Adrenocorticotropic Hormone (and Challenge Tests)

Synonym/Acronym:
Corticotropin, ACTH.

Rationale
To assist in the investigation of adrenocortical dysfunction using ACTH and cortisol levels in diagnosing disorders such as Addison disease, Cushing disease, and Cushing syndrome.

Patient Preparation
There are no food or fluid restrictions unless by medical direction. Drugs that enhance steroid metabolism may be withheld by medical direction before metyrapone stimulation testing. Instruct the patient to refrain from smoking, avoid alcohol use, avoid strenuous exercise for 12 hr before the test, and remain in bed or at rest for 1 hr immediately before the test. Samples should be collected at the same time of day, between 0600 and 0800.

Procedure	Indications	Medication Administered, Adult Dosage	Recommended Collection Times
ACTH stimulation, rapid test	Suspect adrenal insufficiency (Addison disease) or congenital adrenal hyperplasia	1 mcg (low-dose physiological protocol) cosyntropin intramuscular (IM) or IV; 250 mcg (standard pharmacological protocol) cosyntropin IM or IV	Three cortisol levels: Baseline immediately before bolus, 30 min after bolus, and 60 min (optional) after bolus. Baseline and 30-min levels are adequate for accurate diagnosis using either dosage; low-dose protocol sensitivity is most accurate for 30-min level only.
Corticotropin-releasing hormone (CRH) stimulation	Differential diagnosis between ACTH-dependent conditions such as Cushing disease (pituitary source) or Cushing syndrome (ectopic source) and ACTH-independent conditions such as Cushing syndrome (adrenal source)	IV dose of 1 mcg/kg human CRH	Eight cortisol and eight ACTH levels: Baseline collected 15 min before injection, 0 min before injection, and then 5, 15, 30, 60, 120, and 180 min after injection
Dexamethasone suppression (overnight)	Differential diagnosis between ACTH-dependent conditions such as Cushing disease (pituitary source) or Cushing syndrome (ectopic source) and ACTH-independent conditions such as Cushing syndrome (adrenal source)	Oral dose of 1 mg dexamethasone (Decadron) at 2300	Cortisol level at 0800 on the morning after the dexamethasone dose
Metyrapone stimulation (overnight)	Suspect hypothalamic/pituitary disease such as adrenal insufficiency, ACTH-dependent conditions such as Cushing disease (pituitary source) or Cushing syndrome (ectopic source), and ACTH-independent conditions such as Cushing syndrome (adrenal source)	Oral dose of 30 mg/kg metyrapone (up to a maximum of 3 g) with snack at 2400	Cortisol, 11-deoxycortisol, and ACTH at 0800 on the morning after the metyrapone dose

Normal Findings
Method: Immunochemiluminescent assay for ACTH and cortisol; high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) for 11-deoxycortisol.

ACTH

Age	Conventional Units	SI Units (Conventional Units × 0.22)
Cord blood	50–570 pg/mL	11–125 pmol/L
Newborn	10–185 pg/mL	2–41 pmol/L
1 wk–9 yr	5–46 pg/mL	1.1–10.1 pmol/L
10–18 yr	6–55 pg/mL	1.3–12.1 pmol/L
19 yr–Adult
Male supine (specimen collected in morning)	7–69 pg/mL	1.5–15.2 pmol/L
Female supine (specimen collected in morning)	6–58 pg/mL	1.3–12.8 pmol/L
Values may be unchanged or slightly elevated in healthy older adults. Long-term use of corticosteroids, to treat arthritis and autoimmune diseases, may suppress secretion of ACTH.

ACTH Challenge Tests

ACTH (Cosyntropin) Stimulated, Rapid Test	Conventional Units	SI Units (Conventional Units × 27.6)
Baseline	Cortisol greater than 5 mcg/dL	Greater than 138 nmol/L
30- or 60-min response	Cortisol 18–20 mcg/dL or incremental increase of 7 mcg/dL over baseline value	497–552 nmol/L or incremental increase of 193.2 nmol/L over baseline value

Corticotropin-Releasing Hormone Stimulated	Conventional Units	SI Units (Conventional Units × 27.6)
	Cortisol peaks at greater than 20 mcg/dL within 30–60 min	Greater than 552 nmol/L
		SI Units (Conventional Units × 0.22)
	ACTH increases twofold to fourfold within 30–60 min	Twofold to fourfold increase within 30–60 min

Dexamethasone Suppressed Overnight Test	Conventional Units	SI Units (Conventional Units × 27.6)
	Cortisol less than 1.8 mcg/dL next day	Less than 49.7 nmol/L

