ACTH stimulation test
Encyclopedia
The ACTH stimulation test (also called the cosyntropin
test, tetracosactide
test or Synacthen test) is a medical test
usually ordered and interpreted by endocrinologists to assess the functioning of the adrenal gland
s stress response by measuring the adrenal response to adrenocorticotropic hormone
(ACTH). ACTH is a hormone produced in the pituitary gland
that stimulates the adrenal glands to release cortisol
.
During the test, a small amount of synthetic ACTH is injected, and the amount of cortisol, and sometimes aldosterone
, the adrenals produce in response is measured. This test may cause mild to moderate side effects in some individuals.
This test is used to diagnose or exclude primary and secondary adrenal insufficiency
, Addison's disease
and related conditions. In addition to quantifying adrenal insufficiency, the test can distinguish whether the cause is adrenal (low cortisol and aldosterone production) or pituitary (low ACTH production). The ACTH stimulation test is recognized as the gold standard assay of adrenal insufficiency, although this test is primarily used to determine the presence of Addison's disease and pituitary impairment. If the test does not show Addison's, the test interpreter may see it as showing the adrenal glands are working, not recognizing any degree of adrenal insufficiency between Addison's (the worst degree of adrenal insufficiency) and healthy adrenal function. The test is extremely sensitive (97% at 95% specificity) to primary adrenal insufficiency, but less so to secondary adrenal insufficiency (57-61% at 95% specificity); while secondary adrenal insufficiency may thus be dismissed by some interpreters on the basis of the test, additional testing may be called for if probability of secondary adrenal insufficiency is particularly high.
Adrenal insufficiency is a potentially life-threatening condition. Treatment should be initiated as soon as the diagnosis is confirmed, or sooner if the patient presents in apparent adrenal crisis.
In the low-dose short test, 1 µg of an ACTH drug is injected into the patient. In the conventional-dose short test, 250 µg of drug are injected. Both of these short tests last for about an hour and provide the same information. Studies have shown the cortisol response of the adrenals is the same for the low-dose and conventional-dose tests.
The prolonged-stimulation test, which is also called a long conventional-dose test, can last up to 48 hours. This form of the test can differentiate between primary, secondary, and tertiary adrenal insufficiency. This form of the test is rarely performed because earlier testing of cortisol and ACTH levels in association with the short test may provide all the necessary information.
. Spironolactone
, contraceptives, licorice, estrogen
, androgen
(including DHEA) and progesterone
therapy may also affect both aldosterone and cortisol stimulation test results. To stimulate aldosterone, added salt and foods significant in sodium must be avoided for 24 hours prior to testing. Women should ideally undergo testing during the first week of their menstrual cycle as aldosterone (and occasionally cortisol) may be falsely elevated in the luteal cycle secondary to progesterone inhibition, leading to a compensatory rise in aldosterone levels.
or Cortrosyn aka Cosyntropin
) is injected. Approximately 20 mL of heparinized venous blood is collected at 30 and 60 minutes after the synthetic ACTH injection to measure cortisol levels.
All blood samples are kept on ice and sent immediately to the laboratory for testing.
Although uncommon, some people report feeling better or sense of well being after the test.
Interpretation for primary adrenal insufficiency and Addison's disease
The baseline cortisol level in people with adrenal insufficiency is usually near 15 ug/dl. An ACTH stimulation test that raises the cortisol concentration to 20 ug/dl would support the diagnosis of primary adrenal insufficiency
. In Addison's disease, baseline cortisol is well below 10 ug/dl and rises no more than 25 percent.
Interpretation for secondary adrenal insufficiency
ACTH may dramatically stimulate cortisol from the low baseline value encountered in patients suffering from secondary adrenal insufficiency. Stimulation resulting in a greater than 14-fold increase in serum concentration over 30 minutes has been reported, although more typically serum cortisol levels will double or triple from baseline. The lower the baseline cortisol, the more likely it is that the patient's cortisol will increase by a large amount.
In some instances, a second test can suggest primary adrenal insufficiency (cortisol value less than doubled). The diagnosis may be changed from secondary to primary adrenal insufficiency or to include primary adrenal insufficiency. In secondary adrenal insufficiency, if the adrenal glands lack ACTH for enough time, cortisol production can atrophy
and fail to rise to a value at least double the base cortisol value. It is proper to continue with the diagnosis of secondary adrenal insufficiency.
