by Cat Troiano

Hypoadrenocorticism, more commonly known as Cushing’s syndrome, is an endocrine disorder that is characterized by hypercortisolism, which is an abnormally high level of the hormone cortisol in the blood. Between 10 and 15 million individuals in the United States are diagnosed with this condition each year. Diagnosing Cushing’s syndrome can be challenging due to the fact that some of its presenting symptoms mimic those of other conditions as well as to the fact that there are a number of potential causes of hypercortisolism.

What Is Cortisol?

Often coined the stress hormone, cortisol is produced in the adrenal cortex, which is the outer layer of the adrenal glands, which are situated just superior to the kidneys. Cortisol is secreted in response to stressful conditions to prepare the body to function optimally during such times. Similarly, the slow-acting hormone is also released in response to imposed physical demands during exercise. Regulatory functions of cortisol include:

• Maintains blood pressure
• Prompts glucose synthesis in the liver
• Decreases the rate of glucose utilization by the cells
• Stimulates free-fatty acid mobilization from adipose tissue
• Reduces inflammation
• Regulates the body’s hydration level

Multiple glands are responsible for the normal production of cortisol. First, the hypothalamus produces corticotropin-releasing hormone. This hormone stimulates the pituitary gland, which is a pea-sized gland that sits at the base of the brain, just below the hypothalamus. The pituitary gland produces another hormone, called adrenocorticotropic hormone (ACTH) in addition to other hormones, including growth hormone and vasopressin. ACTH is the hormone that stimulates cortisol production in the adrenal glands.

Hypercortisolism Causes and Risk Factors

Both genders can develop Cushing’s syndrome, but it is most commonly diagnosed in women between the ages of 30 and 50. Longterm uncontrolled hypertension and longterm high blood glucose levels in diabetics are risk factors for developing Cushing’s syndrome. There are several causes of high cortisol levels:

Pituitary adenoma, which is a benign tumor on the pituitary gland, promotes an overstimulation of ACTH hormone, which in turn stimulates excess cortisol production from the adrenal gland. The specific name for this condition is Cushing’s disease, and it accounts for more than half of all hypoadrenocorticism cases.

Glucocorticoid drug use over the longterm, such in the treatment of such conditions as asthma and autoimmune disorders as well as injectable formulations used to relieve joint pain and administration of such drugs following organ transplants, is another common cause of hypoadrenocorticism. This exogenous form is referred to as iatrogenic Cushing’s syndrome.

Adrenal tumors, which may be benign or malignant, develop on the adrenal gland and prompt cortisol production. Cancerous adrenocortical carcinomas are the least common cause of hypoadrenocorticism.

Ectopic ACTH-producing tumors overproduce ACTH, which in turn triggers the production of cortisol by the adrenal gland. Such tumors are not located in the pituitary or adrenal glands. Instead, they develop in other parts of the body, such as in a lung, or other glands, such as the thyroid or the pancreas. This form of hypoadrenocorticism is referred to as ectopic Cushing’s syndrome)

While most cases of hypoadrenocorticism are not hereditary, there are incidences of familial Cushing’s syndrome in which younger individuals carry a genetic mutation that predisposes them to develop cortisol-producing tumors on one or more glands of the endocrine system.

Symptoms and Complications of Cushing’s Syndrome

The list of signs and symptoms that present with Cushing’s syndrome is lengthy. These indicators include:

• weight gain around the trunk
• Fatty accumulations superior to the clavicle bone
• Round appearance of the face
• Thin limbs
• muscle weakness
• Fatigue
• Easy bruising
• Thinning of the skin
• Facial redness
• Striae, or purple stretch marks, on the axillary region of the body
• Acne
• Excess facial and body hair growth and thinning hair on the scalp in women
• Amenorrhea in women
• Decreased libido
• Impotence and/or infertility in men
• Depression, anxiety or mood swings

Cushing’s syndrome is usually curable. However, when left untreated, complications ensue, some of which can have fatal repercussions. Complications of longterm hypercortisolism include:

• Myocardial infarction
• Stroke
• Hyperlipidemia
• Insulin resistance, prediabetes, type 2 diabetes
• Hypertension
• Osteoporosis
• Venous thromboembolism

Such complications emphasize the importance of testing all individuals who present with a physical appearance that may be indicative of hypoadrenocorticism in order to make a diagnosis and design a treatment plan. Patients who have hypoadrenocorticism may generate abnormal findings on general laboratory screenings, including elevated white blood cells and neutrophils on a complete blood count, hypokalemia on a metabolic profile or impaired function on a glucose tolerance test. Specific tests for Cushing’s syndrome must then be performed to make a diagnosis.

Diagnosing Cushing’s Syndrome

All tests for Cushing’s syndrome have limitations in that a number of factors can generate false-positive results. One such factor is the condition known as pseudo-Cushing’s. Pseudo-Cushing’s is a state in which an individual produces abnormally high levels of cortisol, but often does not present with the aforementioned physical attributes that are associated with Cushing syndrome. The causes of these elevations differ from those with true Cushing’s syndrome, and they include:

• Alcoholism
• Anorexia nervosa
• Chronic illnesses, such as acquired immunodeficiency syndrome
• Depression
• Obesity
• Pregnancy
• Polycystic ovarian syndrome

Pseudo-Cushing’s can affect the results of many Cushing’s tests, as can the use of certain drugs, such as oral contraceptives, and other medical conditions, such as hyperthyroidism.

