Figure 3. Negative feedback regulates cortisol secretion

Aldosterone

Aldosterone belongs to the class of hormones called mineralocorticoids, also produced by the adrenal glands. Aldosterone helps maintain blood pressure and the balance of sodium and potassium in the blood. When aldosterone production falls too low, the body loses too much sodium and retains too much potassium.

The decrease of sodium in the blood can lead to a drop in both blood volume—the amount of fluid in the blood—and blood pressure. Too little sodium in the body also can cause a condition called hyponatremia. Symptoms of hyponatremia include feeling confused and fatigued and having muscle twitches and seizures.

Too much potassium in the body can lead to a condition called hyperkalemia. Hyperkalemia may have no symptoms; however, it can cause irregular heartbeat, nausea, and a slow, weak, or an irregular pulse.

Dehydroepiandrosterone (DHEA)

Dehydroepiandrosterone (DHEA) is another hormone produced by your adrenal glands. Dehydroepiandrosterone (DHEA) is a precursor hormone, which means it has little biological effect on its own, but has powerful effects when converted into sex hormones such as testosterone and estradiol. The body uses dehydroepiandrosterone (DHEA) to make the sex hormones, androgen and estrogen. Dehydroepiandrosterone (DHEA) is produced from cholesterol mainly by the outer layer of the adrenal glands (the adrenal cortex), although it is also made by the testes and ovaries in small amounts. With adrenal insufficiency, the adrenal glands may not make enough dehydroepiandrosterone (DHEA). Healthy men derive most androgens from the testes. Healthy women and adolescent girls get most of their estrogens from the ovaries. In women, dehydroepiandrosterone (DHEA) is an important source of estrogens in the body – it provides about 75% of estrogens before the menopause, and 100% of estrogens in the body after menopause. However, women and adolescent girls may have various symptoms from DHEA insufficiency, such as loss of pubic hair, dry skin, a reduced interest in sex, and depression.

Addison’s disease pathophysiology

Adrenal gland failure in Addison’s disease results in decreased cortisol production initially followed by that of aldosterone, both of which will eventually result in an elevation of adrenocorticotropic (ACTH) and melanocyte-stimulating hormone (MSH) hormones due to the loss of negative feedback inhibition ¹¹. Melanocyte-stimulating hormone (MSH) is produced from the same precursor molecule as adrenocorticotropic hormone  (ACTH) called pro-opiomelanocortin (POMC).

Hyperpigmentation or abnormal darkening of the skin is found in patients with primary adrenal insufficiency (Addison’s disease). In Addison’s disease, the adrenal glands do not produce enough hormones (including cortisol). As a consequence, the hypothalamus stimulates the pituitary gland to release more adrenocorticotropic hormone (ACTH) to try and stimulate the adrenal glands to produce more cortisol. Adrenocorticotropic hormone can be broken down to produce melanocyte-stimulating hormone, leading to hyperpigmentation of the skin.

Addison’s disease causes

Addison’s disease results when your adrenal glands are damaged, producing insufficient amounts of the hormone cortisol and often aldosterone as well. The adrenal glands are located just above your kidneys. Your adrenal glands are composed of two sections. The interior (the adrenal medulla) produces adrenaline-like hormones. The outer layer (the adrenal cortex) produces a group of hormones called corticosteroids. Corticosteroids include:

• Glucocorticoids. These hormones, which include cortisol, influence your body’s ability to convert food into energy, play a role in your immune system’s inflammatory response and help your body respond to stress.
• Mineralocorticoids. These hormones, which include aldosterone, maintain your body’s balance of sodium and potassium to keep your blood pressure normal.
• Androgens. These male sex hormones are produced in small amounts by the adrenal glands in both men and women. They cause sexual development in men, and influence muscle mass, sex drive (libido) and a sense of well-being in both men and women.

