The Discovery of ACTH

Overview

Adrenocorticotropic hormone (ACTH), also called corticotropin, is a 39-amino-acid peptide secreted by corticotroph cells of the anterior pituitary. It stimulates the adrenal cortex to produce cortisol and other glucocorticoids, constituting the core of the hypothalamic-pituitary-adrenal (HPA) axis. ACTH was recognized in the 1930s through experiments that showed adrenal atrophy after hypophysectomy, and it was purified in the 1940s from animal pituitaries.

Choh Hao Li at Berkeley and, independently, Paul Bell at the University of Toronto made crucial contributions to ACTH purification and sequencing in the late 1940s and 1950s. Geoffrey Harris's work on the hypothalamic-pituitary portal circulation at the University of Oxford clarified how the hypothalamus regulates ACTH release via corticotropin releasing hormone (CRH). CRH itself was isolated much later, in 1981, by Wylie Vale and colleagues at the Salk Institute.

Clinical use of ACTH preparations began in the late 1940s when Philip Hench at the Mayo Clinic demonstrated dramatic improvement in rheumatoid arthritis patients treated with cortisone, and shortly afterward with ACTH. This work earned Hench, Edward Kendall, and Tadeus Reichstein the 1950 Nobel Prize in Physiology or Medicine.

Key People

• Choh Hao Li (1913–1987): Berkeley biochemist central to ACTH purification and sequencing.
• Paul Bell: Toronto biochemist who collaborated on ACTH structural work.
• Geoffrey W. Harris (1913–1971): British neuroendocrinologist who established the hypothalamic-pituitary portal connection.
• Philip Hench, Edward Kendall, Tadeus Reichstein: 1950 Nobel laureates for cortisone and ACTH.
• Wylie Vale (1941–2012): Identified CRH at the Salk Institute.

Timeline

• 1930s: Hypophysectomy experiments show adrenal dependence on the pituitary.
• 1943: Li and colleagues obtain highly purified ACTH from sheep pituitary.
• 1948: Hench administers cortisone to rheumatoid arthritis patients.
• 1949: Clinical use of ACTH begins.
• 1950: Nobel Prize for cortisone and ACTH.
• 1956: Complete amino acid sequence of ACTH is established.
• 1981: Vale's group isolates CRH.

Background

ACTH is derived from a larger precursor, pro-opiomelanocortin (POMC), which also gives rise to alpha-MSH, beta-endorphin, and related peptides. This single-gene, multi-product organization was one of the earliest examples of how precursor processing generates a family of biologically distinct peptides from a common source. Different tissues (anterior pituitary, intermediate lobe, hypothalamus) process POMC differently, producing different mixtures of mature peptides.

The hypothalamic-pituitary-adrenal axis itself — with CRH and vasopressin driving ACTH release, ACTH stimulating cortisol production, and cortisol feeding back to suppress the hypothalamus and pituitary — is the paradigm of neuroendocrine regulation. Stress research, pioneered by Hans Selye in the 1930s and 1940s, gave the HPA axis its enduring role as the "stress system" of the body.

Modern Relevance

Synthetic ACTH (1-24), known as cosyntropin or tetracosactide, is the standard tool for testing adrenal function (the ACTH stimulation test). Longer-acting ACTH preparations are used in some settings, including infantile spasms. CRH is a useful research and diagnostic tool (e.g., in petrosal sinus sampling for Cushing disease).

The molecular dissection of POMC processing has opened therapeutic opportunities. Setmelanotide, a melanocortin-4 receptor agonist derived from POMC biology, is approved for certain rare genetic obesity syndromes. The CRH and ACTH pathways continue to drive research on stress-related disorders, depression, and autoimmune disease.

Related Compounds

• ACTH
• Cosyntropin
• Pro-opiomelanocortin
• CRH
• Setmelanotide