Adrenocorticotropic Hormone (and Challenge Tests)

General

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
Single ACTH level: Samples should be collected at the same time of day, between 0600 and 1000.

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; or 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. Note: 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 (up to a maximum of 100 mcg)	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)	Low dose: Oral dose of 1 mg dexamethasone (Decadron) at 2300 *High dose (overnight test* where a second, higher dose is given if cortisol level after low-dose test is not suppressed):** Oral dose of 8 mg dexamethasone (Decadron) at 2300	Cortisol level at 0800 on the morning after the dexamethasone dose

Normal Findings
Method: Electrochemiluminescent immunoassay for ACTH and cortisol.

ACTH

Age	Conventional Units	SI Units (Conventional Units × 0.22)
Birth to adult (specimen collected in morning)	7–62 pg/mL	1.5–13.6 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 two- to fourfold within 30–60 min	Two- to fourfold increase within 30–60 min

Dexamethasone Suppressed Overnight Test	Conventional Units	SI Units (Conventional Units × 27.6)
	Low dose: Cortisol less than 2 mcg/dL next dayHigh dose: An overnight decrease of greater than 50% from baseline	Less than 55.2 nmol/L

Critical Findings and Potential Interventions
N/A

Overview

(Study type: Blood collected in a prechilled lavender-top [EDTA] tube for ACTH and in a prechilled red-top tube for cortisol; 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. Immediately transport specimen, tightly capped and in an ice slurry, to the laboratory.

The hypothalamic-releasing factor, corticotropin-releasing hormone (CRH), 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 often evaluated together because a change in one normally causes a change in the other. Primary adrenal insufficiency is indicated by an increased ACTH level with a corresponding low cortisol level. Secondary adrenal insufficiency (related to a dysfunction of the pituitary gland or hypothalamus) is suspected if the ACTH level is not elevated.

ACTH and cortisol are also measured together because cortisol and ACTH levels vary diurnally, with the peak values in both hormones occurring between 0600 and 0800 and reaching the lowest levels between 2200 and 2400. Bursts of cortisol excretion can occur at night. This diurnal pattern may be reversed in individuals who sleep during daytime hours and are active during nighttime hours. Cortisol levels are typically collected at 0800 (peak) and 1600 (trough); ACTH specimens are typically collected between 0600 and 1000.

Cortisol excess from any source is termed Cushing syndrome. Cortisol excess resulting from ACTH excess produced by the pituitary is termed Cushing disease.

Two other studies that measure cortisol are recommended for assisting in the diagnosis of Cushing syndrome: late-night (2300) salivary cortisol and 24-hr urine free cortisol. Salivary cortisol levels are known to parallel blood levels and have superior sensitivity as an early indicator of Cushing syndrome. For additional information, refer to the study titled “Cortisol Studies.” The health-care provider (HCP) may also request CT scan or MRI to confirm the presence of tumors affecting normal adrenal function.

Challenge testing (stimulation and suppression) with measurements of ACTH and cortisol is used to form a differential diagnosis for determining the cause of adrenal insufficiency, tumor (adrenal or pituitary), and abnormal production of cortisol (too much or too little). ACTH secretion is stimulated by cosyntropin and CRH. It is suppressed 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

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.

Potential Medical Diagnosis: Clinical Significance of Results

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.

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

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.

Adrenal adenoma
Adrenal cancer
Cushing syndrome
Exogenous steroid therapy

Challenge Tests and Results

ACTH (cosyntropin) stimulated rapid test
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.

CRH stimulation test
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).

DST
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).

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

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 small-cell lung cancer (oat-cell cancer) and large-cell cancer of the lung and by benign bronchial carcinoid tumor.

Nursing Implications, Nursing Process, Clinical Judgement

Potential Problems: Assessment & Nursing Diagnosis/Analysis

Problems	Signs and Symptoms
Body image *(related to increased androgen production, disturbed protein metabolism, altered bone structure)*	Virilism, hirsutism (abnormal hair growth in women), muscle wasting, fragile capillaries, bone matrix wasting, ecchymosis, osteoporosis, slender limbs, purple striae, abnormal fat distribution, edema with moon face, buffalo hump back (cervicodorsal fat), trunk obesity, preoccupation with physical changes, changed social interactions, hides body part
Fluid volume *(excess—related to retention of sodium and water secondary to cortisol excess, mineralocorticoid excess)*	Weight gain, hypertension, tachycardia, edema, jugular vein distention, shortness of breath, crackles in lungs, abnormal blood gas results, hypokalemia, hypernatremia

Before the Study: Planning and Implementation

Teaching the Patient What to Expect

Discuss how 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 and that samples are obtained at specific times to determine high and low levels of ACTH; if challenge testing is requested, cortisol levels will also be evaluated. More than one blood sample may be necessary to ensure accurate results.
Instruct the patient to report any postadministration reaction to the ACTH challenge drug used for the study.

Potential Nursing Actions

Weigh patient and report weight to the pharmacy for accurate dosing of ACTH challenge drug to be used for the study.
Instruct the patient to minimize stress to avoid raising cortisol levels, if challenge testing is requested.

After the Study: Implementation & Evaluation Potential Nursing Actions

Avoiding Complications

Observe/assess the patient for side effects of ACTH stimulation. Side effects of cosyntropin administration include nausea, sweating, anxiety, dizziness that can be severe, injection site redness and swelling, itchy skin, palpitations, facial flushing, difficulty breathing, headache, blurry vision, and severe swelling. Administration of CRH is usually well tolerated; the most common side effect is brief facial flushing.
Observe/assess the patient for side effects of ACTH suppression. Administration of dexamethasone is usually well tolerated.

Treatment Considerations

Body Image

Facilitate management of body image concerns.
Interventions/actions related to body image include the following: Assess for any notable physical changes. Discuss feelings related to changes if present, including coping. Suggest referral to support groups to mitigate concerns, and facilitate emotional adjustment toward physical changes.

Fluid Volume

Facilitate management of fluid volume excess.
Interventions/actions related to fluid volume excess include the following: Assess for symptoms of fluid overload (shortness of breath, tachycardia, hypertension, positive jugular vein distention, edema). Monitor and trend intake and output, heart rate, blood pressure, daily weight, fluid, and electrolytes for imbalance (K⁺, Na⁺). Facilitate a low-sodium diet. Administer prescribed medications (antihypertensive, diuretics).

Safety Considerations

Discuss adherence to the HCP’s request to wear a medic alert bracelet indicating adrenal insufficiency and steroid use.
Interventions/actions related to the management of fall risk include the following: Evaluate the severity of mobility deficits. Implement the use of assistive devices, shoes, and nonskid slippers. Provide activity assistance as needed.
Interventions/actions related to the management of skin risk include the following: Promote of good hygiene. Monitor and trend vital signs and laboratory values that would indicate an infection. Place in a private room or isolation, as appropriate. Frequently assess for bruising and breakdown; observe wound healing progress. Turn every 2 hr.

Clinical Judgement

Consider the best way to support self-esteem, facilitate social interactions, and normalize lifestyle choices.

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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