The failure of your adrenal glands to produce adrenocortical hormones is most commonly the result of the body attacking itself (autoimmune disease). An auto-immune disorder in which the body’s immune system makes antibodies which attack the cells of the adrenal cortex and slowly destroys them. This can take months to years. For unknown reasons, your immune system views the adrenal cortex as foreign, something to attack and destroy.

Other causes of adrenal gland failure may include:

• Tuberculosis (TB). Tuberculosis was the leading cause of Addison disease up until the middle of the 20th century, when antibiotics were introduced that successfully treated tuberculosis. Tuberculosis (TB) is the most common cause of Addison’s disease worldwide, but it’s rare in the US. Tuberculosis (TB) is a bacterial infection that mostly affects the lungs but can also spread to other parts of your body. It can cause Addison’s disease if it damages your adrenal glands.
• Infections (bacterial, fungal, tuberculosis) of the adrenal glands e.g. cytomegalovirus (CMV)
• Cancer that spreads to the adrenal glands
• Surgical removal of the adrenal glands
• Amyloidosis—protein build up in organs (very rare)
• Bleeding into the adrenal glands, which may present as adrenal crisis without any preceding symptoms.

Primary Adrenal Insufficiency: Addison’s Disease

The outer layer of the adrenal glands is called the adrenal cortex. If the cortex is damaged, it may not be able to produce enough cortisol.

A common cause of primary adrenal insufficiency is an autoimmune disease that causes the immune system to attack healthy tissues. In the case of Addison’s disease, the immune system turns against the adrenal gland(s). There are some very rare syndromes (several diseases that occur together) that can cause autoimmune adrenal insufficiency.

Autoimmune Disorders

Up to 80 percent of Addison’s disease cases are caused by an autoimmune disorder, which is when the body’s immune system attacks the body’s own cells and organs ¹². In autoimmune Addison’s disease, which mainly occurs in middle-aged females, the immune system gradually destroys the adrenal cortex—the outer layer of the adrenal glands ¹².

Autoimmune Addison’s disease can be divided into stages of progression (Table 1) ¹³, ¹⁴. As autoimmune Addison’s disease develops, individuals lose adrenocortical function over a period of years. In the first three stages, the human leukocyte antigen genes confer genetic risk; an unknown precipitating event initiates antiadrenal autoimmunity; and 21-hydroxylase antibodies are produced, which predict future disease. The production of 21-hydroxylase antibodies can precede symptom onset by years to decades, and they are present in more than 90% of recent-onset cases ¹⁵. In the fourth stage, overt adrenal insufficiency develops. Primary adrenal insufficiency (Addison’s disease) occurs when at least 90 percent of the adrenal cortex has been destroyed ². As a result, both cortisol and aldosterone are often lacking. Sometimes only the adrenal glands are affected. Sometimes other endocrine glands are affected as well, as in polyendocrine deficiency syndrome.

One of the first metabolic abnormalities to occur is an increase in plasma renin level, followed by the sequential development of other abnormalities, including a decreased response to adrenocorticotropic hormone (ACTH) stimulation in the fifth stage. If symptoms of adrenal insufficiency are present but go undiagnosed, an Addisonian crisis can occur.

Table 1. Development stages of Autoimmune Addison’s disease

Approximately 50% of persons with Addison’s disease caused by autoimmune adrenalitis develop another autoimmune disorder during their lifetime, necessitating lifelong vigilance for associated autoimmune conditions ¹⁶. Of note, 10% of women with Addison disease experience autoimmune premature ovarian failure or primary ovarian insufficiency, in their reproductive years with signs and symptoms of estrogen deficiency (e.g., amenorrhea, flushing, fatigue, poor concentration) ¹⁷. It is appropriate to offer these patients evaluation and counseling on other options for building a family ¹⁸.