Metyrapone Stimulated Overnight Test	Conventional Units	SI Units (Conventional Units × 27.6)
	Cortisol less than 3 mcg/dL next day	Less than 83 nmol/L
		SI Units (Conventional Units × 0.22)
	ACTH greater than 75 pg/mL	Greater than 16.5 pmol/L
		SI Units (Conventional Units × 28.9)
	11-deoxycortisol greater than 7 mcg/dL	Greater than 202 nmol/L

Salivary Cortisol	Conventional Units
0700–0900	100–750 ng/dL
1500–1700	Less than 401 ng/dL
2300–midnight	Less than 100 ng/dL

24 hr Urine Free Cortisol by Age	Conventional Units

3–8 yr	1.4–20 mcg/24 hr
9–12 yr	2.6–37 mcg/24 hr
13–17 yr	4–56 mcg/24 hr
18 yr–adult	3.5–45 mcg/24 hr

Critical Findings and Potential Interventions
N/A

Overview

(Study type: Blood collected in a prechilled lavender-top [EDTA] tube for ACTH and from a prechilled red-top tube for cortisol and 11-deoxycortisol; related body system: Endocrine system.) Gold-, tiger-, and green-top (heparin) tubes are also acceptable for cortisol, but care must be taken to use the same type of collection container for serial measurements. Alternatively, specimens can be collected in a prechilled heparinized plastic syringe and carefully transferred into the appropriate tube types by gentle injection to avoid hemolysis. Immediately transport specimen, tightly capped and in an ice slurry, to the laboratory.

Hypothalamic-releasing factor stimulates the release of ACTH from the anterior pituitary gland. ACTH stimulates adrenal cortex secretion of glucocorticoids, androgens, and, to a lesser degree, mineralocorticoids. Cortisol is the major glucocorticoid secreted by the adrenal cortex. ACTH and cortisol test results are evaluated together because a change in one normally causes a change in the other.

Cortisol levels vary diurnally, with the peak values occurring between 0600 and 0800 and reaching the lowest levels between 2000 and 2400. Specimens are typically collected at 0800 and 1600. This pattern may be reversed in individuals who sleep during daytime hours and are active during nighttime hours. Cortisol excess from any source is termed Cushing syndrome. Three studies are recommended for assisting in the diagnosis of Cushing syndrome: late night (2300) salivary cortisol, 24-hr urine free cortisol, and overnight dexamethasone suppression test. Cortisol excess resulting from ACTH excess produced by the pituitary is termed Cushing disease. Salivary cortisol levels are known to parallel blood levels and can be used to screen for Cushing disease and Cushing syndrome.

ACTH levels exhibit a diurnal variation, peaking between 0600 and 0800 and reaching the lowest point between 1800 and 2300. Evening levels are generally one-half to two-thirds lower than morning levels. ACTH secretion is stimulated by insulin, metyrapone, and vasopressin. It is decreased by dexamethasone.

Indications

Determine adequacy of replacement therapy in congenital adrenal hyperplasia.
Determine adrenocortical dysfunction.
Differentiate between increased ACTH release with decreased cortisol levels and decreased ACTH release with increased cortisol levels.

Interfering Factors

Contraindications

The metyrapone stimulation test is contraindicated in patients with suspected adrenal insufficiency because it may induce an acute adrenal crisis, a life-threatening condition, in patients whose adrenal function is already compromised.

Factors that may alter the results of the study

Drugs and other substances that may increase ACTH levels include diuretics (spironolactone), gastrointestinal agents (metoclopramide), estrogens, insulin, vasopressin, and metyrapone.
Drugs and other substances that may decrease ACTH levels include corticosteroids (e.g., dexamethasone) and statins (pravastatin).
Excessive physical activity can produce elevated levels.
Test results are affected by the time the test is done because ACTH levels vary diurnally, with the highest values occurring between 0600 and 0800 and the lowest values occurring at night.

Rapid clearance of metyrapone, resulting in falsely increased cortisol levels, may occur if the patient is taking drugs that enhance steroid metabolism (e.g., corticosteroids, mitotane, phenytoin, phenobarbital, and rifampin). The requesting health-care provider (HCP) should be consulted prior to a metyrapone stimulation test regarding a decision to withhold these medications.

Other Considerations:

Metyrapone may cause gastrointestinal distress and/or confusion. Administer oral dose of metyrapone with milk and snack.

