Adrenocorticotropic hormone, commonly known as ACTH, is a polypeptide hormone produced and released by the pituitary gland, a small gland at the base of the brain. The primary function of ACTH is to stimulate the adrenal glands, which sit atop the kidneys, to produce and release cortisol, often referred to as the “stress hormone.” Cortisol plays a role in regulating metabolism, blood pressure, and immune responses. When plasma ACTH levels are high, it indicates an imbalance in this intricate hormonal system.
ACTH’s Role in the Body’s Hormonal System
The body’s hormonal balance is maintained through a network called the hypothalamic-pituitary-adrenal (HPA) axis. This system involves three key organs: the hypothalamus in the brain, the pituitary gland, and the adrenal glands. When the body experiences stress or low cortisol levels, the hypothalamus releases corticotropin-releasing hormone (CRH).
CRH then travels to the anterior pituitary gland, prompting it to secrete ACTH into the bloodstream. ACTH circulates to the adrenal glands, stimulating the production and release of cortisol. As cortisol levels in the blood rise, a negative feedback loop is activated, signaling the hypothalamus to reduce CRH production and the pituitary gland to decrease ACTH release, thus maintaining hormonal equilibrium.
Conditions Causing High ACTH
Elevated ACTH levels can stem from several distinct medical conditions. Primary adrenal insufficiency, also known as Addison’s disease, occurs when the adrenal glands are damaged and cannot produce sufficient amounts of cortisol and aldosterone. In response to these low cortisol levels, the pituitary gland attempts to compensate by releasing an excessive amount of ACTH.
Cushing’s disease is another condition that leads to high ACTH. This disorder is characterized by a benign pituitary tumor, called an adenoma. This pituitary adenoma produces and secretes excess ACTH, disrupting the normal feedback mechanism. The elevated ACTH then overstimulates the adrenal glands, resulting in an overproduction of cortisol.
Ectopic ACTH syndrome is a less common cause of high ACTH levels. In this scenario, tumors outside of the pituitary gland, often found in organs such as the lungs, pancreas, or thyroid gland, aberrantly produce and secrete ACTH. These non-pituitary tumors lead to high circulating ACTH, causing the adrenal glands to produce excessive cortisol, similar to Cushing’s disease but originating from a different source.
Diagnosing Elevated ACTH
Detecting elevated ACTH begins with a plasma ACTH blood test. Since ACTH levels fluctuate throughout the day, often peaking in the morning, the timing of the blood draw is important for accuracy. However, a single high ACTH reading alone is not sufficient for diagnosis, as it must be evaluated in conjunction with cortisol levels.
Concurrent measurement of cortisol levels is important to differentiate between ACTH-dependent and ACTH-independent causes. This often involves tests like 24-hour urine cortisol collection, midnight salivary cortisol measurements, or a low-dose dexamethasone suppression test. These tests help determine if the high cortisol is a direct result of excessive ACTH stimulation or if it is being produced independently by the adrenal glands.
Once high ACTH is confirmed and its cause is determined to be ACTH-dependent, imaging studies pinpoint the source. Magnetic resonance imaging (MRI) of the pituitary gland can identify pituitary adenomas, while computed tomography (CT) scans of the chest and abdomen can locate ectopic ACTH-producing tumors. In complex cases, inferior petrosal sinus sampling, an invasive procedure, may be performed to definitively distinguish between a pituitary and an ectopic source of ACTH.
Managing High ACTH Levels
Treatment for elevated ACTH levels depends on the specific underlying cause. For individuals diagnosed with Cushing’s disease, the primary treatment is surgical removal of the pituitary adenoma, often via transsphenoidal adenomectomy. If surgery is not feasible or fails to achieve a cure, radiation therapy to the pituitary gland or medications that reduce cortisol production, like ketoconazole or metyrapone, may be considered.
In cases of Ectopic ACTH Syndrome, the main treatment is surgical removal of the ACTH-producing tumor, if it can be located and removed. If the tumor is malignant or has spread, chemotherapy or radiation therapy may be used to manage the disease. Medications to block cortisol production, such as metyrapone or mifepristone, are also used, especially in acute situations or when surgical removal is not possible.
For primary adrenal insufficiency, or Addison’s disease, the primary management is lifelong hormone replacement therapy. This involves taking synthetic glucocorticoids, such as hydrocortisone or prednisone, to replace the missing cortisol, often in divided doses to mimic the body’s natural rhythm. Mineralocorticoid replacement with fludrocortisone is required to maintain salt and water balance. Patients are educated on “stress dosing,” increasing their medication during periods of illness or physical stress to prevent an adrenal crisis.