The body’s endocrine system relies on chemical messengers called hormones to regulate nearly every physiological process, including metabolism and stress response. A significant component of this system is the hypothalamic-pituitary-adrenal (HPA) axis, which governs the production of the hormone cortisol. Adrenocorticotropic Hormone (ACTH) is a peptide hormone produced by the pituitary gland, located at the base of the brain. ACTH acts as the primary signal to the adrenal glands, which sit atop the kidneys, prompting them to release cortisol. This finely tuned system maintains circulating cortisol levels within a healthy range through a negative feedback loop, ensuring the body can respond to stress appropriately. Ectopic ACTH secretion represents a rare and serious disruption of this normal hormonal balance, leading to uncontrolled cortisol production.
Defining Ectopic ACTH Secretion
ACTH is normally produced only by the corticotroph cells within the anterior pituitary gland. The term “ectopic” refers to the production of a substance from a source outside of the organ where it is typically found. Ectopic ACTH secretion (EAS) describes the unregulated production and release of ACTH by cells from a non-pituitary tumor, which then enters the bloodstream.
This excess, non-pituitary ACTH continuously stimulates the adrenal glands, leading to the chronic and excessive release of cortisol, a condition termed hypercortisolism. The resulting clinical condition is known as Ectopic Cushing Syndrome (ECS). Unlike the normal feedback system, the tumor-derived ACTH production is unresponsive to the high levels of cortisol, meaning the hormonal overproduction continues unchecked.
Ectopic Cushing Syndrome is distinct from Cushing’s Disease, although both result in hypercortisolism due to excess ACTH. In Cushing’s Disease, the source of the excessive ACTH is a benign tumor, or adenoma, within the pituitary gland itself. ECS, by contrast, involves a tumor located outside the pituitary, accounting for approximately 5% to 20% of all endogenous Cushing syndrome cases.
The Common Sources of Ectopic ACTH
The primary cause of ectopic ACTH secretion is the synthesis of the hormone by neoplastic cells, particularly those of neuroendocrine origin. These tumors, which can arise in various locations throughout the body, produce and secrete ACTH as a paraneoplastic phenomenon. The tumor location can influence the clinical presentation and the severity of the resulting hypercortisolism.
The most common sources of ectopic ACTH production are tumors within the chest, with the lungs and mediastinum being frequent sites. Small cell lung carcinoma (SCLC) is a highly aggressive tumor often associated with EAS. Bronchial carcinoid tumors, which are generally more slow-growing, are also a frequent source, sometimes presenting with a more subtle clinical course.
Beyond the lungs, other neuroendocrine tumors are known to aberrantly produce ACTH:
- Pancreatic neuroendocrine tumors.
- Tumors of the thymus gland.
- Medullary thyroid carcinoma.
- In a minority of cases, the source remains “occult,” meaning it is too small or difficult to locate.
Physiological Effects and Clinical Presentation
The chronic hypercortisolism caused by ectopic ACTH secretion leads to a range of physiological effects throughout the body. Cortisol excess impairs the body’s ability to utilize glucose, frequently leading to glucose intolerance or overt Type 2 diabetes mellitus. High cortisol levels also contribute to the development of hypertension, or high blood pressure, which can be difficult to manage.
Physical changes often associated with general Cushing syndrome may be present, such as central obesity, a rounded “moon face,” and the development of wide, reddish-purple stretch marks called striae. However, patients with EAS, particularly those with aggressive tumors, may display less typical weight gain. Instead, they often experience muscle wasting and weakness, which can be a leading symptom. The catabolic effects of excess cortisol break down muscle protein, resulting in weakness, especially in the proximal muscles of the arms and legs.
A common feature of EAS is hypokalemia, or abnormally low blood potassium levels. The high circulating cortisol acts like a mineralocorticoid at high concentrations, causing the kidneys to excrete potassium and retain sodium. This further contributes to hypertension and muscle weakness. Psychological effects, including depression, anxiety, and irritability, are also common due to the hormonal imbalance.
Diagnosis and Management
The diagnostic process for ectopic ACTH secretion begins with biochemical confirmation of hypercortisolism, typically using tests such as the 24-hour urine free cortisol test and the overnight low-dose dexamethasone suppression test. Once hypercortisolism is confirmed, blood tests measure ACTH levels. Elevated ACTH confirms the condition is ACTH-dependent, narrowing the cause to either the pituitary or an ectopic source. The high-dose dexamethasone suppression test is often performed next to help distinguish the source, though results can sometimes overlap between Cushing’s Disease and EAS.
Localization of the ACTH source is pursued using various imaging techniques, including computed tomography (CT) or magnetic resonance imaging (MRI) of the chest and abdomen. If the source remains elusive, a specialized procedure called bilateral inferior petrosal sinus sampling (IPSS) is used. This test compares ACTH levels in the veins draining the pituitary gland to peripheral blood; the absence of a central gradient suggests an ectopic source.
Management of EAS focuses on two concurrent goals: controlling the life-threatening effects of hypercortisolism and treating the underlying tumor. Medications known as steroidogenesis inhibitors, such as metyrapone or ketoconazole, are administered to rapidly lower cortisol production by the adrenal glands. The definitive treatment, when possible, involves the surgical resection of the ACTH-secreting tumor. If the tumor is malignant or cannot be fully removed, other therapies like chemotherapy or radiation may be considered, and medical management of hypercortisolism may need to be continued long-term.