The adrenocorticotropic hormone (ACTH) stimulation test is a diagnostic procedure used to evaluate the function of the adrenal glands, specifically their capacity to produce cortisol. The test is administered in two primary forms: a low-dose and a high-dose version. Each version is tailored to investigate different aspects of the adrenal response, providing clinicians with specific information to diagnose conditions related to cortisol production.
The ACTH Stimulation Test Procedure
The ACTH stimulation test is a dynamic procedure that measures how well the adrenal glands respond to hormonal signals. The process begins with a baseline blood draw to determine the patient’s initial cortisol level. This sample is collected in the morning, between 8 and 9 a.m., when cortisol concentrations are naturally at their peak. This timing provides a standardized starting point for interpreting the test results.
Following the initial blood draw, the patient receives an injection of a synthetic version of ACTH. This synthetic hormone is known as cosyntropin or tetracosactide. The purpose of this injection is to mimic the action of natural ACTH, which is to signal the adrenal glands to release cortisol. The administration can be either intravenous (IV) or intramuscular (IM).
After the cosyntropin is administered, one or more subsequent blood samples are taken to measure the body’s cortisol response. Blood is drawn 30 and 60 minutes after the injection. These timed samples allow clinicians to observe the peak cortisol output and assess the adrenal glands’ reserve capacity.
Diagnosing Primary Adrenal Insufficiency with the High Dose Test
The high-dose ACTH stimulation test is primarily used to diagnose primary adrenal insufficiency, also known as Addison’s disease. This condition occurs when the adrenal glands themselves are damaged and cannot produce enough cortisol. The standard high-dose test involves the administration of 250 micrograms (mcg) of cosyntropin. This is a supraphysiologic dose, much higher than what the body would naturally produce.
The rationale behind using such a large dose is to provide a maximum stimulus to the adrenal glands. In a person with healthy adrenal function, this potent signal will trigger a significant and rapid increase in serum cortisol levels. A normal response is defined as a peak cortisol level exceeding a certain threshold, often around 18 to 20 micrograms per deciliter (mcg/dL).
In contrast, if an individual has primary adrenal insufficiency, their adrenal glands will not be able to mount an adequate response. Even with the powerful stimulation from the 250 mcg dose, the damaged glands cannot synthesize and release sufficient cortisol. The resulting post-injection cortisol levels will be low and fail to rise above the diagnostic cutoff, confirming the diagnosis.
Diagnosing Secondary and Tertiary Adrenal Insufficiency with the Low Dose Test
The low-dose ACTH stimulation test is a more sensitive tool for detecting secondary and tertiary forms of adrenal insufficiency. This version of the test uses a 1 mcg dose of cosyntropin, which more closely mimics the physiological levels of ACTH the adrenal glands would encounter. Secondary adrenal insufficiency is caused by the pituitary gland failing to produce adequate ACTH, while tertiary adrenal insufficiency stems from the hypothalamus not providing the correct signals to the pituitary.
In both secondary and tertiary cases, the adrenal glands are not inherently damaged but have become dormant or atrophied due to a prolonged lack of stimulation. A large 250 mcg dose might be potent enough to jolt these sluggish glands into producing a seemingly normal amount of cortisol, potentially leading to a false-negative result. The much smaller 1 mcg dose is less likely to overwhelm the system.
This more subtle stimulation accurately reflects the glands’ true, diminished responsiveness. If the adrenal glands have been understimulated for a long time, they will not be able to respond adequately to this small, physiological prompt. A failure to reach the target cortisol level after a 1 mcg injection suggests the issue lies with the signaling from the pituitary or hypothalamus.
Choosing Between the Low and High Dose Tests
The decision to use a low-dose or high-dose ACTH stimulation test is guided by the patient’s clinical picture and the specific diagnostic question at hand. The selection process involves a careful evaluation of symptoms and medical history to determine the most likely cause of adrenal dysfunction.
If a clinician suspects primary adrenal insufficiency, the high-dose (250 mcg) test is the established standard. Symptoms such as hyperpigmentation, low blood pressure, and specific electrolyte imbalances (low sodium, high potassium) point toward a problem with the adrenal glands themselves.
Conversely, if secondary or tertiary adrenal insufficiency is the primary concern, the low-dose (1 mcg) test is preferred. This suspicion may arise in patients with a history of long-term glucocorticoid use, which can suppress the pituitary’s ACTH production, or in those with known or suspected pituitary tumors.