Adrenal Gland Disorders

The adrenal glands, located on the top of each kidney, are responsible for releasing different classes of hormones.

The outer part of the gland, called the adrenal cortex, produces the hormones cortisol (pronounced KAWR-tuh-sohl) and aldosterone (pronounced al-DOS-tuh-rohn). The inner part of the gland, called the adrenal medulla (pronounced muh-DUHL-uh), produces the hormones adrenaline and noradrenaline.

These hormones—cortisol, aldosterone, adrenaline, and noradrenaline—control many important functions in the body, including¹:

 

• Maintaining metabolic processes, such as managing blood sugar levels and regulating inflammation
• Regulating the balance of salt and water
• Controlling the "fight or flight" response to stress
• Maintaining pregnancy
• Initiating and controlling sexual maturation during childhood and puberty

The adrenal glands are also an important source of sex steroids, such as estrogen and testosterone.

Adrenal gland disorders occur when the adrenal glands do not work properly. They can be classified into disorders that occur when too much hormone is produced or when too little hormone is produced.

These disorders can occur if there is a problem with the adrenal gland itself, such as a disease, genetic mutation, tumor, or infection. Or, sometimes the disorder results from a problem in another gland, such as the pituitary, which helps to regulate the adrenal gland. In addition, some medications can cause problems with how the adrenal glands function. When the adrenal glands produce too little or too many hormones, or when too many hormones come into the body from an outside source, serious health problems can develop.^2,3

Most adrenal gland tumors—abnormal growths on the adrenal glands—are not cancerous. They often do not cause symptoms or require treatment. However, adrenal gland tumors can produce a variety of different hormones, leading hormone levels to get too high.

Adrenal tumors can cause:

• Cushing's syndrome, by producing cortisol so that body levels get too high
• Primary hyperaldosteronism, by creating high levels of the hormone aldosterone (controls blood pressure and body salt and potassium levels)
• Pheochromocytoma, by producing too much adrenaline (regulates the "fight-or-flight" response)

This is a cancerous adrenal tumor that tends to develop in the outer layer of the adrenal gland. Cancerous adrenal tumors are often found years after they start growing, at which point the cancer have spread to other organs.

Cushing syndrome is a rare disease that results from having too much cortisol hormone in the body. In some cases, Cushing syndrome develops from long-term or overuse of steroid medications(medicines that act like cortisol in the body). In other cases, the body itself produces too much cortisol. This overproduction can happen for several reasons, including the presence of tumors(abnormal growths) such as a:

• Tumor of the pituitary gland (this is called Cushing disease)
• Tumor of the adrenal gland (as explained above)
• Tumor in another part of the body (these are called "ectopic" tumors and are more commonly found in the pancreas, lung, or the thyroid gland)

CAH is a common genetic disorder in which the body makes too little cortisol. People with CAH may also have other hormone imbalances. For example, their bodies might not make enough aldosterone (controls blood pressure and body salt and potassium levels), but might make too much androgen (promotes the development of male sexual organs).

The pituitary gland is located at the base of the brain. It releases hormones that affect many of the body's functions. Among those hormones is the adrenocorticotropic (pronounced a-DREE-noh kawr-tuh-koh-TRO-pic) hormone (ACTH), which stimulates the adrenal glands to release the hormone cortisol.

Sometimes, benign (noncancerous) pituitary tumors or—more rarely cancerous tumors¹—may grow on the pituitary gland, which can cause a variety of problems. Some pituitary tumors release too much ACTH, which, in turn, can cause the adrenal glands to produce too much cortisol. Cushing's disease refers to pituitary tumors that cause Cushing's syndrome.

Pheochromocytomas (pronounced fee-oh-kroh-moh-sigh-TOH-muhs) are part of a larger family of tumors, called paragangliomas (pronounced pair-uh-gang-lee-OH-muhs). Pheochromocytoma is a type of tumor that develops in the adrenal medulla, the inner part of the adrenal gland. It produces adrenaline, causing high levels of this hormone in the body. In most cases, the tumors are not cancerous and do not spread to other parts of the body. But in about 10% of cases, the tumors are cancerous and can spread.⁵

The normal activity of the adrenal glands can be suppressed—or reduced—when people take steroid medications (medicines that act like cortisol in the body) such as prednisone, hydrocortisone, or dexamethasone.² Steroid medications, most often prednisone, may be prescribed to treat certain types of arthritis, severe allergic reactions, asthma, autoimmune (pronounced awh-toh-im-YOON) diseases, and other conditions.³

Ordinarily, someone taking steroids takes gradually lower and lower doses as time goes by until they stop taking the drug completely. This is called "tapering" the dose. When steroid medications are stopped suddenly, especially after being taken for several weeks or more, the adrenal glands may be unable to produce steroid hormones (most importantly, cortisol) in sufficient amounts for several weeks or even months.¹ This situation can cause health problems because of the imbalance of hormone levels that continues until the adrenal glands start functioning normally again.

