Adrenocorticotropic Hormone (ACTH) is a peptide hormone produced and secreted by the pituitary gland (specifically, the anterior pituitary). ACTH plays a critical role in regulating the adrenal glands, particularly the cortex (the outer part of the adrenal glands), and stimulates the production and release of cortisol and other glucocorticoids.

Function of ACTH:

• Cortisol Production: The primary function of ACTH is to stimulate the adrenal cortex to produce and release cortisol, a steroid hormone involved in various vital processes such as:
• Regulating metabolism (increases glucose production, helps with fat and protein breakdown).
• Responding to stress (enhances the body's ability to cope with physical or emotional stress).
• Suppressing inflammation (acts as an anti-inflammatory agent).
• Immune system regulation (modulates immune responses).
• Control of the Hypothalamic-Pituitary-Adrenal (HPA) Axis: ACTH is a key component of the HPA axis, which regulates the body's response to stress and the circadian rhythm:
• The hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release ACTH.
• In turn, ACTH stimulates the adrenal glands to secrete cortisol.
• Elevated cortisol levels provide negative feedback to the hypothalamus and pituitary to reduce the release of CRH and ACTH, maintaining balance.

Clinical Significance of ACTH:

1. Evaluation of Adrenal Function:

• ACTH testing is used to assess the function of the adrenal glands and diagnose conditions affecting the HPA axis, such as Addison’s disease (adrenal insufficiency), Cushing's syndrome (excessive cortisol production), and other disorders.

1. Cushing's Syndrome vs. Cushing's Disease:

• Cushing’s syndrome refers to a condition caused by excessive cortisol production, which can occur due to an ACTH-secreting pituitary tumor, adrenal tumors, or the overuse of corticosteroid medications.
• Cushing’s disease is a specific form of Cushing’s syndrome where an ACTH-secreting pituitary tumor (known as an adenoma) causes the adrenal glands to produce too much cortisol.
• Measuring ACTH levels helps differentiate between the different causes of Cushing’s syndrome:
• Low ACTH levels typically indicate adrenal tumors (which directly produce cortisol) or steroid medication use.
• High ACTH levels are associated with pituitary tumors (Cushing’s disease) or other causes of excess ACTH production, such as ectopic ACTH production by non-pituitary tumors (e.g., small cell lung cancer).

1. Addison’s Disease (Adrenal Insufficiency):

• Addison's disease is a condition in which the adrenal glands do not produce enough cortisol, often due to autoimmune destruction of the adrenal glands.
• ACTH levels are typically elevated in Addison's disease because the pituitary gland responds to low cortisol levels by producing more ACTH in an attempt to stimulate the adrenal glands to produce cortisol.
• An ACTH stimulation test can be used to confirm adrenal insufficiency, where a low or absent increase in cortisol levels after ACTH administration indicates a problem with the adrenal glands.

1. Adrenal Hyperplasia:

• Congenital adrenal hyperplasia (CAH) is a group of genetic disorders affecting the enzymes involved in cortisol production. In response to low cortisol, ACTH levels can become elevated, leading to increased adrenal gland activity and abnormal hormone production (e.g., excess androgens).

1. Diagnostic Tests Involving ACTH:

• ACTH Stimulation Test: This test involves administering synthetic ACTH to stimulate the adrenal glands. In a normal response, cortisol levels should rise. A poor or absent cortisol response suggests adrenal insufficiency.
• ACTH Suppression Test: This is used to test the functioning of the pituitary-adrenal axis in conditions like Cushing's syndrome, assessing how the body responds to ACTH inhibition.
• Basal ACTH Levels: Measuring basal (unstimulated) ACTH levels helps diagnose disorders like Cushing's disease, Addison’s disease, or ectopic ACTH syndrome.

1. Ectopic ACTH Syndrome:

• Some non-pituitary tumors, such as small cell lung cancer, can secrete ACTH, leading to Cushing’s syndrome even though the pituitary gland is not involved. In this case, ACTH levels are high, and the source of the ACTH production is outside the pituitary.

Factors Affecting ACTH Levels:

1. Diurnal Variation:

• ACTH follows a diurnal rhythm, with levels typically being higher in the early morning and lower in the evening, reflecting the body’s internal clock and the need for cortisol during waking hours.

1. Stress:

• Physical or emotional stress can lead to an increase in ACTH secretion, which in turn increases cortisol production to help the body handle stress.

1. Medications:

• Glucocorticoids (steroid medications) suppress ACTH production through negative feedback, leading to lower ACTH levels, which can impact the results of ACTH tests.

1. Pituitary or Hypothalamic Dysfunction:

• Damage to the pituitary or hypothalamus (e.g., from a tumor, surgery, or injury) can disrupt the regulation of ACTH secretion and cortisol production, leading to either high or low levels of ACTH.

Normal Range for ACTH:

• The normal range for ACTH can vary slightly depending on the laboratory and the specific assay used, but typical values are:
• Morning ACTH: 10 to 60 pg/mL (picograms per milliliter) or 2.2 to 13.2 pmol/L.
• Evening ACTH: Should be lower than the morning levels, reflecting the body’s natural circadian rhythm.

Interpretation of ACTH Results:

1. High ACTH:

• Primary adrenal insufficiency (Addison’s disease): The adrenal glands fail to produce cortisol, leading to increased ACTH as the pituitary tries to stimulate the adrenal glands.
• Cushing's disease: Pituitary tumors produce excess ACTH, leading to excessive cortisol secretion by the adrenal glands.
• Ectopic ACTH production: Non-pituitary tumors (e.g., lung cancer) secrete ACTH, causing high levels in the bloodstream.

1. Low ACTH:

• Secondary adrenal insufficiency: This occurs when the pituitary or hypothalamus does not produce enough ACTH, often due to damage or dysfunction in these areas. The adrenal glands are not sufficiently stimulated, leading to reduced cortisol production.
• Adrenal tumors or exogenous corticosteroid use: These can cause low ACTH levels because they directly increase cortisol, providing negative feedback to the pituitary.

Conclusion:

ACTH is a crucial hormone in the regulation of cortisol and the overall stress response. Testing ACTH levels can help diagnose disorders of the adrenal glands (like Addison’s disease and Cushing’s syndrome), pituitary function, and ectopic ACTH production. Proper interpretation of ACTH levels, in conjunction with other tests such as cortisol measurements, is vital for understanding the underlying cause of various endocrine disorders.