JAK Stat and the Beanstalk Growth Hormone, Mecasermin, Octreotide, Pegvisomant

4.1 - "JAK Stat and the Beanstalk": Growth Hor Hormone, mone, Meca Mecasermin, sermin, Octreot Octreotide, ide, Pegvisomant Physiology • Growth hormone (GH) is an anterior pituitary secreted peptide (beans spilling from front of burlap pituitary sack). Secreted with prolactin, which has significant homology. • Effects: o enters circulation and binds GH receptor → Dimerization and recruitment of receptor-associated JAK tyrosine kinase → intracellular JAK/STAT pathway (Tire swing for tyrosine; JAK/STAT “jacks up cell growth”) o Effects on carbohydrate, protein, & lipid metabolism, mainly mediated through IGF1 produced in the liver (rock).– acts similar to insulin with similar tyrosine kinase receptor (“welcome Inside” mat). In contrast with insulin, which stimulates sugar and fat storage, IGF1 is responsible for long bone growth (mat getting lifted by lanky bean sprout). ▪ High circulating levels with pubertal growth spurt (mat growing up). ▪ Required in childhood and adolescence for normal adult size & proper lean body mass & bone density () o GH has anabolic effects in muscle directly → muscle mass (striated muscle leaf on bulky vine). Catabolic effects in adipose tissues. Essentially shifts mass from fat to muscle (dumping donut jar for adipocyte lipolysis). • Excess serum GH most commonly seen in hormone secreting pituitary adenoma. Most commonly seen in adults → acromegaly (characterized by deep voice, Large hands and feet, Increased risk of colorectal polyps/cancer, Coarse facial features, impaired glucose tolerance or insulin resistance). Seen less commonly in children; before closure of growth plates, can cause gigantism. First line treatment is trans-sphenoidal resection. Rx • Somatotropin (exogenous GH) o Indications ▪ GH deficiency • Abnormal height increase + abnormal serum GH levels with appropriate stimulation (short kid holding up bean). • May be primary (genetic, developmental) or acquired (pituitary trauma, intracranial tumors, infection, radiation). ▪ Idiopathic short stature. Somewhat controversial. $$$ ▪ Increasing growth in Prader Willi syndrome (Padre Willi – missing father gene) →↓body fat and ↑lean muscle mass ▪ Increasing growth in Turner’s syndrome (turning X girl) o GH reduces insulin sensitivity, but IGF-1 exerts insulin like effects so the effects usually balance out. • Mecasermin(sermon) o recombinant IGF-1 o Indications ▪ Small number of children have growth failure d/t deficiencies in the IGF-1 rather than growth hormone. ▪ patients who are unable to respond to GH d/t resistance (e.g. anti-GH antibodies, receptor mutations). o May see hypoglycemia d/t exerting insulin effects (falling candy) • octreotide o Indications (generally counteract secretory effects of many hormone secreting tumors): ▪ Medical therapy for gigantism/acromegaly by inhabiting secretion of GH (octagon stop sign held up to giant). ▪ VIPoma & serotonin-secreting carcinoid tumors as well (crab sign over stop sign for “VIP customers only”). Generally used to reduce secretory diarrhea in these conditions, especially in incomplete resections. ▪ glucagonoma (ridiculously huge giant glucagon packet). Usually presents was weight loss & necrolytic migratory erythema ▪ insulinoma (big “welcome inside” mat – from excess). Fasting hypoglycemia ▪ Gastrinoma, with Zollinger-Ellison syndrome (massive gas tank) ▪ Can control bleeding of esophageal varices (decreased portal blood flow & variceal pressure). MOA poorly understood (exposed variceal pipes) o Adverse effects ▪ GI adverse effects (N/V, abdominal pain), steatorrhea d/t decreased pancreatic secretions & decreased gallbladder secretion (ill looking townsperson standing on yellow stool) • Cabergoline & bromocriptine o D2 receptor agonists o treat acromegaly by inhibiting secretion of GH from the pituitary (burglar with broomstick, climbing down two dope ropes). Also inhibit prolactin release (more effective than GH inhibition) (sac holding magic beans). • Pegvisomant: o GH Receptor antagonist; inhibits GH receptor preventing downstream effects (ants picking up beans off tire swing). May increase GH secretion d/t lack of feedback, and provoke adenoma growth.