If secondary adrenal insufficiency is diagnosed, the insulin tolerance test (ITT) or the CRH (Corticotropin-releasing hormone
) stimulation test can be used to distinguish between a hypothalamic (tertiary) and pituitary (secondary) cause, but is rarely used in clinical practice.
An ACTH plasma test should always be given at the same time as the ACTH stimulation, although many doctors consider the test inaccurate. This test measures how much ACTH the pituitary gland is producing. A healthy ACTH value should be just into the upper third of the range (assuming a range of 10–60 ng/L). The ACTH plasma and ACTH stimulation test together can give a clearer picture, especially for secondary adrenal insufficiency.
Interpretation for primary adrenal insufficiency and Addison's disease
ACTH will be high - either at the top or above range. In Addison's disease, ACTH may be way above range and may reach the hundreds. In very rare cases can reach the 1000s and 2000s.
Interpretation for secondary adrenal insufficiency
ACTH will be low - Usually below 35, but most people with secondary fall within the range limit. Although uncommon, values for ACTH can reach into the low 40s.
In some cases, actual cause of low ACTH is from low CRH in the hypothalamus. It is possible to have separate ACTH and CRH impairment such as can happen in a head injury.
is present. Human ACTH has a slight stimulatory effect on aldosterone, but the amount of synthetic ACTH given in the stimulation is equivalent to more than a whole days production of natural ACTH, so the aldosterone response can be easily measured in blood serum. Same as cortisol, aldosterone should double from a respectable base value (around 20 ng/dl, must fast salt 24 hours and sit upright for blood draw) in a healthy individual.
Interpretation for primary aldosterone deficiency
The aldosterone response in the ACTH stimulation test is blunted or absent in patients with primary adrenal insufficiency including Addison's disease. The base value is usually in the mid teens or less and rise to less than double the base value thus indicating primary hypoaldosteronism (sodium
low, potassium
and renin enzyme
will be high) and is an indicator of primary adrenal insufficiency or Addison's disease.
Interpretation for secondary aldosterone deficiency
Aldosterone response of several factors from a low base value. This factoring indicates secondary hypoaldosteronism (sodium low, potassium and renin enzyme will be low). Usually doubling to quadrupling from a low base aldosterone value is what is seen in secondary adrenal insufficiency. Decupling of aldosterone in the ACTH stimulation test is possible (i.e. 2 ng/dl stimming to 20). A result of doubling of more of aldosterone may help in tandem with a cortisol stimulation that doubled or more confirm a diagnosis of secondary adrenal insufficiency. In rare cases, an aldosterone stimulation which did not double, but with the presence of low potassium, low renin and low ACTH indicates atrophy of aldosterone production from the prolonged lack of renin.
Similar to the cortisol stimulation in ACTH deficiency, the test interpreter may lack knowledge of how to properly interpret for secondary hypoaldosteronism and think a result of aldosterone doubling or more from a low base value is good.
Cosyntropin
Cosyntropin is a synthetic derivative of adrenocorticotropic hormone that is used in the ACTH stimulation test to evaluate and diagnose cortisol disorders...
test, tetracosactide
Tetracosactide
Tetracosactide is a synthetic analogue of the naturally occurring adrenocorticotrophic hormone .-Pharmacology:...
test or Synacthen test) is a medical test
Medical test
A diagnostic test is any kind of medical test performed to aid in the diagnosis or detection of disease. For example:* to diagnose diseases, and preferably sub-classify it regarding, for example, severity and treatability...
usually ordered and interpreted by endocrinologists to assess the functioning of the adrenal gland
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
s stress response by measuring the adrenal response to adrenocorticotropic hormone
Adrenocorticotropic hormone
Adrenocorticotropic hormone , also known as 'corticotropin', 'Adrenocorticotrophic hormone', is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It is an important component of the hypothalamic-pituitary-adrenal axis and is often produced in response to biological...
(ACTH). ACTH is a hormone produced in the pituitary gland
Pituitary gland
In vertebrate anatomy the pituitary gland, or hypophysis, is an endocrine gland about the size of a pea and weighing 0.5 g , in humans. It is a protrusion off the bottom of the hypothalamus at the base of the brain, and rests in a small, bony cavity covered by a dural fold...
that stimulates the adrenal glands to release cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
.
During the test, a small amount of synthetic ACTH is injected, and the amount of cortisol, and sometimes aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
, the adrenals produce in response is measured. This test may cause mild to moderate side effects in some individuals.