To complicate matters further, as mentioned above, there are multiple potential causes of Cushing’s syndrome, and it is crucial to determine not only whether or not a patient actually has Cushing’s syndrome, but to determine the cause of their condition as well. Fortunately, there are multiple tests for diagnosing Cushing’s syndrome, and a testing sequence is the recommended method for attainting a diagnosis. First, one or more initial tests are performed to detect abnormal cortisol levels. Once abnormal levels are confirmed, then secondary tests are performed to determine the cause of the abnormal results.

Initial Tests:

24-Hour Urinary Free-Cortisol Test

The 24-hour urinary free-cortisol test provides a measurement of how much cortisol a patient’s body produces over the course of a 24-hour duration. This is typically the initial test performed to determine if a patient has hypoadrenocorticism. The normal reference range for the 24-hour urinary free-cortisol test is less than 40 to 50 ug/d. A result that exceeds this range is suggestive of Cushing’s syndrome. However, patients with early or mild cases may generate normal results on the 24-hour urinary free-cortisol test.

Low-Dose Dexamethasone Suppression Test

The low-dose dexamethasone suppression test evaluates how the cortisol-producing adrenal glands respond to the ACTH hormone. The testing procedure requires that the patient receives one milligram of dexamethasone, which is a synthetic glucocorticoid drug, in the evening, followed by a blood draw on the next morning. Normally, the dose of dexamethasone should suppress the production of ACTH during the overnight hours, resulting in a low morning serum cortisol level. However, if a patient does indeed have Cushing’s syndrome, then this normal response does not kick in, and thus their morning cortisol level will be abnormally high. A test result of 1.8 ug/dL or greater is a positive result. It is important to note that patients who slept poorly, who are currently under excessive emotional or physical stress or those who are obese may generate false-positive results on this test.

Late-Night Salivary Cortisol Test

The late-night salivary cortisol test measures cortisol levels in 1 mL of a patient’s saliva over the span of one hour, typically between 11 p.m. and midnight when cortisol production is low in patients without Cushing’s syndrome. A result that exceeds the normal reference range of 0.10 to 0.15 ug/dL is suggestive of Cushing’s syndrome.

If any of these initial tests generate positive results, repeat testing should be ordered to rule out false-positive results before proceeding to the secondary phase of testing. The secondary tests are performed to discern the cause of hypercortisolism.

Secondary Tests:

Corticotropin-Releasing Hormone Stimulation Test (CRH stimulation test)

This test measures the level of cortisol in the blood in response to the injection of a synthetic CRH. An initial blood sample is taken prior to the injection, and then additional blood samples are collected at intervals during the one to three hours that follow the injection. The result of this test helps the physician to determine the cause of a patient’s abnormal ACTH and cortisol secretion levels. As mentioned above, Cushing’s syndrome can result from pituitary adenomas or from ectopic tumors. The results of the CRH stimulation test can distinguish between pituitary adenoma, which will yield peaks in ACTH and cortisol levels on the CRH stimulation test, and ectopic Cushing’s syndrome, which will not exhibit these elevations.

High-Dose Dexamethasone Suppression Test

This test can also help to pinpoint the cause of a patient’s Cushing’s syndrome. The procedure for administering the high-dose dexamethasone test differs from that of the low-dose dexamethasone suppression test only in that the patient must take a higher dose – 8 mg – of dexamethasone. At this dose, patients whose test results reveal low morning serum cortisol levels may have pituitary tumors, whereas those with high morning serum cortisol levels may have adrenal tumors or ACTH-producing tumors elsewhere in the body, such as in the lungs.

Dexamethasone-Suppressed Corticotropin-Releasing Hormone Test

This test combines the dexamethasone suppression test with the CRH stimulation test with the goal of ruling out a pseudo-Cushing diagnosis. Patients with Cushing’s syndrome will have elevated cortisol levels, whereas those with pseudo-Cushing will not have elevated cortisol levels as a result of this test.

Petrosal Sinus Sampling Test

This invasive testing procedure is relegated only to patients for which a Cushing’s syndrome diagnosis has been confirmed. ACTH normally drains from the pituitary gland into the inferior petrosal sinus veins. For the petrosal sinus sampling test, blood samples are taken from these veins through a catheter. One sample is taken before the administration of corticotropin-releasing hormone, and then additional samples are taken at intervals over a short time span that follows the injection. The ACTH levels that are revealed in these samples are compared to those of samples that are taken from a peripheral vein. Higher ACTH levels in the samples taken from the petrosal sinus veins are indicative of pituitary adenoma. If the ACTH level in these samples is similar to that of the samples taken from the peripheral vein, then such a result is suggestive of ectopic Cushing’s syndrome.

Additional Screening Tests

Once a diagnosis of Cushing’s syndrome has been achieved, diagnostic imaging tests, such as magnetic resonance imaging, computed tomography and ultrasound, may be ordered to evaluate the patient’s lungs, abdominal organs and pituitary and adrenal glands for tumors, hyperplasia and other abnormalities.

Treatment for Hypoadrenocorticism

The treatment for hypoadrenocorticism depends upon the cause of the hypercortisolism. In the case of iatrogenic Cushing’s syndrome, a patient’s use of glucocorticoid drugs will likely need to be weaned down to the most minimal dose that can be sustained to effectively manage the condition for which he/she is taking the medication. Surgery to remove pituitary adenomas is the effective treatment method for patients with Cushing’s disease, and surgical removal is also performed when ACTH-producing tumors are diagnosed elsewhere in the body. Other treatment options for Cushing syndrome include radiation, chemotherapy and drug therapy to reduce the production of cortisol. Patients who are suspected to have Cushing’s syndrome are usually referred to an endocrinologist for testing, treatment and management plans.

Thanks to Johns Hopkins for the image.