Adrenocorticotropic Hormone (ACTH) is a central messenger in the body’s system for managing stress and metabolism. This hormone signals the adrenal glands, located above the kidneys, to produce necessary steroid hormones. A high plasma level of ACTH is not a diagnosis, but an indicator that the body’s hormonal balance is disrupted. Understanding this result requires looking at the entire feedback loop that governs hormone production to identify where the system has broken down.
The Role of ACTH in the Body
ACTH is a peptide hormone synthesized and released by the pituitary gland, a small structure at the base of the brain. Its release is controlled by Corticotropin-Releasing Hormone (CRH), which originates in the hypothalamus. Together, the hypothalamus, pituitary gland, and adrenal glands form the Hypothalamic-Pituitary-Adrenal (HPA) axis, the body’s system for regulating stress reactions and maintaining internal balance.
ACTH’s primary function is to travel through the bloodstream and stimulate the outer layer of the adrenal glands, known as the adrenal cortex. This stimulation prompts the adrenal cortex to synthesize and release cortisol, the body’s natural stress response hormone. Cortisol is involved in managing blood sugar levels, regulating metabolism, and modulating the immune system.
The entire HPA system operates under a principle called negative feedback. Under normal circumstances, when cortisol levels in the blood rise sufficiently, they signal back to the hypothalamus and the pituitary gland to reduce the production of CRH and ACTH. This regulatory mechanism ensures that hormone levels do not become excessively high or remain elevated unnecessarily. A high ACTH level suggests that this carefully maintained feedback loop has been overridden or is failing at some point.
High ACTH Due to Adrenal Failure
An elevated ACTH level can result from a problem stemming directly from the adrenal glands. This condition, primary adrenal insufficiency (Addison’s disease), occurs when the adrenal glands are damaged and cannot produce sufficient cortisol, despite receiving the ACTH signal. The most common cause is an autoimmune response that attacks the adrenal tissue, leading to hormone deficiency. The pituitary gland senses the resultant low cortisol levels and ramps up ACTH production dramatically to restore balance.
This compensatory mechanism results in a biochemical profile characterized by high ACTH and simultaneously low cortisol. The pituitary gland increases its signal, but the damaged adrenal glands are incapable of responding.
High ACTH levels are derived from a precursor molecule that stimulates melanocytes, the cells responsible for skin pigmentation. Consequently, individuals with primary adrenal insufficiency often develop a generalized darkening of the skin. This hyperpigmentation is especially noticeable in areas like scars, gums, and skin creases, providing a distinct physical clue to the imbalance.
High ACTH Driven by Pituitary or Ectopic Sources
In contrast to adrenal failure, a high ACTH level can sometimes be the direct cause of the hormonal problem, leading to an overabundance of cortisol. This scenario is called ACTH-dependent hypercortisolism, where both ACTH and cortisol levels are high because the source of ACTH production ignores the normal negative feedback signal. This excess ACTH production can originate from two distinct locations.
The first source is a benign tumor (adenoma) in the pituitary gland, specifically termed Cushing’s disease. The tumor cells autonomously produce ACTH, leading to chronic overstimulation of the adrenal glands and excessive cortisol levels. Although the pituitary tumor is within the HPA axis, its production is largely resistant to the feedback suppression that normal pituitary cells would experience.
The second cause is ectopic ACTH production, where a tumor located outside the pituitary gland secretes the hormone. These tumors are most commonly found in the lungs (e.g., small cell lung cancer or carcinoid tumors), but can also arise in the pancreas or thyroid. Ectopic sources are completely outside the HPA axis’s regulatory control. Their ACTH release is unresponsive to the high cortisol levels circulating in the blood, often making ectopic production an aggressive condition.
Mapping the Diagnostic Path
After an initial blood test reveals high ACTH plasma levels, a physician employs specialized tests to pinpoint the exact origin of the imbalance. The first step involves assessing the circadian rhythm of both ACTH and cortisol, as their levels naturally peak in the morning and drop significantly at night. A loss of this rhythm, particularly elevated late-night levels, is highly suggestive of a hormone-producing tumor.
To differentiate the causes of hypercortisolism, the dexamethasone suppression test is utilized. Dexamethasone is a synthetic steroid that mimics cortisol; in a low-dose test, it should suppress ACTH and cortisol in a healthy individual. If cortisol remains high after the low-dose test, a high-dose version helps distinguish between a pituitary tumor and an ectopic source. A pituitary tumor may show some suppression with the high dose, but an ectopic tumor remains unaffected due to its independence from the HPA axis.
CRH Stimulation Test
Further differentiation may involve a Corticotropin-Releasing Hormone (CRH) stimulation test, where synthetic CRH is administered. Pituitary adenomas often show an exaggerated ACTH response to this stimulus, while ectopic tumors generally show no response.
Imaging studies, such as high-resolution MRI of the pituitary gland or CT scans of the chest and abdomen, are used to physically locate the source of hormone overproduction. In challenging cases, Inferior Petrosal Sinus Sampling measures ACTH levels in the veins near the pituitary to definitively confirm if the source is the pituitary gland.