Risk factors for the autoimmune type of Addison’s disease include other autoimmune diseases:

• Type 1 diabetes
• Hypoparathyroidism
• Hypopituitarism
• Pernicious anemia
• Graves’ disease
• Chronic thyroiditis
• Dermatis herpetiformis
• Vitiligo
• Myasthenia gravis

Table 2. Autoimmune diseases occurring with Addison’s disease

Footnote: Data compiled from multiple studies across different populations.

Autoimmune Polyendocrine Syndrome

Autoimmune polyendocrine syndrome is a rare cause of Addison’s disease. Sometimes referred to as multiple endocrine deficiency syndrome, polyendocrine deficiency syndrome is classified into type 1 and type 2.

Autoimmune polyendocrine syndrome type 1

Autoimmune polyendocrine syndrome type 1 is inherited and occurs in children. Symptoms start during childhood. Almost any organ can be affected by autoimmune damage. Fortunately it is extremely rare—only several hundred cases have been reported worldwide. Conditions associated with autoimmune polyendocrine syndrome type 1 include:

In addition to adrenal insufficiency, these children may have:

• Underactive parathyroid glands, which are four pea-sized glands located on or near the thyroid gland in the neck; they produce a hormone that helps maintain the correct balance of calcium in the body.
• Delayed or slow sexual development.
• Vitamin B12 malabsorption / deficiency (pernicious anemia), a severe type of anemia; anemia is a condition in which red blood cells are fewer than normal, which means less oxygen is carried to the body’s cells. With most types of anemia, red blood cells are smaller than normal; however, in pernicious anemia, the cells are bigger than normal.
• Candidiasis (chronic yeast infection).
• Chronic hepatitis, a liver disease.

Autoimmune polyendocrine syndrome Type 2

Researchers think autoimmune polyendocrine syndrome type 2, which is sometimes called Schmidt’s syndrome, is also inherited. Autoimmune polyendocrine syndrome type 2 usually affects young adults, symptoms primarily develop in adults aged 18 to 30 and may include:

• Addison’s disease
• Underactive or overactive thyroid function
• Delayed or slow sexual development
• Diabetes, in which a person has high blood glucose, also called high blood sugar or hyperglycemia
• White skin patches, a loss of pigment on areas of the skin (vitiligo)
• Celiac disease ²³

Secondary adrenal insufficiency

Adrenal insufficiency can also occur if your pituitary gland is diseased. The pituitary gland makes a hormone called adrenocorticotropic hormone (ACTH), which stimulates the adrenal cortex to produce its hormones. Inadequate production of ACTH can lead to insufficient production of hormones normally produced by your adrenal glands, even though your adrenal glands aren’t damaged. Secondary adrenal insufficiency can occur if your pituitary gland becomes damaged – for example, because of a tumor on the pituitary gland (pituitary adenoma). Doctors call this condition secondary adrenal insufficiency and is a separate condition to Addison’s disease.

Another more common cause of secondary adrenal insufficiency occurs when people who take corticosteroids for treatment of chronic conditions, such as asthma or arthritis, abruptly stop taking the corticosteroids.

Stoppage of Corticosteroid Medication

A temporary form of secondary adrenal insufficiency may occur when a person who has been taking a synthetic glucocorticoid hormone, called a corticosteroid, for a long time stops taking the medication. Corticosteroids are often prescribed to treat inflammatory illnesses such as rheumatoid arthritis, asthma, and ulcerative colitis. In this case, the prescription doses often cause higher levels than those normally achieved by the glucocorticoid hormones created by the body. When a person takes corticosteroids for prolonged periods, the adrenal glands produce less of their natural hormones. Once the prescription doses of corticosteroid are stopped, the adrenal glands may be slow to restart their production of the body’s glucocorticoids. To give the adrenal glands time to regain function and prevent adrenal insufficiency, prescription corticosteroid doses should be reduced gradually over a period of weeks or even months. Even with gradual reduction, the adrenal glands might not begin to function normally for some time, so a person who has recently stopped taking prescription corticosteroids should be watched carefully for symptoms of secondary adrenal insufficiency.

