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?
GH stimulates fat metabolism and gluconeogenesis when glucose is low
- Amino acids
Necessary for bone growth/protein synthesis
Arginine is most potent
- Deep sleep
- 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?
hypopituitary dwarfism (Laron syndrome)
What is Laron syndrome?
Defect in GH receptor
--> GH cannot stimulate somatomedin C (IGF-1) synthesis and release
--> leads to stunted growth
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
Broadening of nose
Elongationg of Mandible
Severe narrowing of joints (degenerative arthritis)
Carpal tunnel syndrome
Hypertrophy of organs (cardiomegaly and CHF)
What is the pathophysiology of acromegaly?
GHRH is needed to activate Gs --> stimulates adenylyl cyclase in somatotrophs
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
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
What is Pasireotide?
New in 2013!
- somatostatin analog to treat Cushing's disease that persists after surgical removal of an ACTH-secreting pituitary tumor
What is Pegvisomant?
A mutant form of GH acts as an antagonist at the GH receptor
--> used to treat acromegaly
--> It's a pegylated mutant hormone (PEG decreases antigenicity) that causes GH receptors to dimeraize, but not become activated
How does dopamine affect prolactin release?
Increased dopamine levels --> decreased prolactin; decreased milk production
Decreased dopamine --> increased prolactin; increased milk production
--> Increased prolactin levels feed back to activate dopamine release (negative biofeedback)
What is the MOA of TRH on prolactin release?
TRH can cause prolactin release:
TRH receptors activate Gq protein --> Phospholipase C (PLC) is activated to cleave PIP2 into IP3 --> IP3 goes to ER to release Ca stores --> increased Ca leads to prolactin release
What is the MOA of dopamine on prolactin?
Dopamine receptors activate Gi/Go proteins, leading to decreased Ca entering cells and decreased Adenylyl cyclase --> leading to decreased cAMP
--> no cAMP and closed Ca channels inhibits production and release of prolactin
What are causes of Hyperprolactinemia?
- Lack of sufficient dopamine
- Adenoma of lactotrophs
microadenoma vs macroadenoma
Excess TRH stimulates lactotrophs
Most block D2 receptors
What are symptoms of hyperprolactinemia?
- Galactorrhea in females (rarely in males)
- Gynecomastia in males
- Amenorrhea due to elevated prolactin decreasing GnRH release leading to reversible infertility
- Loss of vision due to compression of optic nerves (macroadenoma only)
What are the treatments of hyperprolactinemia?
- Surgical removal of adenoma
- Dopamine agonists:
Is bromocriptine safe during pregnancy? Why might it be necessary?