The ACTH stimulation test is the primary tool healthcare providers use to evaluate the function of the adrenal glands and the production of the hormone cortisol. Cortisol is a glucocorticoid hormone that plays a fundamental role in regulating metabolism, blood pressure, and the body’s response to stress. When the adrenal glands fail to produce enough cortisol, a potentially life-threatening condition called adrenal insufficiency can occur. The test involves administering a synthetic version of ACTH to determine if the adrenal glands respond appropriately by releasing cortisol.
Understanding Cortisol and the Adrenal Axis
Cortisol production is regulated by a complex feedback system known as the Hypothalamic-Pituitary-Adrenal (HPA) axis. This axis begins in the brain, where the hypothalamus releases corticotropin-releasing hormone (CRH) in response to physical or psychological stress. CRH then travels to the pituitary gland, prompting it to secrete ACTH into the bloodstream.
ACTH is the direct chemical signal that stimulates the adrenal glands, which sit atop the kidneys, to synthesize and release cortisol. The ACTH stimulation test bypasses the hypothalamus and pituitary gland by directly injecting synthetic ACTH, called cosyntropin. This allows clinicians to isolate and test the responsiveness of the adrenal glands themselves.
If the adrenal glands are healthy, they should quickly increase cortisol production following the injection of cosyntropin. A blunted or absent rise in cortisol indicates a problem somewhere along the HPA axis. The choice between a low-dose or high-dose version of the test is based on where the problem is suspected to lie.
The Standard High-Dose Stimulation Test
The high-dose ACTH stimulation test, often referred to as the standard test, utilizes a pharmacological dose of 250 micrograms (mcg) of synthetic cosyntropin. This large amount represents a massive, supraphysiological signal, far exceeding the level of ACTH the pituitary gland would naturally produce. The test procedure typically involves drawing a baseline blood sample, injecting the 250 mcg of cosyntropin, and then drawing follow-up blood samples at 30 and 60 minutes.
The purpose of using such a strong signal is to maximally stimulate the adrenal glands. This makes the high-dose test highly effective at diagnosing Primary Adrenal Insufficiency, where the adrenal gland tissue itself is damaged and incapable of producing cortisol. Even with this overwhelming signal, a failing adrenal gland will not respond adequately.
A patient is typically considered to have a normal response if the peak cortisol level reaches or exceeds 18 to 20 micrograms per deciliter (\(\mu\)g/dL) after the injection. Because the 250 mcg dose is so potent, it can often successfully stimulate adrenal glands that are only mildly dysfunctional. This can sometimes lead to a misleading “normal” result in patients with milder forms of adrenal problems.
The More Sensitive Low-Dose Stimulation Test
In contrast, the low-dose ACTH stimulation test employs a much smaller, more physiological dose of cosyntropin, typically just 1 microgram (mcg). This dose is designed to mimic the normal, non-stressful levels of ACTH that circulate in the body. The procedure follows the same general timing as the standard test, with blood drawn at baseline, 30 minutes, and often 60 minutes post-injection.
The rationale behind using this weaker signal is to increase the test’s sensitivity to subtle adrenal impairment. Over time, a lack of natural ACTH from a dysfunctional pituitary gland can cause the adrenal glands to shrink or atrophy. A mildly atrophied gland may still respond to the massive 250 mcg dose, but it will fail to respond to the more delicate 1 mcg signal.
This increased sensitivity makes the low-dose test the preferred method for assessing Secondary or Tertiary Adrenal Insufficiency, where the problem originates in the pituitary gland or the hypothalamus. The subtle nature of the 1 mcg dose is better at revealing a weakened adrenal reserve before complete failure occurs.
Choosing the Right Diagnostic Approach
The selection of the appropriate ACTH test dose depends entirely on the suspected location and severity of the adrenal dysfunction. If a patient presents with clear signs of severe adrenal failure, the high-dose test is generally performed first. The strong, maximal stimulation of 250 mcg provides a definitive answer regarding the adrenal gland’s capacity for cortisol production.
If the clinical suspicion points toward a central issue (in the pituitary gland or hypothalamus), the low-dose test is often preferred. The high dose can “over-stimulate” a partially functional adrenal gland that has been under-stimulated, potentially masking a true case of central adrenal insufficiency. While the interpretive cut-off values for a normal response are similar for both tests, the low-dose approach is the more sensitive tool for detecting mild and central forms of the disease.