Patient education: Adrenal insufficiency (Beyond the Basics)

ADRENAL INSUFFICIENCY OVERVIEW — The adrenal glands are located on top of each kidney (figure 1) and normally produce three types of hormones: glucocorticoids, mineralocorticoids, and androgens. Adrenal insufficiency occurs when the adrenal glands produce an insufficient amount of glucocorticoids or mineralocorticoids.

Early detection of adrenal insufficiency can be difficult, although treatment is usually successful once it is initiated. Treatment is tailored to the underlying cause and, in most cases, lifelong treatment is necessary. With appropriate treatment and a few added precautions, people with adrenal insufficiency can lead active lives and have a normal life expectancy.

TYPES OF ADRENAL HORMONES

Glucocorticoids — Cortisol is the main glucocorticoid produced by the adrenal glands. Corticotropin, or "ACTH," is made in the pituitary and stimulates the adrenal glands to produce cortisol. Cortisol has many important functions including:

●Help to regulate blood glucose (sugar) levels

●Help to regulate appetite and body fat

●Help to defend the body against infection

●Help the body respond to stress

Mineralocorticoids — Aldosterone is the main mineralocorticoid produced by the adrenal glands. It helps to regulate the body's sodium and potassium levels, blood volume, and blood pressure.

Androgens — Androgen hormones, including testosterone, dehydroepiandrosterone (DHEA), and DHEA sulfate, are present in both males and females:

●In females, androgens are produced in the adrenal glands and the ovaries. Adrenal androgens promote the development of sex characteristics, such as underarm and pubic hair.

●In males, most androgens (eg, testosterone) are produced in the testes. Testosterone is more important than androgens made by the adrenal glands for normal sexual function.

ADRENAL GLAND PRODUCTION OF HORMONES — Cortisol levels are normally regulated by the hypothalamus and pituitary gland (figure 2). The hypothalamus sends corticotropin-releasing hormone (CRH) to the pituitary gland. The pituitary gland responds by producing several hormones, one of which is corticotropin (ACTH). ACTH stimulates the adrenal gland to produce cortisol. Cortisol levels help to control the pituitary's production of ACTH.

Primary adrenal insufficiency — Primary adrenal insufficiency, also known as Addison disease, occurs when the adrenal glands cannot produce an adequate amount of any adrenal hormones despite a normal or increased corticotropin (ACTH) level (figure 2). This is a rare disease, occurring in approximately 35 to 120 in every one million people.

Most people with Addison disease experience fatigue, generalized weakness, loss of appetite, and weight loss. The type and severity of symptoms depend upon the speed with which the condition develops, the severity of the hormone deficiency, the underlying cause of the condition, and other stresses on the body. Other common symptoms include:

●Darkening of the skin, especially on the face, neck, and back of hands (picture 1 and picture 2)

●Gastrointestinal symptoms such as nausea and vomiting (vomiting and abdominal pain may be a sign of an adrenal crisis) (see 'Adrenal crisis' below)

●Low blood pressure with lightheadedness after standing or sitting up

●Muscle and joint pain

●Salt cravings

●In women, decreased hair in the armpits and pubic area and decreased sexual desire

Central adrenal insufficiency — In central adrenal insufficiency, corticotropin (ACTH) production by the pituitary gland is insufficient. This can happen for one of two reasons:

●The pituitary is unable to make ACTH (termed "secondary adrenal insufficiency").

●The hypothalamus does not produce enough corticotropin-releasing hormone (CRH) to stimulate ACTH production (termed "tertiary adrenal insufficiency").

Insufficient ACTH levels lead to a deficiency of cortisol but not aldosterone. Aldosterone production is mostly regulated by other hormones, and it remains normal in people with central adrenal insufficiency.

The symptoms of central adrenal insufficiency are similar to those of primary insufficiency, with a few exceptions:

●Darkening of the skin and dehydration do not occur

●Gastrointestinal symptoms are less common

●Symptoms of hypoglycemia (low blood sugar) are more common; these can include sweating, anxiety, shaking, nausea, or heart palpitations

In some cases, central adrenal insufficiency can be caused by a tumor or other growth in the pituitary or hypothalamus. When this happens, the tumor can cause other symptoms in addition to those of adrenal insufficiency. These include headaches and difficulty seeing objects in the periphery of vision (to the far left and right). In this setting, low levels of other pituitary hormones can develop and may cause infertility, erectile dysfunction, fatigue, hoarseness, or constipation. In children, low levels of pituitary hormones can lead to delayed puberty or shorter than average height.

