ACTH

ACTH
Name	Adrenocorticotropic hormone
Caption	Amino acid sequence of human ACTH.
Width	200
Precursor	Proopiomelanocortin
Source	Anterior pituitary
Target	Adrenal cortex
Receptor	Melanocortin 2 receptor
Function	Stimulates cortisol production

ACTH. It is a polypeptide tropic hormone produced and secreted by the anterior pituitary gland. Its primary function is to stimulate the production and release of cortisol from the adrenal cortex. The synthesis and secretion of ACTH are tightly regulated by the hypothalamus via corticotropin-releasing hormone and influenced by factors such as the circadian rhythm and stress.

Structure and synthesis

ACTH is a 39-amino acid peptide derived from the larger precursor molecule proopiomelanocortin, which is synthesized in corticotroph cells of the anterior pituitary. The cleavage of proopiomelanocortin by specific enzymes like prohormone convertase 1 also yields other biologically active peptides, including melanocyte-stimulating hormone and beta-endorphin. The gene responsible for proopiomelanocortin is located on chromosome 2 in humans. The biologically active core of the hormone resides in its first 24 amino acids, a sequence that is identical across many species, while the remaining segment shows more variability.

Regulation and secretion

Secretion is primarily controlled by corticotropin-releasing hormone from the hypothalamus, which travels via the hypophyseal portal system to the anterior pituitary. This system is part of the hypothalamic–pituitary–adrenal axis. Secretion follows a pronounced circadian rhythm, with peak levels in the early morning and the lowest levels around midnight, as regulated by the suprachiasmatic nucleus. Negative feedback is exerted by cortisol, which inhibits the release of both corticotropin-releasing hormone and this hormone at the level of the pituitary gland and hypothalamus. Stressors, including surgery, hypoglycemia, and psychological stress, can significantly stimulate secretion.

Physiological effects

The principal action is to stimulate the adrenal cortex, specifically the zona fasciculata, to synthesize and secrete glucocorticoids like cortisol. It binds to the melanocortin 2 receptor, a G protein-coupled receptor, activating adenylate cyclase and increasing intracellular cyclic AMP. This hormone also has a minor role in promoting the secretion of adrenal androgens from the zona reticularis and supports the growth and maintenance of the adrenal cortex. At high concentrations, it can exhibit extra-adrenal effects, including weak lipolysis and stimulation of melanocytes, leading to skin hyperpigmentation.

Clinical significance

Abnormally high levels are a hallmark of conditions like Cushing's disease, typically caused by a pituitary adenoma. Ectopic production can occur with certain lung cancers, such as small cell lung carcinoma. Primary insufficiency of the adrenal cortex, as seen in Addison's disease, leads to markedly elevated levels due to the loss of cortisol feedback. Conversely, secondary adrenal insufficiency, often due to pituitary tumors or Sheehan's syndrome, results in low levels. The dexamethasone suppression test is a key diagnostic tool for differentiating the causes of hypercortisolism.

Measurement and testing

Levels are measured in plasma or serum using techniques like immunoradiometric assay or chemiluminescence. Blood samples are typically drawn in the morning due to diurnal variation. Dynamic function tests are crucial for diagnosis; the cosyntropin stimulation test assesses adrenal gland responsiveness, while the corticotropin-releasing hormone stimulation test helps distinguish pituitary from ectopic sources of excess hormone. The inferior petrosal sinus sampling procedure is used to localize a pituitary adenoma when imaging is inconclusive.

History and discovery

The existence of a pituitary factor controlling the adrenal gland was first inferred from clinical observations of patients with Addison's disease and Cushing's syndrome. In the 1930s, pioneering work by scientists like Harvey Cushing and J. B. Collip laid the groundwork. The hormone was first isolated and its sequence determined in the 1950s by teams including that of Klaus Hofmann. The full understanding of its precursor, proopiomelanocortin, and its role within the hypothalamic–pituitary–adrenal axis was elucidated through later research by endocrinologists like Roger Guillemin and Andrew Schally.

Category:Peptide hormones Category:Anterior pituitary hormones