Surgical Removal of Pituitary Tumors

Another cause of secondary adrenal insufficiency is surgical removal of the usually noncancerous, ACTH-producing tumors of the pituitary gland that cause Cushing’s syndrome. Cushing’s syndrome is a hormonal disorder caused by prolonged exposure of the body’s tissues to high levels of the hormone cortisol. When the tumors are removed, the source of extra ACTH is suddenly gone and a replacement hormone must be taken until the body’s adrenal glands are able to resume their normal production of cortisol. The adrenal glands might not begin to function normally for some time, so a person who has had an ACTH-producing tumor removed and is going off of his or her prescription corticosteroid replacement hormone should be watched carefully for symptoms of adrenal insufficiency.

Changes in the Pituitary Gland

Less commonly, secondary adrenal insufficiency occurs when the pituitary gland either decreases in size or stops producing ACTH. These events can result from

• tumors or an infection in the pituitary
• loss of blood flow to the pituitary
• radiation for the treatment of pituitary or nearby tumors
• surgical removal of parts of the hypothalamus
• surgical removal of the pituitary

Infections

Tuberculosis (TB), an infection that can destroy the adrenal glands, accounts for 10 to 15 percent of Addison’s disease cases in developed countries. When primary adrenal insufficiency was first identified by Dr. Thomas Addison in 1849, tuberculosis (TB) was the most common cause of the disease. As tuberculosis (TB) treatment improved, the incidence of Addison’s disease due to tuberculosis (TB) of the adrenal glands greatly decreased. However, recent reports show an increase in Addison’s disease from infections such as tuberculosis (TB) and cytomegalovirus. Cytomegalovirus is a common virus that does not cause symptoms in healthy people; however, it does affect babies in the womb and people who have a weakened immune system—mostly due to HIV/AIDS. Other bacterial infections, such as Neisseria meningitidis, which is a cause of meningitis, and fungal infections can also lead to Addison’s disease.

Other Causes

Less common causes of Addison’s disease are:

• Spread of cancer to the adrenal glands
• Amyloidosis, a serious, though rare, group of diseases that occurs when abnormal proteins, called amyloids, build up in the blood and are deposited in tissues and organs
• Surgical removal of both adrenal glands (adrenalectomy) – for example, to remove a tumor
• Bleeding into the adrenal glands, which may present as adrenal crisis without any preceding symptoms. Very heavy bleeding into the adrenal glands, sometimes associated with meningitis or other types of severe sepsis.
• Genetic defects including abnormal adrenal gland development, an inability of the adrenal glands to respond to ACTH, or a defect in adrenal hormone production
• Medication-related causes, such as from anti-fungal medications (e.g., ketoconazole) and the anesthetic etomidate, which may be used when a person undergoes a rapid sequence intubation for patients requiring mechanical ventilation. The effect of etomidate is dose-dependent ²⁴.
• Intubation—the placement of a flexible, plastic tube through the mouth and into the trachea, or windpipe, to assist with breathing.
• Adrenoleukodystrophy – a rare, life-limiting inherited condition that affects the adrenal glands and nerve cells in the brain, and is mostly seen in young boys
• Certain treatments needed for Cushing’s syndrome – a collection of symptoms caused by very high levels of cortisol in the body

Addison’s disease symptoms

Addison’s disease symptoms usually develop slowly, often over several months. Often, Addison’s disease progresses so slowly that symptoms are ignored until a stress, such as illness or injury, occurs and makes symptoms worse.

Addison’s disease signs and symptoms may include:

• Extreme fatigue, chronic, or long lasting, fatigue
• Weight loss
• Loss of appetite or decreased appetite
• Darkening of your skin (hyperpigmentation)
• Low blood pressure that drops further when a person stands up, causing dizziness or fainting
• Salt craving
• Low blood sugar (hypoglycemia)
• Nausea, vomiting, constipation or diarrhea
• Abdominal pain
• Muscle or joint pains
• Muscle weakness
• Irritability
• Depression
• Body hair loss or sexual dysfunction in women
• Headache
• Sweating
• Irregular or absent menstrual periods
• In women, loss of interest in sex.

