History of Growth Hormone Research

Overview

Growth hormone (GH), also called somatotropin, is a 191-amino-acid peptide produced by somatotroph cells of the anterior pituitary. Its role in somatic growth was first hinted at in the nineteenth century by the clinical observations of Pierre Marie, who in 1886 described acromegaly as a distinct syndrome associated with pituitary tumors. The modern picture emerged slowly over the next century, as endocrinologists and biochemists successively characterized, isolated, purified, synthesized, and recombinantly produced the hormone.

Herbert Evans and Joseph Long at Berkeley provided an early landmark in the 1920s, showing that injections of bovine anterior pituitary extracts caused gigantism in rats. By the 1940s, Choh Hao Li and colleagues had purified growth hormone from animal pituitaries, and by the 1950s pediatric endocrinologists, led by Maurice Raben and later Alfred Wilhelmi, were using cadaveric human pituitary extracts to treat pituitary dwarfism.

The era of pituitary-derived GH ended abruptly in 1985, when several patients who had received human pituitary GH were diagnosed with Creutzfeldt-Jakob disease. Fortunately, recombinant human GH had just become available, developed by Genentech and Eli Lilly, and it quickly replaced the cadaveric product.

Key People

• Pierre Marie (1853–1940): French neurologist who described acromegaly.
• Herbert Evans and Joseph Long: Berkeley researchers who showed pituitary extracts stimulate growth.
• Choh Hao Li (1913–1987): Chinese-American biochemist who purified and later synthesized growth hormone.
• Maurice Raben: Pioneer of pediatric GH therapy in the 1950s.
• Roberto Salmon and Bill Daughaday: Pioneers of the somatomedin (IGF-1) concept.

Timeline

• 1886: Marie describes acromegaly.
• 1921: Evans and Long demonstrate growth-promoting activity of pituitary extracts.
• 1944: Li purifies bovine growth hormone.
• 1958: First successful human treatment with pituitary-derived GH.
• 1966: Human growth hormone sequence is determined.
• 1979–1981: Genentech clones and expresses human GH in E. coli.
• 1985: Pituitary-derived GH is withdrawn after CJD cases; recombinant human GH is approved.
• 1990s–2000s: GH therapy expands to adult GH deficiency and selected short-stature syndromes.

Background

Growth hormone research intersects with several threads in twentieth-century endocrinology. The hypothalamic control of GH secretion was worked out by Roger Guillemin and Andrew Schally, who isolated somatostatin and, later, growth hormone releasing hormone. The peripheral action of GH turned out to be mediated largely by insulin-like growth factor 1 (IGF-1), initially called "somatomedin," produced by the liver and other tissues in response to GH.

The concept of a "GH axis" — hypothalamic GHRH and ghrelin stimulating, somatostatin inhibiting, and pituitary GH stimulating IGF-1 — is now a cornerstone of endocrine teaching. It also provides multiple pharmacological targets, from GH itself to GHRH analogs, ghrelin mimetics, and GH receptor antagonists such as pegvisomant.

Modern Relevance

Recombinant human GH is used for pediatric GH deficiency, Turner syndrome, Prader-Willi syndrome, small-for-gestational-age children who fail to catch up, chronic kidney disease-associated growth failure, idiopathic short stature, and adult GH deficiency. Long-acting weekly GH formulations have been approved for some indications, improving convenience compared with daily injections.

Growth hormone is also a prominent example of a peptide with significant off-label and performance use. GH and GH secretagogues are on the WADA Prohibited List and are monitored in competitive sport. Research continues into tissue-specific effects of GH, its role in aging, and its relationship with cancer risk and insulin resistance. For related topics, see gh-igf1-research.

Related Compounds

• Growth hormone
• IGF-1
• GHRH
• Somatostatin
• Pegvisomant