Pharmacology: Pituitary II Flashcards
What are the direct actions of growth hormone?
- GH directly stimulates fat metabolism throughout the body and directly stimulates gluconeogenesis in the liver
- *- GH stimulates IGF-1 (somatomedin C) synthesis and release in the liver**
- -> GH receptors are also on chondrocytes where GH stimulates IGF-1 synthesis and releas
- -> IGF-1 increases AA transport into tissues and increase protein synthesis and is responsible for elongation of bone
How does somatostatin affect Growth Hormone actions?
Somatostatin is released from the hypothalamus SST receptors on the anterior pituitary –> Activates both Gi and Go proteins
Go –> shuts down Ca channels and GH isn’t released
Gi –> shuts down adenylate cyclase and cAMP
(an inhibitory affect on growth hormone release)
–> leads to decreased GH release, and decreased IGF-1 activity
How does Growth Hormone Releasing Hormone affect Growth Hormone actions?
GHRH is released from the hypothalamus onto GHRH receptors on the anterior pituitary –> Gs stimulation –> adenylate cyclase stimulation –> cAMP activates Protein Kinase A –> GH gene transcription –> Ca is allowed into the cell and along with other enzymes (which were activated by PKA) allows GH release into the blood
–> GH stimulates fat metabolism and gluconeogenesis and IGF-1 synthesis and release in liver
What are factors that stimulate GH release?
- Hypoglycemia
GH stimulates fat metabolism and gluconeogenesis when glucose is low
- Amino acids
Necessary for bone growth/protein synthesis
Arginine is most potent
- Deep sleep
- Exercise
- Dopamine agonists
DA normally stimulates GH release by inhibiting SST release, but in acromegaly DA inhibits GH release
What is the MOA of GH?
Growth hormone causes to GH receptors to dimerize and bind to JAK2 kinase
–> JAK2 kinase phosphorylates the GH receptor and itself and then STAT5 (all on tyrosine residues)
–> Phosphorylated STAT5 proteins dimerize, translocate to nucleus, and activate gene transcription
What are the types of recombinant GH?
Somatrem (mild allergies occur in 50% of patients)
Somatropin (less allergenic)
What is growth hormone therapy used for?
Treatment of:
hypopituitary dwarfism (Laron syndrome)
Short stature
What is Laron syndrome?
Defect in GH receptor
–> GH cannot stimulate somatomedin C (IGF-1) synthesis and release
–> leads to stunted growth
Characteristic labs:
HIGH growth hormone
LOW somatomedin C
What is Mecasermin?
rhIGF-1 combined with rhIGF-BP-3 to increase IGF-1 stability
–> effective in treating Laron dwarfism
What is acromegaly?
- Excess GH production after closure epiphyseal plates
- Usually due to adenoma of somatotrophs
Features include:
Broadening of nose
Elongationg of Mandible
Severe narrowing of joints (degenerative arthritis)
Carpal tunnel syndrome
Glucose intolerance
Hypertension
Hypertrophy of organs (cardiomegaly and CHF)
What is the pathophysiology of acromegaly?
Normally:
GHRH is needed to activate Gs –> stimulates adenylyl cyclase in somatotrophs
Acromegalyl:
GTPase of Gs is inactive –> Gs and adenylyl cyclase are constitutively active in absence of GHRH
What are the possible treatments for acromegaly?
Surgical removal or irradiation
Bromocriptine
Cabergoline
Octreotide
Pegvisomant
What is the MOA of bromocriptine?
A treatment option for acromegaly, on tumors made up of somatotrophs that have reverted to a stem cell-like phenotype with D2 dopamine receptors
- these progenitors generally secrete both GH and prolactin
Bromocriptine (a dopamine agonist) is able to treat these tumors
What is cabergoline? Serious side effect?
A very long-acting D2 agonist that works on somatotrophic adenomas that are in progenitor form (have D2 receptors and secrete both prolactin and GH)
–> can cause mitral valve thickening and valve issues
What is octreotide?
Somatostatin analog treatment for acromegaly
–> is a peptide and must be injected every 30-45 days
