Somatostatin

Somatostatin is an inhibitory peptide hormone produced from a single precursor as two active forms, a 14-residue peptide closed by a disulfide bond and a 28-residue N-terminally extended version. It was isolated from hypothalamic extracts as the factor blocking growth hormone release, hence the name somatotropin release-inhibiting factor. Hypothalamic somatostatin comes chiefly from the periventricular nucleus and reaches the pituitary by the portal circulation, but the peptide is also made by pancreatic delta cells, gut endocrine cells and brain neurons.

It acts through five G protein-coupled receptors, SSTR1 to SSTR5, coupled to Gi and thus to inhibition of adenylyl cyclase, the opposite arm to the one GHRH uses on the same somatotroph. Its inhibitory reach is broad: growth hormone and TSH from the pituitary, insulin and glucagon from the islets, gastrin and secretin from the gut, and pancreatic exocrine output. Its circulating half-life is a couple of minutes, which is why native somatostatin has no therapeutic use and all clinical agents are engineered analogues.

Within the growth hormone axis somatostatin is the reason secretion is pulsatile at all. The trough between bursts is actively imposed, not passively empty, and the size of a pulse depends as much on how far somatostatin tone has fallen as on how much GHRH arrives. Falling somatostatin tone in slow-wave sleep is what permits the large nocturnal burst.

The point most often missed is that somatostatin is not selective for growth hormone. Suppressing this axis pharmacologically also suppresses insulin, glucagon, TSH and gut hormones, which is the source of the hyperglycaemia, gallstones and gastrointestinal effects seen with analogues. It is also why blunted growth hormone responses in the obese or the acutely ill reflect regulation working, not a pituitary that has failed.