Hyperpigmentation, or darkening of the skin, can occur in Addison’s disease. This darkening is most visible on scars; skin folds; pressure points such as the elbows, knees, knuckles, and toes; lips; and mucous membranes such as the lining of the cheek.

The slowly progressing symptoms of adrenal insufficiency are often ignored until a stressful event, such as surgery, a severe injury, an illness, or pregnancy, causes them to worsen.

Figure 3. Hyperpigmentation in the hand

Figure 4. Hyperpigmentation in the mouth

Figure 5. Hyperpigmentation in the mouth

Acute adrenal failure (Addisonian crisis or adrenal crisis)

Sudden, severe worsening of adrenal insufficiency symptoms is called adrenal crisis. If the person has Addison’s disease, this worsening can also be called an Addisonian crisis. Each year, typically 8% of people with Addison’s disease experience Addisonian crisis (adrenal crisis). This means they need extra steroid medication immediately, in the form of an emergency injection of intra-muscular hydrocortisone. In most cases, symptoms of adrenal insufficiency become serious enough that people seek medical treatment before an adrenal crisis occurs. However, sometimes symptoms appear for the first time during an adrenal crisis.

The danger signs of Addisonian crisis include:

• Extreme weakness, feeling terrible, vomiting, headache
• Light-headedness or dizziness on sitting up or standing up
• Feeling very cold, uncontrollable shaking; back, limb or abdominal pain
• Confusion, drowsiness, loss of consciousness

Addisonian crisis (adrenal crisis) the signs and symptoms may also include:

• Sudden, severe pain in your lower back, abdomen or legs
• Severe vomiting and diarrhea, leading to dehydration
• Low blood pressure
• Loss of consciousness
• High potassium (hyperkalemia) and low sodium (hyponatremia)

If this happens to yourself or someone you are caring for, do not delay. If not treated, an adrenal crisis can cause death:

• inject yourself (or the person you are caring for) with your hydrocortisone ampoule (100mg)
• seek immediate medical attention – call your local emergency services number, stating “Addisonian crisis”
• Other key phrases to use are: Steroid-dependent, risk of adrenal crisis, adrenal insufficiency crisis, Addison’s or Addisonian emergency
• AND describe symptoms (vomiting, diarrhea, dehydration, injury/shock).

How is adrenal crisis treated ?

Adrenal crisis is treated with adrenal hormones. People with adrenal crisis need immediate treatment. Any delay can cause death. When people with adrenal crisis are vomiting or unconscious and cannot take their medication, the hormones can be given as an injection.

A person with adrenal insufficiency should carry a corticosteroid injection at all times and make sure that others know how and when to administer the injection, in case the person becomes unconscious.

The dose of corticosteroid needed may vary with a person’s age or size. For example, a child younger than 2 years of age can receive 25 milligrams (mg), a child between 2 and 8 years of age can receive 50 mg, and a child older than 8 years should receive the adult dose of 100 mg.

How can a person prevent adrenal crisis ?

The following steps can help a person prevent adrenal crisis:

• Ask a health care provider about possibly having a shortage of adrenal hormones, if always feeling tired, weak, or losing weight.
• Learn how to increase the dose of corticosteroid for adrenal insufficiency when ill. Ask a health care provider for written instructions for sick days. First discuss the decision to increase the dose with the health care provider when ill.
• When very ill, especially if vomiting and not able to take pills, seek emergency medical care immediately.

How can someone with adrenal insufficiency prepare in case of an emergency ?

People with adrenal insufficiency should always carry identification stating their condition, “adrenal insufficiency,” in case of an emergency. A card or medical alert tag should notify emergency health care providers of the need to inject corticosteroids if the person is found severely injured or unable to answer questions.