ADRENAL INSUFFICIENCY DIAGNOSIS — The diagnosis of adrenal insufficiency is a four-part process:

●The blood cortisol level is measured

●Other tests are usually needed to confirm the diagnosis of adrenal insufficiency

●The level of the defect is determined (primary versus secondary/tertiary) by measuring corticotropin (ACTH)

●Once the level of the defect is known, further evaluation is done to determine the cause of the defect or to evaluate for other associated problems

Cortisol and ACTH level testing — To determine a person's cortisol and corticotropin (ACTH) level, a blood sample is taken early in the morning after waking, usually at around 8 AM, when levels should be high.

●If the cortisol level is very low, the person is likely to have adrenal insufficiency

●If the cortisol level is above a certain normal level, the person is very unlikely to have adrenal insufficiency

●Many people have cortisol results in an intermediate zone and need to have additional testing

A variety of other tests can be done to confirm the diagnosis of adrenal insufficiency.

Most often, an ACTH stimulation test is done to establish the diagnosis. To perform this test, a blood sample is taken at any time of day to measure the "baseline" cortisol level. A high dose of ACTH is then given into a vein. A blood sample is then taken again 30 to 60 minutes later to remeasure the cortisol level. A low cortisol level after a dose of ACTH confirms that the person has adrenal insufficiency.

Measurement of a blood ACTH level helps to determine if the problem lies within the adrenal gland (causing primary adrenal insufficiency) or in the pituitary or hypothalamus (causing central adrenal insufficiency):

●If the ACTH level is high, the person probably has primary adrenal insufficiency

●If the ACTH level is low, the person probably has central (secondary or tertiary) adrenal insufficiency

Determine the underlying cause

For primary adrenal insufficiency — To determine the cause of primary adrenal insufficiency, your health care provider will consider your age, sex, and other medical problems. Most providers recommend an abdominal computed tomography (CT) scan to evaluate the adrenal glands. In some cases, blood tests or a chest X-ray will also be recommended.

In the past, tuberculosis was the most common cause of primary adrenal insufficiency. Currently, the most common cause of Addison disease is autoimmune adrenalitis (a disease in which antibodies develop against the adrenal glands and lead to their damage).

For central adrenal insufficiency — Possible causes of central adrenal insufficiency include:

●Long-term treatment with glucocorticoid medications (eg, taking prednisone for asthma); this can interfere with normal pituitary function and is the most common cause of central adrenal insufficiency

●An abnormal growth or tumor in the pituitary or hypothalamus

●Deficiencies in ACTH and possibly other pituitary hormones (partial or panhypopituitarism) that are present at birth; these are called congenital deficiencies

●Previous radiation to the pituitary gland or brain, or pituitary gland surgery

Your provider can order a detailed magnetic resonance imaging (MRI) scan of the pituitary gland and hypothalamus to determine if a mass or abnormal growth is present. Blood tests of pituitary hormones are usually done to be sure that they are normal.

ADRENAL INSUFFICIENCY TREATMENT — The treatment of adrenal insufficiency includes replacement of the deficient hormones. The goal of treatment is to relieve the symptoms of hormone deficiency without causing signs of hormone excess. Treatment usually requires lifelong hormone replacement. Correct use of these hormone medications is essential to minimize symptoms and the chance of adrenal crisis.

Hormone deficiencies

Primary adrenal insufficiency — Treatment of adrenal insufficiency requires daily treatment with glucocorticoid and mineralocorticoid pills, usually for life. Androgen replacement may be helpful for some females. The goal of treatment is to stabilize hormone levels and relieve symptoms. Fatigue and nausea usually begin to disappear within days of starting treatment.

Central adrenal insufficiency — People with central adrenal insufficiency require only glucocorticoid (eg, hydrocortisone) replacement (not mineralocorticoid replacement). Androgen replacement may be helpful for some females. Treatment may also include replacement of other deficient pituitary hormones.

