Flashcards in Pituitary Physiology Deck (11)
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1
Growth hormone - general notes on structure/function
- Starts as prohormone
- Contains many introns and exons, can be spliced for different types of GH
- Most important type is 191 AA long
- Signal peptide cleaved, stored in secretory granules of somatotrophs of adenohypophysis
- Secretion controlled primarily by GHRH & somatostatin (GH feeds back on both of these)
- GHRH --> increased GH --> increased cAMP
- Somatostatin --> decreased GH --> decreased cAMP
- Increased serum AA --> increased GH
- Test by injecting arginine
- Decreased serum glucose --> increased GH
- Significant counter-regulatory hormone for insulin action
- Metabolically GH dominates; with growth IGF dominates
- GHRH --> increased GH --> increased cAMP
- Somatostatin --> decreased GH --> decreased cAMP
- Test by injecting arginine
- Significant counter-regulatory hormone for insulin action
2
Effects of GH malfunction (table)
3
Prolactin: actions and MOA
- Tonically inhibited by hypothalamic secretion of prolactin inhibitory hormone (PIH) aka dopamine
- If hypothalamus is inhibited: adenohypophysis secretes larger amounts of PRL, other pituitary hormones
- Lactotrophs secrete PRL
- Principal target (and main site of action): breast (mammary gland)
- Plays role in production of milk
- High levels of PRL inhibit pulsatile secretion of GnRH by hypothalamic neurons
- Specific receptors in: breast, liver, ovary, testis, prostate
- Prolactin receptors --> members of growth hormone/cytokine receptor families
- Long form of receptor: 620 AA's in length
- Single chain proteins, cross the membrane only once
- Ligand binding causes receptor dimerization --> activation of JAK/STAT pathway
- PRL/GH share structural homology (so do their receptors)
- PRL receptors well-stimulated by GH
- Lactotrophs secrete PRL
- Plays role in production of milk
- Long form of receptor: 620 AA's in length
- Single chain proteins, cross the membrane only once
- Ligand binding causes receptor dimerization --> activation of JAK/STAT pathway
4
Direct action of growth hormones on organs and systems
- Adipose tissue
- Increases lipolysis, leads to mobilization of lipids and increased FFAs in plasma
- Leads to eventual loss of subcutaneous fat
- GH is counter-regulatory to insulin
- Muscle --> strong anabolic effect
- Increases amino acid transport and protein synthesis
- Liver --> increases RNA, protein, glucose synthesis
- Increases IGF-1 secretion in presence of insulin, mediates indirect effects
- Increases glucose due to increase in gluconeogenesis and glycogenolysis (small extent)
- General --> GH is anti-insulin-like (decrease glucose uptake/increase glucose in plasma)
- FFAs in plasma provide energy source
- Glucose preserved for CNS
- Protein sparing
5
Other effects of growth hormone on organs and systems
- Fundamental for postnatal growth
- Stimulates somatic growth
- Regulates metabolism
- Indirect actions: mediated via IGF-1
- Powerful mitogen and growth-promoting agent
- Stimulates somatic growth
- Regulates metabolism
- Powerful mitogen and growth-promoting agent
6
MOA of growth hormone through binding to its receptor
- Cytokine receptor
- Dimerizes on GH binding
- Activates JAK/STAT pathway --> gene expression
7
Effects of IGF-1: bone/cartilage
- Stimulates proliferation of epiphyseal plate
- After puberty, linear growth at plate stops (growth plates close)
8
Effects of IGF-1: muscle
- Stimulates proliferation, differentiation, protein synthesis
- Particularly post-puberty
9
Effects of IGF-1: adipose tissue
- Stimulates uptake of glucose and inhibits lipolysis
- Function is insulin-like and antagonizes GH
10
Effects of diet on IGF-1 function
- Production of IGF-1 requires GH and insulin --> only grow in times of plenty!
- Normal diet --> nice balance
-
Eating lots: increased serum AA --> increased GH and increased glucose --> increased insulin --> increased IGF
-
Starvation: decreased serum AA --> increased GH and decreased glucose --> decreased insulin --> no IGF
- Thus in times of fasting: GH elevated but IGF-1 levels are depressed
- Safety mechanism for body saying not to waste energy on growth
- Normal diet --> nice balance
- Eating lots: increased serum AA --> increased GH and increased glucose --> increased insulin --> increased IGF
- Starvation: decreased serum AA --> increased GH and decreased glucose --> decreased insulin --> no IGF
- Safety mechanism for body saying not to waste energy on growth
11
MOA of IGF-1
- Receptors are EGF/Insulin receptor family
- Inherent tyrosine kinase activity
- Upon ligand binding, can readily phosphorylate themselves (autophosphorylation) and other proteins of signal transduction pathway
- Major pathway --> IGF binds to insulin receptor associated proteins 1 and 2 (IRS I & II) --> IRS then bind other moelcules to activate either:
- MAP kinase pathway, or
- Transduction mediated by PI-3 kinase
- MAP kinase pathway, or
- Transduction mediated by PI-3 kinase