Potential Medical Diagnosis: Clinical Significance of Results

ACTH Result

Because ACTH and cortisol secretion exhibit diurnal variation with values being highest in the morning, a lack of change in values from morning to evening is clinically significant. Decreased concentrations of hormones secreted by the pituitary gland and its target organs are observed in hypopituitarism. In primary adrenal insufficiency (Addison disease), because of adrenal gland destruction by tumor, infectious process, or immune reaction, ACTH levels are elevated, while cortisol levels are decreased. Both ACTH and cortisol levels are decreased in secondary adrenal insufficiency (i.e., secondary to pituitary insufficiency). Excess ACTH can be produced ectopically by various lung cancers such as oat-cell cancer and large-cell cancer of the lung and by benign bronchial carcinoid tumor.

Challenge Tests and Results

The ACTH (cosyntropin) stimulated rapid test directly evaluates adrenal gland function and indirectly evaluates pituitary gland and hypothalamus function. Cosyntropin is a synthetic form of ACTH. A baseline cortisol level is collected before the injection of cosyntropin. Specimens are subsequently collected at 30- and 60-min intervals. If the adrenal glands function normally, cortisol levels rise significantly after administration of cosyntropin.

The CRH stimulation test works as well as the dexamethasone suppression test (DST) in distinguishing Cushing disease from conditions in which ACTH is secreted ectopically (e.g., tumors not located in the pituitary gland that secrete ACTH). Patients with pituitary tumors tend to respond to CRH stimulation, whereas those with ectopic tumors do not. Patients with adrenal insufficiency demonstrate one of three patterns depending on the underlying cause:

Primary adrenal insufficiency—high baseline ACTH (in response to IV-administered ACTH) and low cortisol levels pre- and post-IV ACTH.
Secondary adrenal insufficiency (pituitary)—low baseline ACTH that does not respond to ACTH stimulation. Cortisol levels do not increase after stimulation.
Tertiary adrenal insufficiency (hypothalamic)—low baseline ACTH with an exaggerated and prolonged response to stimulation. Cortisol levels usually do not reach 20 mcg/dL (SI = 552 nmol/L).

(The DST is useful in differentiating the causes of increased cortisol levels. Dexamethasone is a synthetic glucocorticoid that is significantly more potent than cortisol. It works by negative feedback. It suppresses the release of ACTH in patients with a normal hypothalamus. A cortisol level less than 1.8 mcg/dL [SI = 49.7 nmol/L] usually excludes Cushing syndrome. With the DST, a baseline morning cortisol level is collected, and the patient is given a 1-mg dose of dexamethasone at bedtime. A second specimen is collected the following morning. If cortisol levels have not been suppressed, adrenal adenoma is suspected. The DST also produces abnormal results in the presence of certain psychiatric illnesses [e.g., endogenous depression]).

The metyrapone stimulation test is used to distinguish corticotropin-dependent causes (pituitary Cushing disease and ectopic Cushing disease) from corticotropin-independent causes (e.g., cancer of the lung or thyroid) of increased cortisol levels. Metyrapone inhibits the conversion of 11-deoxycortisol to cortisol. Cortisol levels should decrease to less than 3 mcg/dL if normal pituitary stimulation by ACTH occurs after an oral dose of metyrapone. Specimen collection and administration of the medication are performed as with the overnight dexamethasone test.

Increased In:

Overproduction of ACTH can occur as a direct result of either disease (e.g., primary or ectopic tumor that secretes ACTH) or stimulation by physical or emotional stress, or it can be an indirect response to abnormalities in the complex feedback mechanisms involving the pituitary gland, hypothalamus, or adrenal glands.

ACTH Increased in

Addison disease (primary adrenocortical hypofunction)
Carcinoid syndrome
Congenital adrenal hyperplasia
Cushing disease (pituitary-dependent adrenal hyperplasia)
Cushing syndrome (ectopic secretion of ACTH)
Depression
Ectopic ACTH-producing tumors
Menstruation
Nelson syndrome (ACTH-producing pituitary tumors)
Pregnancy
Sepsis
Septic shock
Type 2 diabetes

Decreased In:

Secondary adrenal insufficiency due to hypopituitarism (inadequate production by the pituitary) can result in decreased levels of ACTH. Conditions that result in overproduction or availability of high levels of cortisol can also result in decreased levels of ACTH.

