Adrenocorticotropic Hormone (ACTH)

1. Overview

Adrenocorticotropic hormone (ACTH), also known as corticotropin, is a polypeptide hormone that plays a central role in regulating the adrenal cortex and the body’s response to stress. It stimulates the production and release of glucocorticoids—primarily cortisol—from the adrenal cortex. ACTH is part of the hypothalamic-pituitary-adrenal (HPA) axis and is essential for maintaining homeostasis, especially during physiological or psychological stress.

2. Location

ACTH is secreted by the anterior pituitary gland, specifically from the corticotroph cells located in the pars distalis. Its release is regulated by corticotropin-releasing hormone (CRH), which is produced by the hypothalamus. ACTH acts primarily on the adrenal cortex, particularly the zona fasciculata and zona reticularis.

3. Structure

ACTH is a single-chain polypeptide composed of 39 amino acids. It is derived from a larger precursor molecule called pro-opiomelanocortin (POMC). When POMC is cleaved, it produces several biologically active peptides, including ACTH, melanocyte-stimulating hormones (MSHs), β-endorphins, and lipotropins. The first 24 amino acids of ACTH are crucial for its biological activity and are highly conserved across species.

4. Function

The primary function of ACTH is to regulate the secretion of glucocorticoids from the adrenal cortex:

• Stimulates cortisol production in the zona fasciculata of the adrenal cortex.

• Promotes androgen synthesis in the zona reticularis to a lesser extent.

• Enhances adrenal cortex growth and sustains its functional integrity.

ACTH exerts its effects by binding to the melanocortin 2 receptor (MC2R) on adrenal cortical cells, which activates the cyclic AMP (cAMP) signaling pathway, leading to steroidogenesis.

5. Physiological role(s)

ACTH is a critical component of the body’s hormonal regulation and stress response:

• Stress adaptation: During physical or emotional stress, ACTH levels rise, increasing cortisol output to mobilize energy and suppress inflammation.

• Circadian rhythm: ACTH and cortisol follow a diurnal pattern, peaking in the early morning and declining throughout the day. This rhythm supports wakefulness, metabolism, and immune function.

• Glucose homeostasis: Through cortisol, ACTH helps maintain blood glucose during fasting or stress via gluconeogenesis.

• Immune modulation: Cortisol dampens excessive immune activity and inflammation, indirectly mediated by ACTH.

• Developmental role: ACTH contributes to adrenal gland development during fetal life and childhood.

6. Clinical Significance

Abnormal ACTH production or response can result in various endocrine disorders:

• Cushing’s Disease: Caused by a pituitary adenoma that secretes excessive ACTH, leading to hypercortisolism. Symptoms include central obesity, moon face, muscle wasting, striae, hypertension, and glucose intolerance.

• Ectopic ACTH Syndrome: Non-pituitary tumors (e.g., small-cell lung carcinoma) produce ACTH, leading to unregulated cortisol secretion.

• Primary Adrenal Insufficiency (Addison’s Disease): Due to destruction of the adrenal cortex. ACTH levels are elevated due to lack of cortisol negative feedback. Features include hyperpigmentation, hypotension, fatigue, and weight loss.

• Secondary Adrenal Insufficiency: Caused by pituitary dysfunction or suppression (e.g., chronic steroid use). ACTH is low or inappropriately normal, leading to cortisol deficiency without hyperpigmentation or major electrolyte abnormalities (aldosterone is typically preserved).

• Congenital Adrenal Hyperplasia (CAH): Deficient cortisol synthesis (e.g., 21-hydroxylase deficiency) leads to elevated ACTH, causing adrenal hyperplasia and excessive androgen production.

• ACTH Stimulation Test: A diagnostic tool to assess adrenal function. Synthetic ACTH is administered, and cortisol levels are measured. Lack of response indicates adrenal insufficiency.