Glucocorticoids (primary or central adrenal insufficiency) — All individuals with adrenal insufficiency need glucocorticoid replacement. Several options are available for replacing glucocorticoids; your health care provider will work with you to determine the regimen that is most effective, convenient, and that causes minimal side effects.

Many providers prescribe the short-acting preparation oral hydrocortisone (identical to cortisol produced by the adrenal glands), with two or three doses per day. The largest dose is taken in the early morning, and a smaller dose is taken in the late-morning and/or afternoon; this mimics the normal variation in blood cortisol levels. Because hydrocortisone is available in a variety of doses, the amount of hydrocortisone can be adjusted easily, which may be an advantage over the longer-acting glucocorticoids.

A longer-acting glucocorticoid like prednisone is sometimes preferred because it can be taken once per day. Occasionally, a small additional dose is needed in the afternoon. However, it can be more difficult to adjust the dose of these longer-acting medications to avoid overtreatment.

●Monitoring during treatment – The development of weight gain or a puffy face is usually a sign of overtreatment and indicates that the glucocorticoid dose should be decreased. Higher doses of glucocorticoids are of no benefit and may increase the risk of complications including bone thinning (osteoporosis). Your provider will monitor closely for these complications.

●Dosing – The dose of any of glucocorticoid is tailored to your body size and age; people with greater body size may need a higher dose, while children and smaller adults may need a lower dose. Adjustments in dose are often necessary when starting treatment.

Mineralocorticoids (primary adrenal insufficiency only) — People with primary but not central adrenal insufficiency also need mineralocorticoid replacement. Mineralocorticoids are replaced with an oral, synthetic mineralocorticoid drug called fludrocortisone (brand name: Florinef). The dose of this medication is tailored to manage blood pressure and fluid balance.

When you are on the correct dose, you should not experience lightheadedness or dizziness when standing up. If the dose is too high, you may notice swelling in your ankles, and your health care provider may note hypertension (high blood pressure) or low blood potassium levels. In this case, your provider will most likely decrease your dose of fludrocortisone.

Androgens (females with primary or central adrenal insufficiency) — Androgen replacement is sometimes helpful for females with primary or central adrenal insufficiency. A daily dose of dehydroepiandrosterone (DHEA) may improve libido and provide an improved overall sense of well-being. However, there are potential side effects associated with DHEA that are related to elevated androgen levels (eg, acne, facial hair, deepened voice). In addition, DHEA is only available as a dietary supplement in the United States. Because it is not regulated by the US Food and Drug Administration (FDA), there are concerns about quality control and safety.

ADRENAL CRISIS — Adrenal crisis refers to overwhelming and life-threatening adrenal insufficiency. The most common signs of adrenal crisis are shock (very low blood pressure with a loss of consciousness), dehydration, and an imbalance of sodium and potassium levels in the body. In some cases, shock is preceded by fever; nausea, vomiting, and abdominal pain; weakness or fatigue; and confusion. Adrenal crisis usually occurs after an infection, trauma, or another stressor.

Adrenal crisis is a life-threatening condition that requires emergency medical treatment. The person with adrenal insufficiency or a family member or friend should immediately give an emergency injection of a glucocorticoid at the first signs of adrenal crisis (see 'Emergency precautions' below). In the emergency department or ambulance, treatment usually includes several liters of a salt solution (saline) and an injection of a glucocorticoid (eg, hydrocortisone) into a vein. Mineralocorticoid treatment (if needed) is usually started at a later time, when the saline treatment is completed.

Following initial treatment, it is important to look for and treat any factors that may have triggered the crisis, such as infection.

ADRENAL INSUFFICIENCY PRECAUTIONS AND SPECIAL SITUATIONS — People with adrenal insufficiency should learn as much as possible about their condition and should be aware of early warning signs of hormone deficiency. It is important to share this information with family, friends, and any caregivers, so that they can also identify signs of trouble and be prepared to act in case of adrenal crisis.