The card or tag should also include the name and telephone number of the person’s health care provider and the name and telephone number of a friend or family member to be notified. People with adrenal insufficiency should always carry a needle, a syringe, and an injectable form of corticosteroids for emergencies.

What problems can occur with adrenal insufficiency ?

Problems can occur in people with adrenal insufficiency who are undergoing surgery, suffer a severe injury, have an illness, or are pregnant. These conditions place additional stress on the body, and people with adrenal insufficiency may need additional treatment to respond and recover.

Surgery

People with adrenal insufficiency who need any type of surgery requiring general anesthesia must be treated with IV corticosteroids and saline. IV treatment begins before surgery and continues until the patient is fully awake after surgery and is able to take medication by mouth. The “stress” dosage is adjusted as the patient recovers until the regular, presurgery dose is reached.

In addition, people who are not currently taking corticosteroids, yet have taken long-term corticosteroids in the past year, should tell their health care provider before surgery. These people may have sufficient ACTH for normal events; however, they may need IV treatment for the stress of surgery.

Severe Injury

Patients who suffer severe injury may need a higher, “stress” dosage of corticosteroids immediately following the injury and during recovery. Often, these stress doses must be given intravenously. Once the patient recovers from the injury, dosing is returned to regular, pre-injury levels.

Illness

During an illness, a person taking corticosteroids orally may take an adjusted dose to mimic the normal response of the adrenal glands to this stress on the body. Significant fever or injury may require a triple dose. Once the person recovers from the illness, dosing is then returned to regular, pre-illness levels. People with adrenal insufficiency should know how to increase medication during such periods of stress, as advised by their health care provider. Immediate medical attention is needed if severe infections, vomiting, or diarrhea occur. These conditions can lead to an adrenal crisis.

Pregnancy

Women with adrenal insufficiency who become pregnant are treated with the same hormone therapy taken prior to pregnancy. However, if nausea and vomiting in early pregnancy interfere with taking medication orally, injections of corticosteroids may be necessary. During delivery, treatment is similar to that of people needing surgery. Following delivery, the dose is gradually lessened, and the regular dose is reached about 10 days after childbirth.

Addison’s disease complications

Addison’s disease can develop into an adrenal crisis (Addisonian crisis) if not recognized and promptly treated. This can result in hypotension (low blood pressure), shock, hypoglycemia (low blood levels of sugar), acute cardiovascular decompensation, and death ²⁵. Patients with adrenal insufficiency are also at higher risk of death due to infections, cancer, and cardiovascular causes. Delayed recognition and treatment of hypoglycemia (low blood sugar) can cause neurologic consequences. A supraphysiologic glucocorticoid replacement can lead to the development of Cushing syndrome ²⁶. Growth suppression can occur in children. Premature ovarian failure or primary ovarian insufficiency may develop in up to 10% of women with Addison disease ²⁷.

Addisonian crisis

If you have untreated Addison’s disease, you may develop an Addisonian crisis as a result of physical stress, such as an injury, infection or illness. Normally, the adrenal glands produce two to three times the usual amount of cortisol in response to physical stress. With adrenal insufficiency, the inability to increase cortisol production with stress can lead to an Addisonian crisis.

An Addisonian crisis is a life-threatening situation that results in low blood pressure, low blood levels of sugar and high blood levels of potassium. You will need immediate medical care.

People with Addison’s disease commonly have associated autoimmune diseases.

Addison’s disease prevention

Addison’s disease can’t be prevented, but there are steps you can take to avoid an addisonian crisis:

• Talk to your doctor if you always feel tired, weak, or are losing weight. Ask about having an adrenal shortage.
• If you have been diagnosed with Addison’s disease, ask your doctor about what to do when you’re sick. You may need to learn how to increase your dose of corticosteroids.
• If you become very sick, especially if you are vomiting and you can’t take your medication, go to the emergency room.

