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The ACTH stimulation test (also called the Cortrosyn (aka Cosyntropin) or Synacthen test) is a medical test usually ordered and interpreted by endocrinologists to assess the functioning of the adrenal glands stress response by measuring the adrenal response to ACTH adrenocorticotropic hormone.[1][2] ACTH is a hormone produced in the pituitary gland that stimulates the adrenal glands to release cortisol.[2] Specifically, the test is used to diagnose or exclude primary and secondary adrenal insufficiency, Addison's disease and related conditions.[2] It involves the injection of synthetic ACTH (Cortrosyn or Synacthen) and measures the amount of cortisol, and sometimes aldosterone, the adrenals produce in response.[3] Apart from objectivating adrenal insufficiency, the test can distinguish whether the cause is adrenal (low cortisol and aldosterone production) or pituitary (low ACTH production).[1]

This test can be given as a low dose short test (1 microgram of Cortrosyn or Synacthen) (ie short Synacthen test) or conventional dose short test (250 micrograms). Studies have shown there is no significant difference between the low dose and conventional dose of Cortrosyn or Synacthen in the measured stress response of the adrenals.[4]

Prolonged stimulation with exogenous ACTH is used to differentiate between primary and secondary or tertiary adrenal insufficiency, but is rarely given (as a long conventional dose test which can last up to 48 hours) because earlier testing of cortisol and ACTH levels in association with the short test may provide all necessary information.[5]

The ACTH stimulation test is recognized by the medical community as the final say in whether or not an individual has a degree of adrenal insufficiency, although this test is primarily used to determine the presence of Addison's disease and pituitary impairment.[6] If the test does not show Addison's (for example, in true Addison's, the stimulation may start at 3 ug/dl and rise to 4 ug/dl or 6 ug/dl rising to 8 ug/dl), the test interpreter may see the it as showing the adrenal glands are working, not recognizing any degree of adrenal insufficiency between Addison's (the worst degree of adrenal insufficiency which can cause death) and healthy adrenal function.

Secondary adrenal insufficiency is often missed by uninformed interpreters of this test. They may see doubling or more of a low base cortisol value along with low ACTH being okay or even great, not recognizing this indicates low ACTH production.

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 adrenal crisis.[5]

This test may cause mild to moderate side effects[1] in some individuals.[7][8]

Method of preparation and administration

  • 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.[9] The test shouldn't be given if on glucocorticoids, pregnenolone, or adrenal extract supplement as these will affect test results. Stress and recently administered radioisotope scans can artificially increase levels and may invalidate test results. Spironolactone, contraceptives, licorice, estrogen, androgen (including DHEA) and progesterone therapy may also affect both aldosterone and cortisol stimulation test results.[10][11] If aldosterone is to be stimulated, salt and foods significant in sodium must be fasted for 24 hours prior to testing. This allows aldosterone to rise as far as possible. Women must test the first week of their cycle or aldosterone (and occasionally cortisol) results may appear ok in the last half of the cycle when progesterone is higher (progesterone breaks down into aldosterone and cortisol).[12]
  • Administration
    Blood is drawn to get a starting or base cortisol (plasma ACTH is also tested from this draw) and or aldosterone level. Next, synthetic ACTH (Synacthen aka Tetracosactide 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.[13][14]
    All blood samples are kept on ice and sent immediately to the laboratory for testing.[9]

Potential side effects

These are normal reactions, but should be reported. These side effects should disappear in a few hours.[7][8]

  • nausea
  • anxiety
  • sweating
  • dizziness
  • itchy skin
  • redness and or swelling of injection site
  • palpitations (a fast or fluttering heart beat).
  • facial flushing (may also include arms and torso)

These side effects are rare, but emergency care must be sought immediately if these reactions are present.[8]

  • 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 for cortisol stimulation

Location of the adrenal glands
Click to enlarge photo

In healthy individuals, the cortisol level should double from a value at least in the 20s within 60 minutes. If the cortisol level was a 25 before the stimulation (base level), after the stimulation it should reach at least 50 ug/dl.

  • Interpretation for primary adrenal insufficiency and Addison's disease
The base cortisol level in people with adrenal insufficiency is usually in the mid teens. If the ACTH stimulation test raises cortisol level to 20 ug/dl, that is not doubling and supports the diagnosis of primary adrenal insufficiency. In Addison's, base cortisol is well below 10 ug/dl and rises no more than 25 percent.
  • Interpretation for secondary adrenal insufficiency
Cortisol stimulates by a factor doubling, tripling, quadrupling or more from a low base value. Other examples of multiple factoring reported include quintupling (5 stimulating to 25 ng/dl, 6 to 30), sextupling (4 ug/dl stimulating to 24, 4.1 to 26.9, 5 to 30), septupling (0.7 ug/dl stimulating to 4.9), decupling (2 ug/dl stimulating to 20, 2.7 to 27.6), tridecupling (1.25 ug/dl stimulating to 16, a factor of 12.8) and quadecupling (1.7 ug/dl stimulating to 24, after 1 1/2 hours reached 27.5 for sexdecupling). These examples illustrate how extreme the ACTH stimulation test result can be in secondary adrenal insufficiency, but most secondaries only double or triple and most start with a base cortisol value of at least 10. The lower the base cortisol value, the more likely the persons cortisol will stimulate by a high factor if they are secondary adrenal insufficient. The base cortisol can be very low because of the bodies lack of natural ACTH. When the synthetic ACTH is given to secondaries, the adrenals go hog wild because they can work, just not getting enough ACTH from the pituitary gland.[9]
In some instances, a second test performed later 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[15] 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.[15]

