Growth Hormone-Releasing Hormone (GHRH)

Growth hormone-releasing hormone is a 44-amino-acid peptide released by arcuate nucleus neurons into the hypophyseal portal circulation. It binds a class B G protein-coupled receptor confined almost entirely to pituitary somatotrophs, raising cyclic AMP to drive both release of stored hormone and new synthesis. Its first 29 residues carry the full activity, and GHRH(1-29) is the template for every clinical analogue.

Native GHRH is fragile. Dipeptidyl peptidase-4 cleaves it after the alanine at position 2, leaving an inactive fragment and a circulating half-life of minutes. Sermorelin, plain GHRH(1-29), was approved in the United States for paediatric growth hormone deficiency and later withdrawn. Tesamorelin, a GHRH(1-44) analogue carrying an N-terminal trans-3-hexenoyl group that blocks that cleavage, was approved by the FDA in 2010 to reduce excess visceral fat in HIV-associated lipodystrophy.

GHRH only works through cells that can still respond. Because it amplifies the somatotroph's own secretory machinery rather than substituting for it, the response is capped by pituitary reserve and remains under somatostatin restraint: the same pulse arriving during a somatostatin trough produces a far larger burst than one arriving during a peak. That dependence is the practical difference between stimulating the axis and injecting growth hormone, and it is why a failed pituitary does not respond at all.

The recurring error is treating GHRH-receptor agonists and ghrelin-receptor peptides as interchangeable releasers. They act on different receptors through different second messengers, and in combination the growth hormone response is supra-additive rather than cumulative, so single-agent data cannot be read across. The second error is citing sermorelin's approval history as evidence of an anti-ageing indication; that approval was for short stature in children.