This rare disorder develops when the adrenal glands do not make enough cortisol. In most cases of Addison's disease, the body also doesn't make enough of the hormone aldosterone.

Addison's is an autoimmune disease—a condition in which the immune system, which is supposed to protect the body, mistakenly attacks the body's own tissues and cells. In the case of Addison's disease, this reaction results in damage to the adrenal glands.⁴ In the long term, this damage can get worse until eventually the adrenal glands aren't working at all.

This disorder occurs when the body produces too much aldosterone, a hormone that controls blood pressure and regulates the body's salt and potassium levels. The extra aldosterone is produced either by a tumor, which typically affects one adrenal gland, or by abnormal growth of both glands, a condition called "hyperplasia."

Common symptoms of Cushing's syndrome (due to an adrenal, pituitary, or ectopic tumor) can include:

• Upper body obesity, round face and neck, and thinning arms and legs
• Skin problems, such as acne or reddish-blue streaks on the abdomen or underarm area
• High blood pressure
• Muscle and bone weakness
• Moodiness, irritability, or depression
• High blood sugars
• Slow growth rates in children

Women may also have increased growth of hair on their face and body and experience menstrual irregularities. Men may become less fertile and have a reduced or absent sex drive.

Symptoms of CAH range from mild to serious. Some people with mild CAH are never diagnosed because their symptoms do not cause them any problems.

Symptoms of the mild form of CAH, which can be diagnosed in children or adults, may include¹:

• Early signs of puberty (in children)
• Acne
• Irregular menstrual periods and possible trouble getting pregnant (in women)
• Excess facial hair (in women)

Symptoms of the severe form of CAH, which is diagnosed in children, may include¹:

• Dehydration
• Low blood pressure
• Low blood sugar level
• Trouble keeping enough salt in the body
• Altered development of the external genitalia in girls, which is noted at birth and may require surgery to correct
• Early signs of puberty
• Irregular periods and possible trouble getting pregnant (in women)
• Excess facial hair (in women)

The symptoms of functioning pituitary tumors depend on the particular hormone the tumor is overproducing.²

Too much prolactin may cause:

• Headache
• Some loss of vision
• Less frequent or no menstrual periods or menstrual periods with a very light flow
• Difficulty getting pregnant
• Impotence in men
• Lower sex drive
• The flow of breast milk in a woman who is not pregnant or breastfeeding

Too much adrenocorticotropic hormone (ACTH) may cause:

• Headache
• Some loss of vision
• Weight gain reflected in the face, neck, and trunk of the body, but thin arms and legs
• A lump of fat on the back of the neck
• Thin skin that may include purple or pink stretch marks on the chest or abdomen
• Easy bruising
• Growth of fine hair on the face, upper back, or arms
• Bones that break easily
• Anxiety, irritability, depression
• Growth deceleration with weight gain in children
• Irregular menses

Too much growth hormone may cause:

• Headache
• Some loss of vision
• In adults, growth of the bones in the face, hands, and feet
• In children, excessive growth of the whole body
• Tingling or numbness in the hands and fingers
• Snoring or pauses in breathing during sleep
• Joint pain
• Sweating more than usual
• Extreme dislike of or concern about one or more parts of the body

Too much thyroid-stimulating hormone (TSH) may cause:

• Irregular heartbeat
• Shakiness
• Weight loss
• Trouble sleeping
• Frequent bowel movements
• Sweating

Nonfunctioning tumors press on or damage the pituitary and prevent it from secreting enough hormones. If there is too little of a particular hormone, the gland or organ it normally controls will not function correctly. Symptoms of nonfunctioning pituitary tumors are²:

