn if pituitary disease (secondary adrenal insufficiency) is the cause of adrenal insufficiency. Glucose and cortisol levels are measured at predetermined intervals after an injection of insulin is used to stress the pituitary gland. In healthy people, blood glucose levels fall and cortisol concentrations increase. In those with adrenal insufficiency, cortisol levels will remain low and glucose levels will fall, then recover slowly. This test should be performed in a specialized facility where there are people experienced in the procedure and where the person tested can be monitored closely.
  • 21-hydroxylase autoantibodies are sometimes ordered as part of the diagnostic process when autoimmune Addison disease is suspected. The test is considered a good indicator of autoimmune Addison disease.
  • 17-hydroxyprogesterone or other adrenal androgens may be used to help diagnose congenital adrenal hyperplasia (CAH), which can cause low cortisol and aldosterone.
  • Very long chain fatty acids (VLCFA) will be assessed in males with adrenal insufficiency of unknown cause to evaluate for adrenoleukodystrophy. (To learn more about this, see the resources listed in the Related Content section.)
  • TB screening test (skin test or blood test) may be done to detect tuberculosis (TB).
  • Other autoimmune markers and hormonal assays may be done to assess conditions that affect multiple endocrine glands (autoimmune polyglandular syndromes).

Non-Laboratory Tests

  • X-rays may be used to look for calcification on the adrenal cortex that may be due to a tuberculosis infection.
  • CT (computerized tomography) or MRI (magnetic resonance imaging) scans are sometimes used to look at the size and shape of the adrenal glands and the pituitary. The adrenal glands can be enlarged with infections and cancers. With autoimmune diseases and secondary adrenal insufficiency, the adrenal glands are often normal or small.


Treatment for adrenal insufficiency involves hormone replacement or substitution. The specific replacement depends on whether cortisol or aldosterone are both deficient. If the condition is due to an adrenal infection, the affected person may regain some adrenal function when the infection resolves. Even when people have extensive and permanent damage to their adrenal cortex, they should be able to live healthy, relatively normal lives by replacing the missing hormones and observing a few precautions.

Damage to the hypothalamus or pituitary causing secondary adrenal insufficiency rarely resolves. Its treatment is the same as primary adrenal insufficiency, namely cortisol and aldosterone replacement. For other causes of secondary adrenal insufficiency, such as corticosteroid therapy, a period of monitoring medication is usually recommended. Cortisol production may eventually resume in these cases.

The major, and mostly avoidable, illness from adrenal insufficiency results from adrenal crisis. An adrenal crisis can be life-threatening and is treated with intravenous (IV) injections of glucocorticoids and large volumes of intravenous saline solution with the sugar dextrose. This treatment usually brings rapid improvement. Initiation of treatment as early as possible improves outcomes.

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