This test is used to diagnose or exclude primary and secondary adrenal insufficiency
Adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
, Addison's disease
Addison's disease
Addison’s disease is a rare, chronic endocrine disorder in which the adrenal glands do not produce sufficient steroid hormones...
and related conditions. In addition to quantifying adrenal insufficiency, the test can distinguish whether the cause is adrenal (low cortisol and aldosterone production) or pituitary (low ACTH production). The ACTH stimulation test is recognized as the gold standard assay of adrenal insufficiency, although this test is primarily used to determine the presence of Addison's disease and pituitary impairment. If the test does not show Addison's, the test interpreter may see it as showing the adrenal glands are working, not recognizing any degree of adrenal insufficiency between Addison's (the worst degree of adrenal insufficiency) and healthy adrenal function. The test is extremely sensitive (97% at 95% specificity) to primary adrenal insufficiency, but less so to secondary adrenal insufficiency (57-61% at 95% specificity); while secondary adrenal insufficiency may thus be dismissed by some interpreters on the basis of the test, additional testing may be called for if probability of secondary adrenal insufficiency is particularly high.
Adrenal insufficiency is a potentially life-threatening condition. Treatment should be initiated as soon as the diagnosis is confirmed, or sooner if the patient presents in apparent adrenal crisis.
Versions of the test
This test can be given as a low-dose short test, a conventional-dose short test, or as a prolonged-stimulation test.In the low-dose short test, 1 µg of an ACTH drug is injected into the patient. In the conventional-dose short test, 250 µg of drug are injected. Both of these short tests last for about an hour and provide the same information. Studies have shown the cortisol response of the adrenals is the same for the low-dose and conventional-dose tests.
The prolonged-stimulation test, which is also called a long conventional-dose test, can last up to 48 hours. This form of the test can differentiate between primary, secondary, and tertiary adrenal insufficiency. This form of the test is rarely performed because earlier testing of cortisol and ACTH levels in association with the short test may provide all the necessary information.
Preparation
The person must fast at least 8 hours before the test which should be started by 10 am, but as close to 7 am as possible. The test shouldn't be given if on glucocorticoids, or adrenal extract supplement as these will affect test results. Stress and recently administered radioisotope scans can artificially increase levels and may invalidate test resultsSpironolactone
Spironolactone , commonly referred to as simply spiro, is a diuretic and is used as an antiandrogen.It is a synthetic 17-lactone drug that is a renal competitive aldosterone antagonist in a class of pharmaceuticals called...
, contraceptives, licorice, estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
, androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
(including DHEA) and progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
therapy may also affect both aldosterone and cortisol stimulation test results. To stimulate aldosterone, added salt and foods significant in sodium must be avoided for 24 hours prior to testing. Women should ideally undergo testing during the first week of their menstrual cycle as aldosterone (and occasionally cortisol) may be falsely elevated in the luteal cycle secondary to progesterone inhibition, leading to a compensatory rise in aldosterone levels.
Administration
Traditionally, cortisol and ACTH levels (separate lavender top tube) are drawn at baseline (time = 0). Next, synthetic ACTH (Synacthen aka TetracosactideTetracosactide
Tetracosactide is a synthetic analogue of the naturally occurring adrenocorticotrophic hormone .-Pharmacology:...
or Cortrosyn aka Cosyntropin
Cosyntropin
Cosyntropin is a synthetic derivative of adrenocorticotropic hormone that is used in the ACTH stimulation test to evaluate and diagnose cortisol disorders...
) is injected. Approximately 20 mL of heparinized venous blood is collected at 30 and 60 minutes after the synthetic ACTH injection to measure cortisol levels.
All blood samples are kept on ice and sent immediately to the laboratory for testing.
Potential side effects
Commonly reported reactions are nausea, anxious sweating, dizziness, itchy skin, redness and or swelling of injection site, palpitations (a fast or fluttering heart beat) and facial flushing (may also include arms and torso), but should disappear within a few hours. Rarely seen, but serious side effects include rash, fainting, headache, blurred vision, severe swelling, severe dizziness, trouble breathing, irregular heartbeat.Although uncommon, some people report feeling better or sense of well being after the test.