• Headache
• Some loss of vision
• Loss of body hair
• In women, less frequent menstrual periods or no periods at all, or no milk from the breasts
• In men, loss of facial hair, growth of breast tissue, and impotence
• In women and men, lower sex drive
• In children, slowed growth and sexual development

Other general symptoms of pituitary tumors include the following:

• Nausea and vomiting
• Confusion
• Dizziness
• Seizure
• Runny or drippy nose

Most people with pheochromocytoma have high blood pressure (hypertension) because the tumor causes the adrenal gland to produce too much adrenaline or noradrenaline. Other symptoms may include³:

• Rapid heart rate
• Headache
• Sweating
• Episodes of high or low blood pressure
• Anxiety or panic attack
• Shaking (tremors) of the hands
• Pale skin
• Blurred vision
• Weight loss
• Constipation
• Abdominal pain
• High blood sugar
• Psychiatric disturbances

Symptoms can vary, depending on what causes the disease. Symptoms typically include^4,5:

• Weight loss
• Weakness
• Extreme fatigue
• Nausea and/or vomiting
• Low blood pressure
• Patches of darker skin
• Craving for salt
• Dizziness upon standing
• Depression

The main symptom is moderate to high blood pressure (hypertension), which can be difficult to control. Other symptoms include:

• Low potassium levels
• Muscle cramping or spasms
• Excessive urination, sometimes at night
• Headache
• Generalized weakness

Cushing's syndrome occurs when the body is exposed to high levels of the hormone cortisol over a long period of time.

Sometimes Cushing's syndrome develops when people take certain hormones for asthma, rheumatoid arthritis, lupus, and other inflammatory diseases. The syndrome also can occur when hormones are taken to suppress the immune system so that a patient's body will not reject a transplanted organ.

Other people develop Cushing's syndrome because their bodies produce too much cortisol.² Other causes of Cushing's syndrome include pituitary adenomas (a type of benign tumor), ectopic adrenocorticotropic hormone syndrome, adrenal tumors, or familial Cushing's syndrome.² Cushing's syndrome due to tumors occurs more commonly in women.²

CAH is a group of inherited disorders of the adrenal glands. It affects men and women equally. Both parents must carry the gene in order for a child to be born with CAH.³

Scientists have not yet discovered what causes pituitary tumors. Most pituitary tumors are not inherited; only a small percentage of cases run in families. ^4,5

Most of the time, pheochromocytoma and paraganglioma tumors are "sporadic," meaning why they develop is not associated with any known risk factor or genetic mutation. However, research increasingly shows that a number of patients, possibly up to one-quarter, have genetic mutations responsible for tumor development.^6,9 In these patients, family members may also be affected.

In all cases of Addison's disease, the adrenal glands do not produce enough of the hormone cortisol. In most cases, the glands also make too little of the hormone aldosterone.⁷ This is also termed primary adrenal insufficiency. This disease can be caused by an autoimmune disorder, infection (for example, tuberculosis), or other rare diseases that cause infiltration and thus destruction of the adrenal glands (for example, sarcoidosis or amyloidosis). The most common cause of Addison's disease in developed countries is autoimmune disorders.

There are two causes of hyperaldosteronism. One cause is an excessive growth of normal cells in both adrenal glands. The other cause is a non-cancerous tumor in one of the glands.⁸ There are no known gene mutations associated with this disorder at this time. However, rarely, hyperaldosteronism can run in families.

To diagnose an adrenal gland tumor, a health care provider may order one or more tests.³

• Blood and urine tests help measure the amount of adrenal hormones, which can detect a functional tumor.
• A computed tomography (CT or CAT) scan or a magnetic resonance imaging (MRI) scan may be useful in diagnosing an adrenal gland tumor and determining whether it is cancerous.
• A metaiodobenzylguanidine (MIBG) scan can detect a neuroendocrine tumor.
• An interventional radiologist can test the blood from the veins of each adrenal gland to identify tumors that CT or MRI scans can't pick up, or to determine if both glands have small masses (and thus both may require surgery).

If a health care provider suspects that a patient has Cushing's syndrome, he or she may order one or more of the three screening tests currently in use for this disorder.

• One of the tests screens for elevated cortisol levels in saliva.
• Another test looks for elevated cortisol levels in the urine over 24 hours.
• A third test checks to see if a synthetic (man-made) steroid, called dexamethasone (pronounced dek-suh-METH-uh-sohn), reduces cortisol production by the body.⁴

The most common way health care providers identify CAH in infants is through newborn screening. If the first screening test indicates that the infant may have CAH, the health care provider will order another blood test to confirm the diagnosis.

