Adrenocorticotropic hormone

Introduction

Adrenocorticotropic hormone (ACTH), also known as corticotropin, is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. It plays a crucial role in the hypothalamic-pituitary-adrenal (HPA) axis, stimulating the adrenal cortex to secrete glucocorticoids, primarily cortisol. ACTH is essential for the body's response to stress, regulation of metabolism, and immune system modulation.

Structure and Synthesis

ACTH is a 39-amino acid peptide derived from the precursor protein pro-opiomelanocortin (POMC). The synthesis of ACTH begins with the transcription of the POMC gene, followed by post-translational processing in the anterior pituitary. Enzymatic cleavage of POMC produces ACTH and other peptides, including beta-endorphin and melanocyte-stimulating hormone (MSH).

Regulation of Secretion

The secretion of ACTH is primarily regulated by the hypothalamus through the release of corticotropin-releasing hormone (CRH). CRH stimulates the anterior pituitary to produce and release ACTH. Negative feedback from circulating cortisol levels modulates this process, ensuring homeostasis. Additionally, factors such as stress, circadian rhythms, and inflammatory cytokines can influence ACTH secretion.

Mechanism of Action

Upon release into the bloodstream, ACTH binds to melanocortin 2 receptors (MC2R) on the surface of adrenal cortex cells. This binding activates the adenylate cyclase-cAMP pathway, leading to the production of steroid hormones, particularly cortisol. Cortisol exerts various physiological effects, including gluconeogenesis, anti-inflammatory actions, and modulation of the immune response.

Physiological Functions

ACTH has several critical functions in the body:

**Stress Response:** ACTH is a key component of the body's response to stress. It stimulates the adrenal cortex to produce cortisol, which helps mobilize energy reserves, suppress inflammation, and modulate the immune system.
**Metabolism:** ACTH influences carbohydrate, protein, and lipid metabolism by regulating cortisol levels. Cortisol promotes gluconeogenesis, increases blood glucose levels, and affects fat distribution.
**Immune System Modulation:** ACTH and cortisol play roles in modulating the immune response, reducing inflammation, and preventing excessive immune activation.

Clinical Significance

ACTH levels can be indicative of various medical conditions:

**Cushing's Disease:** Characterized by excessive ACTH production due to a pituitary adenoma, leading to hypercortisolism. Symptoms include weight gain, hypertension, and glucose intolerance.
**Addison's Disease:** A condition where the adrenal glands produce insufficient cortisol, often due to autoimmune destruction. Elevated ACTH levels are a compensatory response to low cortisol.
**Ectopic ACTH Syndrome:** Non-pituitary tumors, such as small cell lung carcinoma, can produce ACTH, leading to paraneoplastic Cushing's syndrome.

Diagnostic and Therapeutic Applications

ACTH measurements are used in diagnosing adrenal and pituitary disorders. The ACTH stimulation test assesses adrenal gland function by measuring cortisol response to synthetic ACTH. Therapeutically, synthetic ACTH analogs, such as cosyntropin, are used to treat conditions like infantile spasms and multiple sclerosis.