ACTH Decreased in

Adrenal adenoma
Adrenal cancer
Cushing syndrome
Exogenous steroid therapy

Summary of the Relationship Between Cortisol and ACTH Levels in Conditions Affecting the Adrenal and Pituitary Glands
Disease	Cortisol Level	ACTH Level
Addison disease (adrenal insufficiency)	Decreased	Increased
Cushing disease (pituitary adenoma)	Increased	Increased
Cushing syndrome related to ectopic source of ACTH	Increased	Increased
Cushing syndrome (ACTH independent; adrenal cancer or adenoma)	Increased	Decreased
Congenital adrenal hyperplasia	Decreased	Increased

Nursing Implications

Potential Nursing Problems Assessment and Nursing Diagnosis

Problems	Signs and Symptoms
Fluid volume (excess) *(related to retention of sodium and water secondary to cortisol excess)*	Weight gain, hypertension, tachycardia, edema, jugular vein distention, shortness of breath; abnormal blood gas results
Infection *(related to impaired immune response secondary to elevated cortisol level, collagen tissue loss, catabolism of peripheral tissues)*	Delayed wound healing, inhibited collagen formation, impaired blood flow to edematous tissues, symptoms of infection (temperature, increased heart rate, increased blood pressure, shaking, chills, mottled skin, lethargy, fatigue, swelling, edema, pain, localized pressure, diaphoresis, night sweats, confusion, vomiting, nausea, headache)
Injury *(related to poor wound healing, decreased bone density, capillary fragility)*	Easy bruising, blood in stool, skin breakdown, fracture, poor wound healing, thin skin
Mobility *(related to change in muscle and bone structure secondary to excess cortisol)*	Fatigue, muscle weakness, porous bones with fracture risk

Before the Study: Planning and Implementation

Teaching the Patient What to Expect

Explain that this test can assist in evaluating the amount of hormone produced by the pituitary gland located at the base of the brain.
Explain that a blood sample is needed for the test, samples are obtained at specific times to determine high and low levels of ACTH.
Explain that more than one blood sample may be necessary to ensure accurate results.
Instruct the patient to report any postadministration reaction to metyrapone (medication used in ACTH stimulation test).

Potential Nursing Actions

Weigh patient and report weight to the pharmacy for accurate dosing of ordered metyrapone per protocol.

After the Study: Potential Nursing Actions

Avoiding Complications

Observe/assess the patient who has been administered metyrapone for signs and symptoms of an acute adrenal (addisonian) crisis, which may include abdominal pain, anxiety, bone marrow depression, coma, confusion, decreased WBC count, dehydration, dizziness, sudden and significant fatigue or weakness, headache, hypotension, loss of consciousness, nausea and vomiting, excessively increased perspiration of the face and hands, shock, tachycardia, tachypnea.
Potential interventions for an acute adrenal crisis related to metyrapone include immediate corticosteroid replacement (IV or IM), airway protection and maintenance, administration of dextrose for hypoglycemia, correction of electrolyte imbalance, and rehydration with IV fluids.

Treatment Considerations

Fluid volume (excess): Monitor intake and output; assess for symptoms of fluid overload (shortness of breath, tachycardia, hypertension, positive jugular vein distention, edema). Monitor fluid and electrolytes for imbalance (K⁺, Na⁺). Monitor heart rate, blood pressure, daily weight. Low-sodium diet. Administer prescribed medications (antihypertensive, diuretics).
Infection: Decrease environmental exposure by placing the patient in a private room or isolation, as appropriate. Monitor and trend vital signs (heart rate, temperature, blood pressure) and laboratory values that would indicate an infection (WBC count, CRP). Promote good hygiene and assist as needed. Administer prescribed medications (antibiotics, antipyretics) and IV fluids. Use cooling measures and encourage oral fluids. Obtain ordered cultures. Encourage lightweight clothing and bedding.
Injury: Assess skin for bruising and breakdown, stool for occult blood, and wound healing progress. Facilitate ordered bone density screening.

Safety Considerations

Discuss adherence to the HCP’s request to wear a medic alert bracelet indicating adrenal insufficiency and steroid use.
Mobility: Assist with activity and complete activities of daily living. Evaluate the severity of mobility deficits and implement the use of assistive devices as needed to prevent fall risk or injury.

Followup Evaluation and Desired Outcomes

Acknowledges contact information provided for the Cushing’s Support and Research Foundation (https://csrf.net).
Understands that the results of this procedure may require additional testing to evaluate or monitor disease progression or necessary change in therapy. If a diagnosis of Cushing disease is made, pituitary CT or MRI may be indicated prior to surgery. If a diagnosis of ectopic corticotropin syndrome is made, abdominal CT or MRI may be indicated prior to surgery.
Agrees to adhere to the HCP’s request to increase oral fluid intake with a diet high in sodium and low in potassium (Addison disease).
Adheres to the prescribed administration of steroids and understands the necessity of altering the medication regime during times of illness and stress.

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