In some cases, female infants may have visible genital abnormalities that lead health care providers to suspect CAH as the cause. In these cases, health care providers will order an additional test to confirm the diagnosis.⁵ The milder form of CAH, when suspected, can also be diagnosed by the ACTH stimulation test (described below).

The first step in diagnosing pituitary tumors is a physical exam that includes checking neurologic responses, like reflexes and strength, and evaluation for signs of high hormone secretion, such as acne or unusual hair growth. A health care provider may also conduct a vision test to determine whether the growth of a pituitary tumor has affected sight or peripheral vision.

If results of this test lead the health care provider to suspect a pituitary tumor, he or she will order one or more tests of the patient's endocrine function.

To confirm the diagnosis, the health care provider may ask for a test of the patient's visual field (the area visible at a given instant without moving the eyes) or a magnetic resonance imaging scan of the patient's head.⁶

If a health care provider suspects a pheochromocytoma/paraganglioma, he or she may administer a blood or urine test. The test measures the levels of:

• Catecholamines (pronounced kat-i-KOL-uh-meens), hormones that increase the heart rate, blood pressure, rate of breathing, and amount of energy available to the body
• Metanephrines (pronounced met-uh-NEF-reens), molecules produced from the body breaking down catecholamines⁷

Typically, a blood test to measure cortisol levels and levels of adrenocorticotropic hormone (ACTH) is used to diagnose Addison's disease. A health care provider may also use an ACTH stimulation test, an hour-long test during which a person receives a synthetic (man-made) version of ACTH through an intravenous (IV) line. The health care provider compares blood levels of various hormones from before and after the ACTH is given. If cortisol levels are low, the person could have adrenal insufficiency and Addison's disease.⁸

If a health care provider suspects hyperaldosteronism, he or she may order blood and urine tests to check for high levels of aldosterone and low levels of potassium.

The health care provider also may order a computed tomography (called a CT or "cat") scan to determine whether there is a non-cancerous tumor or other abnormal growth of the adrenal glands.⁹

The treatment for Cushing's syndrome depends on the cause. If medication causes the excess cortisol, a health care provider can change the patient's dosage or try a different medication to correct the problem. If the Cushing's syndrome is caused by the body making too much cortisol, treatments may include oral medication, surgery, radiation, or a combination of these treatments.²

CAH cannot be cured, but it can be treated and controlled. People with CAH can take medication to help replace the hormones their bodies are not making. Some people with CAH need only these medications when they are sick, but other people with CAH may need to take medication every day.³

The most widely used treatment for non-cancerous pituitary tumors is removal of the tumors. Using a microscope and small instruments, the health care provider removes the tumor through a nostril or opening below the upper lip. The process is called transsphenoidal adenomectomy (pronounced TRANS-sfee-NOY-dul a-dee-na-MEK-ta-me). Radiation is also used.⁴

The usual treatment for pheochromocytoma/paraganglioma is removal of the tumor through surgery. In most cases, removing the tumor improves the patient's blood pressure control. This treatment seems to be more effective in patients whose high blood pressure is sporadic than in those patients whose high blood pressure is long lasting.⁵

Addison's disease is treated by replacing the cortisol and/or aldosterone that the body is lacking. People with Addison's disease take medication (usually by mouth) each day to replace these hormones. They may also need to consume additional salt.⁶

The treatment for hyperaldosteronism depends on what is causing the disorder.

• For hyperaldosteronism caused by an excessive growth of normal cells in both adrenal glands, the treatment involves medications that block the effect of aldosterone.
• The treatment for hyperaldosteronism caused by a non-cancerous tumor in one adrenal gland is removing the affected gland using laparoscopic (pronounced la-puh-re-SKOP-ic) surgery. This type of surgery is minimally invasive, involving only small incisions in the abdomen, and is usually easier to recover from than traditional surgery.⁷

Through its intramural and extramural organizational units, NICHD supports and conducts a broad range of research on adrenal gland disorders.

