ACTH Stimulation Tests: Demystified (Well, partially.)

It should come as no surprise that administration of ACTH can be used to test for insufficient adrenal function.   Keep in mind that measures of ACTH and cortisol sometimes give an answer and obviate the need for further testing.

If the serum ACTH is elevated and the cortisol is low then the patient probably has primary adrenal insufficiency.  In the right clinical context this pattern may be enough to support a diagnosis.

If the ACTH is low and the cortisol is also low then the patient may have central adrenal insufficiency due to pituitary or hypothalamic disease.   Taking high doses of steroids, though, can lead to the same pattern.  I published results of 8AM cortisol levels obtained in patients with various pituitary disorders many years ago.  All patients also had an insulin hypoglycemia test as a gold standard test of pituitary adrenal function.  I showed that in these patients with pituitary disorders an 8AM cortisol less than 5mcg/dL was an appropriate level to say a patient had central adrenal insufficiency.  A cortisol level over 12 mcg/dL proved normal pituitary-adrenal function.  Levels in between required further study and confirmation by a better test than an AM cortisol.  The lower the level the more likely the patient had central adrenal insufficiency.

Before we discuss the varieties of ACTH stimulation tests it’s important to recognize that the entire pituitary content of ACTH is about 400 micrograms.  That’s not much.  Small amounts are released on an as-needed basis to maintain and stimulate adrenal production of cortisol.

Another important matter is that tests for cortisol have improved over time.  Historical cutoffs for separating normal from abnormal patients have changed.  In the older cortisol assays most recommended cutoffs ranged from 18-20 mcg/dL after ACTH stimulation. Over that level was considered normal.  The newer assays are more specific for cortisol itself and do not detect and cross react with other steroids.  Most of us now employ a cutoff of 14 mcg/dL after ACTH stimulation to separate normal from abnormal patients.

In my practice, the standard or traditional ACTH stimulation test is employed to test for primary adrenal insufficiency.  Some use this test for central adrenal insufficiency.  I’ll discuss the limitations of that approach below.   The traditional test involves the IV or IM injection of 250 mcg ACTH.  That’s a whopping dose!  Cortisol levels are obtained prior to injection and about 60 minutes later; 45 minute samples are probably of equal predictive value.

I use the low-dose ACTH stimulation test in patients suspected of having central adrenal insufficiency.  The dose of ACTH used is only 1 microgram.  Yes. One-two hundred fiftieth of the typical test!   The truth of the matter is that you could give a normal person one microgram or 250 micrograms, check cortisol levels 45 or 60 minutes later and you wouldn’t be able to see a difference in the results.   Where this test shines is in identifying patients with partial central adrenal insufficiency who may have a normal response to the traditional dose but will show a low response to the one microgram test.  This is important as there  are plenty of patients reported in the literature who have had normal responses to the traditional test and later had adrenal crises or severe insufficiency during illness or other physiologic stressors.  I published on this topic many years ago and confirmed the value of the low dose test.

The long ACTH stimulation tests wss formerly employed to test for central adrenal insufficiency.  This test involved the administration of 250 mcg ACTH on three consecutive days and measures of cortisol on day three of the test.   The premise was that patients with central adrenal insufficiency have adrenals that are “sleeping” and unresponsive to ACTH.  Three days of ACTH will, however, awaken the adrenal proving that they simply were unresponsive due to a chronic lack of ACTH secretion.   It takes the adrenals a while to lose their responsiveness so the test is not good for a new case of central adrenal insufficiency.

I conduct a traditional ACTH stimulation test with measures of certain hormones in those suspected of having adrenal hyperandrogenism  or late-onset congenital adrenal hyperplasia.  I will discuss this in future articles.

The ACTH stimulation tests measure the adrenals responsiveness to ACTH.  The metyrapone test can be used in patients with possible central adrenal insufficiency.  It measures the ability of the hypothalamus and pituitary to respond to an acute lowering of cortisol  levels.   In essence, it measures the ability of negative feedback where a drop in cortisol should stimulate ACTH release and activity in the adrenals measured by testing 11-deoxycortisol levels.   The insulin-induced hypoglycemia test is a stress paradigm that measures hypothalamic-pituitary-adrenal responses to hypoglycemia that leads to autonomic system activation and a “stress response.”

Of course, depending on the circumstances, other tests are also useful to get the full picture in patients with suspected adrenal insufficiency.  Those with suspected primary insufficiency should have plasma renin and aldosterone levels, adrenal antibodies, and possibly other studies (perhaps a CT adrenals) guided by the history and physical examination.  Those with possible central adrenal insufficiency should have pituitary functions tests and, when indicated, an MRI of the pituitary gland.   Those suspected of having congenial adrenal
hyperplasia should have adrenal androgens and other tests as indicated based on clinical and biochemical findings.

As you can see, we can test to “get at” several functions of the system with the battery of tests that are available.