Interpretation of results
Cortisol stimulation
In healthy individuals, the cortisol level should double from a baseline of 20-30 ug/dl within 60 minutes. For example, if the serum cortisol level was 25 ug/dl before the stimulation, it should reach at least 50 ug/dl.Interpretation for primary adrenal insufficiency and Addison's disease
The baseline cortisol level in people with adrenal insufficiency is usually near 15 ug/dl. An ACTH stimulation test that raises the cortisol concentration to 20 ug/dl would support the diagnosis of primary adrenal insufficiency
Adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
. In Addison's disease, baseline cortisol is well below 10 ug/dl and rises no more than 25 percent.
Interpretation for secondary adrenal insufficiency
ACTH may dramatically stimulate cortisol from the low baseline value encountered in patients suffering from secondary adrenal insufficiency. Stimulation resulting in a greater than 14-fold increase in serum concentration over 30 minutes has been reported, although more typically serum cortisol levels will double or triple from baseline. The lower the baseline cortisol, the more likely it is that the patient's cortisol will increase by a large amount.
In some instances, a second test can suggest primary adrenal insufficiency (cortisol value less than doubled). The diagnosis may be changed from secondary to primary adrenal insufficiency or to include primary adrenal insufficiency. In secondary adrenal insufficiency, if the adrenal glands lack ACTH for enough time, cortisol production can atrophy
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
and fail to rise to a value at least double the base cortisol value. It is proper to continue with the diagnosis of secondary adrenal insufficiency.
If secondary adrenal insufficiency is diagnosed, the insulin tolerance test (ITT) or the CRH (Corticotropin-releasing hormone
Corticotropin-releasing hormone
Corticotropin-releasing hormone , originally named corticotropin-releasing factor , and also called corticoliberin, is a polypeptide hormone and neurotransmitter involved in the stress response...
) stimulation test can be used to distinguish between a hypothalamic (tertiary) and pituitary (secondary) cause, but is rarely used in clinical practice.
ACTH plasma test plus cortisol stimulation
Interpretation for primary adrenal insufficiency and Addison's disease
ACTH will be high - either at the top or above range. In Addison's disease, ACTH may be way above range and may reach the hundreds. In very rare cases can reach the 1000s and 2000s.
Interpretation for secondary adrenal insufficiency
ACTH will be low - Usually below 35, but most people with secondary fall within the range limit. Although uncommon, values for ACTH can reach into the low 40s.
In some cases, actual cause of low ACTH is from low CRH in the hypothalamus. It is possible to have separate ACTH and CRH impairment such as can happen in a head injury.
Aldosterone stimulation
The ACTH stimulation test is occasionally used to test adrenal production of aldosterone at the same time as cortisol to also help in determining if primary (hyperreninemic) or secondary (hyporeninemic) hypoaldosteronismHypoaldosteronism
In medicine , hypoaldosteronism refers to decreased levels of the hormone aldosterone.The term "isolated hypoaldosteronism" is used to describe lowered aldosterone without corresponding changes in cortisol...
is present. Human ACTH has a slight stimulatory effect on aldosterone, but the amount of synthetic ACTH given in the stimulation is equivalent to more than a whole days production of natural ACTH, so the aldosterone response can be easily measured in blood serum. Same as cortisol, aldosterone should double from a respectable base value (around 20 ng/dl, must fast salt 24 hours and sit upright for blood draw) in a healthy individual.
Interpretation for primary aldosterone deficiency
The aldosterone response in the ACTH stimulation test is blunted or absent in patients with primary adrenal insufficiency including Addison's disease. The base value is usually in the mid teens or less and rise to less than double the base value thus indicating primary hypoaldosteronism (sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
low, potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
and renin enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
will be high) and is an indicator of primary adrenal insufficiency or Addison's disease.
Interpretation for secondary aldosterone deficiency
Aldosterone response of several factors from a low base value. This factoring indicates secondary hypoaldosteronism (sodium low, potassium and renin enzyme will be low). Usually doubling to quadrupling from a low base aldosterone value is what is seen in secondary adrenal insufficiency. Decupling of aldosterone in the ACTH stimulation test is possible (i.e. 2 ng/dl stimming to 20). A result of doubling of more of aldosterone may help in tandem with a cortisol stimulation that doubled or more confirm a diagnosis of secondary adrenal insufficiency. In rare cases, an aldosterone stimulation which did not double, but with the presence of low potassium, low renin and low ACTH indicates atrophy of aldosterone production from the prolonged lack of renin.