Interpretation of ACTH plasma test in conjunction with cortisol stimulation

Location of the pituitary gland
Click to enlarge photo

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 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.[13]

  • Interpretation for primary adrenal insufficiency and Addison's disease
ACTH will be high[13] - 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 -[13] Usually below 35, but most people with secondary fall within the range limit. Although uncommon, values for ACTH can reach into the low 40s. 98% of people with secondary fall within range.
In some cases, actual cause of pituitary production of ACTH is from low CRH. It is possible to have separate ACTH and CRH impairment such as can happen in a head injury that may injure both the pituitary and hypothalamus.[16]

Interpretation for 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) hypoaldosteronism is present.[3] Human ACTH has a slight stimulatory effect on aldosterone[17], 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.[18] 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.[3] 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 (ie 2 ng/dl stimming to 20).[19] 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

Simple diagnostic chart

Source of pathology CRH ACTHDHEAcortisol aldosteronerenin NaKCauses5
low lowlow low3 low lowlow lowtumor of the hypothalamus (adenoma), antibodies, environment,
head injury
high2 low low low3 low low lowlowtumor of the pituitary (adenoma), antibodies, environment,
head injury, surgical removal6, Sheehan's syndrome
adrenal glands
high highhigh low4low highlowhightumor 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

External links


  1. 1.0 1.1 Dorin RI, Qualls CR, Crapo LM (2003). Diagnosis of adrenal insufficiency. Ann. Intern. Med. 139 (3): 194–204.
  2. 2.0 2.1 2.2 Elizabeth H. Holt, MD, PhD (2008). ACTH (cosyntropin) stimulation test.
  3. 3.0 3.1 3.2 unknown. ACTH Stimulation Test. APPENDIX – Endocrinology.
  4. Abdu TA; Elhadd TA; Neary R; Clayton RN (1999). Comparison of the low dose short synacthen test (1 microg), the conventional dose short synacthen test (250 microg), and the insulin tolerance test for assessment of the hypothalamo-pituitary-adrenal axis in patients with pituitary disease..
  5. 5.0 5.1 Evangelia Charmandari, M.D., and George P. Chrousos, M.D.. ADRENAL INSUFFICIENCY Chapter 13.
  6. unknown (2006). ACTH (Cortrosyn) stimulation test.
  7. 7.0 7.1 unknown. Synacthen Test.
  8. 8.0 8.1 8.2 unknown. GENERIC NAME: COSYNTROPIN - INJECTABLE (koe-sin-TROW-pin).
  9. 9.0 9.1 9.2 K. Pagana, PhD, RN and T. Pagana, MD, FACS. Mosby's Diagnostic and Laboratory Test Reference 2nd ed: Adrenocorticotropic hormone stimulation test: 17. Cite error: Invalid <ref> tag; name "Mosby's Diagnostic and Laboratory Test Reference 2nd ed." defined multiple times with different content Cite error: Invalid <ref> tag; name "Mosby's Diagnostic and Laboratory Test Reference 2nd ed." defined multiple times with different content
  10. K. Pagana, PhD, RN and T. Pagana, MD, FACS. Mosby's Diagnostic and Lab Test Reference 2nd ed: Aldosterone, Cortisol: 29 and 260.
  11. unknown (2006). Aldosterone in Blood.
  12. Emily D. Szmuilowicz, Gail K. Adler, Jonathan S. Williams, Dina E.Green, Tham M. Yao, Paul N. Hopkins and Ellen W. Seely. Relationship between Aldosterone and Progesterone in the Human Menstrual Cycle: 3981-3987.
  13. 13.0 13.1 13.2 13.3 unknown. ACTH Rapid Stimulation Test (Cortrosyn, Cosyntropin).
  14. NIDDK's Office of Health Research Reports. Addison's disease.
  15. 15.0 15.1 Ashley B. Grossman, MD (2007). Addison's Disease. Endocrine and Metabolic Disorders. Cite error: Invalid <ref> tag; name "ch153b.html" defined multiple times with different content
  16. Lynnette K Nieman, MD (2008). Corticotropin-releasing hormone stimulation test.
  17. unknown. Role of ACTH in Regulation and Action of Adrenocorticoids: 7 of 52.
  18. unknown. Aldosterone and Renin.
  19. L.A. Cunningham and M.A. Holzwarth (1988). Vasoactive intestinal peptide stimulates adrenal aldosterone and corticosterone secretion. Endocrinology 122: 2090–2097.
  20. 20.0 20.1 Jardena J. Puder, Pamela U. Freda, Robin S. Goland, Michel Ferin,and Sharon L. Wardlaw. [ Stimulatory Effects of Stress on Gonadotropin Secretion in Estrogen-Treated Women*]. The Journal of Clinical Endocrinology & Metabolism 85: 2184-2188. Cite error: Invalid <ref> tag; name "2184.pdf" defined multiple times with different content
  21. unknown. ACTH Stimulation Test for 21-Hydroxylase.


Target-derived NGF, BDNF, NT-3