Some people with Addison’s disease worry about serious side effects from hydrocortisone or prednisone because they know these occur in people who take these steroids for other reasons. However, if you have Addison’s disease, the adverse effects of high-dose glucocorticoids should not occur, since the dose you are prescribed is replacing the amount that is missing. Make sure to follow up with your doctor on a regular basis to make sure your dose is not too high.

Addison’s disease diagnosis

In its early stages, adrenal insufficiency can be difficult to diagnose. A health care provider may suspect it after reviewing a person’s medical history and symptoms.

A diagnosis of adrenal insufficiency is confirmed through hormonal blood and urine tests. A health care provider uses these tests first to determine whether cortisol levels are too low and then to establish the cause. Imaging studies of the adrenal and pituitary glands can be useful in helping to establish the cause.

Your doctor will talk to you first about your medical history and your signs and symptoms. If your doctor thinks that you may have Addison’s disease, you may undergo some of the following tests:

• Blood test. Measuring your blood levels of sodium, potassium, cortisol and adrenocorticotropic hormone (ACTH) gives your doctor an initial indication of whether adrenal insufficiency may be causing your signs and symptoms. Adrenocorticotropic hormone (ACTH) stimulates the adrenal cortex to produce its hormones. A blood test can also measure antibodies associated with autoimmune Addison’s disease. Because the adrenal hormones are gradually lost over years to decades, the levels vary. One of the first indications that there is adrenal cortex dysfunction is an elevated plasma renin level ²⁸. A rise in adrenocorticotropic hormone (ACTH) levels is concomitant with the loss of adrenal hormones. Yearly monitoring of ACTH levels in at-risk individuals shows that measurements greater than 50 pg per mL (11 pmol per L), which exceed the upper limit of normal, are indicative of cortisol deficiency ¹⁵.
• Thyroid function test. Your thyroid gland may also be tested to see if it’s working properly. Your thyroid gland is found in your neck. It produces hormones that control your body’s growth and metabolism. People with Addison’s disease often have an underactive thyroid gland (hypothyroidism), where the thyroid gland does not produce enough hormones. By testing the levels of certain hormones in your blood, your endocrinologist (a specialist in hormone conditions) can determine whether you have hypothyroidism.
• ACTH (Cosyntropin) Stimulation Test. The ACTH (Cosyntropin) Stimulation Test is the most commonly used test for diagnosing adrenal insufficiency. In this test, the patient is given an intravenous (IV) injection of synthetic ACTH, and samples of blood, urine, or both are taken before and after the injection. The cortisol levels in the blood and urine samples are measured in a lab. The normal response after an ACTH injection is a rise in blood and urine cortisol levels. People with Addison’s disease or longstanding secondary adrenal insufficiency have little or no increase in cortisol levels.
  • The serum cortisol, plasma ACTH, plasma aldosterone, and plasma renin levels should be measured before administering 250 mcg of ACTH. At 30 and 60 minutes after intravenous ACTH administration, the serum cortisol level should be measured again. A normal response occurs with peak cortisol levels greater than 18 to 20 mcg per dL (497 to 552 nmol per L); a smaller or absent response is diagnostic for adrenal insufficiency ²⁹.
  • Both low- and high-dose ACTH stimulation tests may be used depending on the suspected cause of adrenal insufficiency. For example, if secondary adrenal insufficiency is mild or has only recently occurred, the adrenal glands may still respond to ACTH because they have not yet shut down their own production of hormone. Some studies have suggested a low dose—1 microgram (mcg)—may be more effective in detecting secondary adrenal insufficiency because the low dose is still enough to raise cortisol levels in healthy people, yet not in people with mild or recent secondary adrenal insufficiency. However, recent research has shown that a significant proportion of healthy children and adults can fail the low-dose test, which may lead to unnecessary treatment. Therefore, some health care providers favor using a 250 mcg ACTH test for more accurate results.