Similar to the cortisol stimulation in ACTH deficiency, the test interpreter may lack knowledge of how to properly interpret for secondary hypoaldosteronism and think a result of aldosterone doubling or more from a low base value is good.
Other hormones and chemicals that will rise in the ACTH stimulation test
- ProgesteroneProgesteroneProgesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
- precursor to cortisol and aldosterone - Luteinizing hormoneLuteinizing hormoneLuteinizing hormone is a hormone produced by the anterior pituitary gland. In females, an acute rise of LH called the LH surge triggers ovulation and development of the corpus luteum. In males, where LH had also been called interstitial cell-stimulating hormone , it stimulates Leydig cell...
- a pituitary hormone that stimulates sex hormone production - 21-Hydroxylase21-HydroxylaseSteroid 21-hydroxylase is a cytochrome P450 enzyme that is involved with the biosynthesis of the steroid hormones aldosterone and cortisol.In humans, 21-Hydroxylase is encoded by the gene CYP21A2.-Names and classification:...
- DHEA and DHEA-S (an androgen hormone produced in the adrenal glands)
Simple diagnostic chart
| Source of pathology | CRH | ACTH | DHEA | DHEA-S | cortisol | aldosterone | renin | Na | K | Causes5 |
| hypothalamus (tertiary)1 |
low | low | low | low | low3 | low | low | low | low | tumor of the hypothalamus (adenoma), antibodies, environment, head injury |
| pituitary (secondary) |
high2 | low | low | low | low3 | low | low | low | low | tumor of the pituitary (adenoma), antibodies, environment, head injury, surgical removal6, Sheehan's syndrome |
| adrenal glands (primary)7 |
high | high | high | high | low4 | low | high | low | high | tumor of the adrenal (adenoma), stress, antibodies, environment, Addison's, injury, surgical removal |
| 1 | Automatically includes diagnosis of secondary (hypopituitarism) |
| 2 | Only if CRH production in the hypothalamus is intact |
| 3 | Value doubles or more in stimulation |
| 4 | Value less than doubles in stimulation |
| 5 | Most common, doesn't include all possible causes |
| 6 | Usually because of very large tumor (macroadenoma) |
| 7 | Includes Addison's disease |
See also
- Insulin tolerance testInsulin tolerance testAn insulin tolerance test is a medical diagnostic procedure during which insulin is injected into a patient's vein to assess pituitary function, adrenal function, and sometimes for other purposes. An ITT is usually ordered and interpreted by endocrinologists.Insulin injections are intended to...
, another test used to identify sub-types of adrenal insufficiency - MetyraponeMetyraponeMetyrapone is a drug used in the diagnosis of adrenal insufficiency and occasionally in the treatment of Cushing's syndrome .-Mechanism:...
, a drug used in the diagnosis of adrenal insufficiency - Triple bolus testTriple bolus testA triple bolus test or a dynamic pituitary function test is a medical diagnostic procedure used to assess a patient's pituitary function.A triple bolus test is usually ordered and interpreted by endocrinologists....
- ReninReninRenin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
, enzyme that converts Angiotensinogen to Angiotensin I, a precursor to Aldosterone - Renin-angiotensin-aldosterone system
- HPA axis, explains the connections of the hypothalamus, pituitary and adrenal glands
- HypopituitarismHypopituitarismHypopituitarism is the decreased secretion of one or more of the eight hormones normally produced by the pituitary gland at the base of the brain...
- Pituitary adenomaPituitary adenomaPituitary adenomas are tumors that occur in the pituitary gland, and account for about 15% of intracranial neoplasms. Tumors which exceed 10 mm in size are defined as macroadenomas, and those smaller than 10 mm are referred to as microadenomas...
- adrenal adenomaAdrenal adenomaA adrenal adenoma is a benign tumor of the glandular type in the adrenal gland. While some adrenal adenomas do not secrete hormones at all , some secrete cortisol , aldosterone , or androgens ....
- corticorelinCorticorelinCorticorelin is a diagnostic agent. It is a corticotropin-releasing hormone.The corticorelin stimulation test helps to differentiate between the etiologies of ACTH-dependent hypercortisolism...
External links
- ACTH (cosyntropin) stimulation test - based on information from Medline Plus Medical Encyclopedia
- ACTH stimulation test - Procedures/Diagnostic tests Warren Grant Magnuson Clinical Center National Institutes of HealthNational Institutes of HealthThe National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
.