Much of this research is conducted through the Section on Genetics and Endocrinology, which is part of the NICHD Division of Intramural Research (DIR). Researchers in this Section study the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with an emphasis on those disorders that are developmental, hereditary, and associated with adrenal hypoplasia or hyperplasia, multiple tumors, and abnormalities in other endocrine glands. Work supported by this Section includes:

• Studying congenital adrenal hypoplasia caused by triple A syndrome and several endocrine deficiencies; familial hyperaldosteronism; adrenocortical and thyroid cancer; pituitary tumors; multiple endocrine neoplasia syndromes affecting the pituitary, thyroid, and adrenal glands; and the Carney complex (CNC), a multisystem disease that is a combination of endocrine overactivity, spotty skin pigmentation, myxomas, and other tumors
• Identifying the chromosome on which the genes for CNC are located, and searching for other possible locations
• Investigating the relationship between these locations and CNC
• Using cell lines established from CNC patients to investigate the consequences of mutations of PRKAR1A, the gene responsible for most cases of CNC
• Using transgenic mouse models to study the role of the PRKAR1A gene
• Identifying novel genetic abnormalities in certain endocrine glands
• Identifying a new syndrome known as "paraganglioma and gastrointestinal stromal tumor syndrome" due to SDH gene mutations

Within the Section on Medical Neuroendocrinology, scientists conduct patient-oriented research into the causes, functions, genetics, diagnosis, location, and treatment of pheochromocytoma and paraganglioma. One recent study assessed whether the size of adrenal tumors plays a role in the development of metastatic disease (disease that moves or spreads from one organ or tissue to another) regardless of the genetic background of these tumors.¹ In another study, researchers discovered an alteration in the HIF2A gene that was associated with growth of pheochromocytomas in two patients. The finding could lead to information on how to hinder the growth of tumors and treat cancers associated with excessive production of red blood cells.²

Other units within the DIR focus on adrenal gland disorders and disorders of female reproduction. Researchers are evaluating the usefulness of basal cortisol and corticotrophin-releasing hormone testing for the prediction of recurrent Cushing's disease.

Within the DIR Developmental Endocrinology, Metabolism, Genetics & Endocrine Oncology, investigators aim to characterize the genotypes of parents of children with congenital adrenal hyperplasia (CAH) and to examine the structure and function of the adrenal glands in these patients. Research also has been conducted to assess complications linked to the disorder, such as hypoglycemia and insulin resistance, and to test new versions of medications intended for use as treatments.

The Pediatric Growth and Nutrition Branch (PGNB), within the Division of Extramural Research, supports research about genetic and molecular mechanisms of adrenal gland hyperplasia, prenatal screening for the disorder, and prenatal treatment of classic CAH with dexamethasone. The PGNB also has supported studies to characterize novel mutations in genes for enzymes involved in CAH.

In addition, the Developmental Biology and Congenital Anomalies Branch advances research with animal models to understand typical pituitary development, as well as growth of pituitary tumors, and investigates the genetic basis of tumor development.

• The biennial Conference on the Adrenal Cortex is for basic and clinical scientists and clinicians with specific interests in the adrenal cortex. Authorities in the field present current findings on topics related to the adrenal cortex. Co-sponsors include the NICHD Developmental Endocrine Oncology and Genetics Group in the DIR.
• The Pediatric Endocrinology Training Program is a 3-year program accredited by the Accreditation Council for Graduate Medical Education. It provides comprehensive training in clinical patient management and guidance in the development of research skills. The fellowship is at NICHD and based at the NIH Clinical Center, which maintains clinical research protocols investigating the treatment of adrenal and pituitary tumors, Cushing's syndrome, obesity, and other conditions.
• The Reproductive Scientist Development Program (RSDP) is a multidisciplinary, multi-institutional research career development program for obstetrician-gynecologists studying cell and/or molecular biology and genetics and related fundamental sciences. The RSDP, sponsored jointly by NICHD's Fertility and Infertility (FI) Branch and other entities, helps academic obstetrics and gynecology departments increase research and discovery in the reproductive sciences.
• The National Centers for Translational Research in Reproduction and Infertility (NCTRI) (Formerly the Specialized Cooperative Centers Program in Reproduction and Infertility Research [SCCPIR]) is a national network of research-based centers, supported by the FI Branch, that aims to promote interactions between basic and clinical scientists with the goal of improving reproductive health. Several centers focus on diseases/disorders of the female reproduction system that may affect women who have undergone treatment for tumors in Cushing's syndrome.