• CRH stimulation test. When the response to the ACTH test is abnormal, a CRH (Corticotropin-releasing hormone) stimulation test can help determine the cause of adrenal insufficiency. In this test, the patient is given an IV injection of synthetic CRH (Corticotropin-releasing hormone) and blood is taken before and 30, 60, 90, and 120 minutes after the injection. The cortisol levels in the blood samples are measured in a lab. People with Addison’s disease respond by producing high levels of ACTH, yet no cortisol. People with secondary adrenal insufficiency do not produce ACTH or have a delayed response. CRH will not stimulate ACTH secretion if the pituitary is damaged, so no ACTH response points to the pituitary as the cause. A delayed ACTH response points to the hypothalamus as the cause.
• Insulin-induced hypoglycemia test. Occasionally, doctors suggest this test if pituitary disease is a possible cause of adrenal insufficiency (secondary adrenal insufficiency). The test involves checking your blood sugar (blood glucose) and cortisol levels at various intervals after an injection of insulin. In healthy people, glucose levels fall and cortisol levels increase.
• Ultrasound of the abdomen. Ultrasound uses a device, called a transducer, that bounces safe, painless sound waves off organs to create an image of their structure. A specially trained technician performs the procedure in a health care provider’s office, an outpatient center, or a hospital, and a radiologist—a doctor who specializes in medical imaging—interprets the images; a patient does not need anesthesia. The images can show abnormalities in the adrenal glands, such as enlargement or small size, nodules, or signs of calcium deposits, which may indicate bleeding.
• Tuberculin skin test. A tuberculin skin test measures how a patient’s immune system reacts to the bacteria that cause tuberculosis. A small needle is used to put some testing material, called tuberculin, under the skin. A nurse or lab technician performs the test in a health care provider’s office; a patient does not need anesthesia. In 2 to 3 days, the patient returns to the health care provider, who will check to see if the patient had a reaction to the test. The test can show if adrenal insufficiency could be related to tuberculosis.To test whether a person has tuberculosis (TB) infection, which is when tuberculosis bacteria live in the body without making the person sick, a special tuberculosis (TB) blood test is used. To test whether a person has tuberculosis (TB) disease, which is when tuberculosis bacteria are actively attacking a person’s lungs and making the person sick, other tests such as a chest x-ray and a sample of sputum—phlegm that is coughed up from deep in the lungs—may be needed.
• Antibody blood tests. The antibody blood test can detect antibodies—proteins made by the immune system to protect the body from foreign substances—associated with autoimmune Addison’s disease. Measurement of 21-hydroxylase antibody levels helps discern the cause of Addison disease. The 21-hydroxylase enzyme is necessary for cortisol synthesis in the adrenal cortex; antibodies directed against the 21-hydroxylase enzyme (21-hydroxylase antibodies are present in more than 90% of recent-onset cases) are specific for autoimmune Addison’s disease and are detectable before symptom onset by years to decades ¹⁴.

The goal of laboratory testing is to document a low cortisol level and determine whether the adrenal insufficiency is primary or secondary, as outlined in Figure 6. Low serum cortisol levels at 8 a.m. (less than 3 mcg per dL [83 nmol per L]) suggest adrenal insufficiency, as do levels ³⁰. Hyponatremia (low blood sodium) can be attributed to cortisol and mineralocorticoid deficiencies, whereas hyperkalemia (high blood potassium) is attributed solely to a lack of mineralocorticoids.

After secondary adrenal insufficiency is diagnosed, health care providers may use the following tests to obtain a detailed view of the pituitary gland and assess how it is functioning:

• Imaging tests. Your doctor may have you undergo a computerized tomography (CT) scan of your abdomen to check the size of your adrenal glands and look for other abnormalities that may give insight to the cause of the adrenal insufficiency. Your doctor may also suggest an MRI scan of your pituitary gland if testing indicates you might have secondary adrenal insufficiency.

Figure 6. Addison’s disease diagnosis