General precautions — People with adrenal insufficiency should wear a medical alert bracelet or necklace. They should also carry an emergency medical information card that lists the names and doses of their daily medications and the health care provider and family member(s) to call in case of emergency. It is extremely important to identify early symptoms of adrenal insufficiency and adrenal crisis; your provider can talk to you about subtle symptoms that should not be ignored.

Emergency precautions — Even with careful use of medications and medical monitoring, some people with adrenal insufficiency will experience adrenal crisis. As a safety measure, it is important to always carry a syringe and a vial of hydrocortisone (or another glucocorticoid). This emergency medication kit should be stored at home and at work or school and carried in a handbag or backpack.

The person with adrenal insufficiency (or a family member or friend) should give the injection into a muscle (usually the thigh) if any of the following occurs:

●After a major injury with substantial blood loss, fracture, or shock

●During an episode of nausea and vomiting if oral medications are thrown up

●If there are any signs or symptoms of adrenal crisis

●If a person is found unconscious

Most people with adrenal insufficiency go years without needing an injection. However, the injection is recommended if there is any reason to believe it might be needed. There is little to no risk from receiving an unnecessary glucocorticoid injection, but there are significant risks from not receiving a glucocorticoid injection when it is needed.

After the injection is given, medical care should be sought immediately. After a major injury or if the person is found unconscious, it is best to call for emergency medical services. In the United States, most people can access emergency care by calling 911.

Illnesses, medical procedures, and surgery — The adrenal glands normally increase cortisol output when the body is stressed by illness, major medical procedures, or surgery. People with adrenal insufficiency do not have this ability. The risk of adrenal crisis can be minimized by adjusting the dose of glucocorticoid treatment.

During symptoms of a cold or flu, it is safe to double or triple the daily dose of glucocorticoid for three days without calling the doctor. However, if symptoms become worse during that time, or if it is not possible to return to the usual glucocorticoid dose on the fourth day, the health care provider should be called for advice.

It is important to call the provider if there are any signs of a stomach illness with nausea, diarrhea, or vomiting. It is also important to call before any medical procedures or surgery. The provider will usually recommend temporarily increasing the glucocorticoid dose for these types of stresses.

Pregnancy — Most females who have primary adrenal insufficiency are able to have a healthy pregnancy, labor, and delivery. Pregnant people should be monitored by an obstetrician and endocrinologist with expertise in adrenal insufficiency.

During this time, it is important to take medications on schedule and have careful monitoring of the growing fetus, as well as the pregnant person. Some people require increases in glucocorticoid doses during pregnancy, especially during the third trimester and during labor. People who have severe morning sickness may need to switch from oral medication to injected medication until the morning sickness subsides.

ADRENAL INSUFFICIENCY PROGNOSIS — The long-term outlook is good for most people with adrenal insufficiency who are treated and monitored. Most people can lead an active life and have a normal life expectancy. Children with primary adrenal insufficiency who are treated and monitored carefully can grow normally and experience puberty without difficulty.

WHERE TO GET MORE INFORMATION — Your health care provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our website (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for health care professionals, are also available. Some of the most relevant are listed below.

Patient level information — UpToDate offers two types of patient education materials.

The Basics — The Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient education: Addison disease (The Basics)
Patient education: Cushing syndrome (The Basics)
Patient education: Adrenal crisis (The Basics)
Patient education: Panhypopituitarism (The Basics)

Beyond the Basics — Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

This topic has no corresponding Beyond the Basics information.

Professional level information — Professional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Causes of primary adrenal insufficiency (Addison disease)
Causes of secondary and tertiary adrenal insufficiency in adults
Clinical manifestations of adrenal insufficiency in adults
Determining the etiology of adrenal insufficiency in adults
Diagnosis of adrenal insufficiency in adults
Hyponatremia and hyperkalemia in adrenal insufficiency
Pathogenesis of autoimmune adrenal insufficiency
Treatment of adrenal insufficiency in adults
Treatment of adrenal insufficiency in children

The following organizations also provide reliable health information.

●National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)

●National Institute of Diabetes and Digestive and Kidney Diseases

(www.niddk.nih.gov)

●Hormone Health Network

(www.hormone.org)

●National Adrenal Diseases Foundation

(www.nadf.us)

ACKNOWLEDGMENT — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.