Posterior Pituitary and the HPL Axis Flashcards
What is the size of oxytocin and vasopressin, and what are they synthesized as?
They are nonapeptides and are transcribed as a preprohormone
What does the preprohormone of OXY and AVP consist of?
signal peptide, hormone (AVP/OXY), neurophysin, and a glycopeptide
What does the prohormone of OXY and AVP consist of?
OXY + Neurophysin I
AVP + Neurophysin II
What is AVP and what is it also known as?
Arginine vasopressin, also known as ADH (antidiuretic hormone)
When is neurophysin removed from the hormone?
during axonal transport in the secretory granules
Where are the cell bodies that produce AVP located?
The paraventricular nucleus (PVN) and supraoptic nucleus (SON)
What are the two types of cells located in the PVN?
Magnocellular and parvocellular
Which PVN cell type has neurons that project to the posterior pituitary?
Only magnocellular
some parvocellular PVN neurons also contain AVP. Where do they project and what do they do?
Parvocellular PVN neurons that contain AVP project to the median eminence and are important in regulating mood(anxiety)/stress
What does AVP in magnocellular SON and PVN do?
regulates fluid balance
What triggers AVP release?
Increase in blood osmolality and a decrease in blood volume
slight changes in what will trigger AVP release?
osmolality
Will thirst occur before or after AVP release?
changes in osmolality will stimulate AVP release well before the thirst mechanism sets in
How does an increase in plasma osmolality lead to AVP release?
decreased osmolality will draw water out of the cells of the osmoreceptors into the vasculature. This shrinking of the osmoreceptors will result in less inhibition of magnocellular neurons resulting in AVP release
What does AVP do?
Acts on kidney to promote water reabsorption in the distal tubules
How does a decrease in MAP lead to AVP release?
a decrease in MAP (i.e. hemorrhage) ill result in decreased baroreceptor firing and an increase in sympathetic tone. This will activate magnocellular neurons resulting in AVP release
What is more sensitive - baroreceptors or osmoreceptors?
Osmoreceptors. Slight changes in osmolality will lead to AVP release. You have to have a 5-10% volume loss in order to activate baroreceptor mediated AVP release
How does AVP result in vasoconstrictive effects?
AVP binds V1 receptors (G-protein coupled and PLC cascade) on vascular smooth muscle resulting in constriction and increasing vascular resistance
What is the principle function of AVP?
To increase water reabsorption and conserve water
How does AVP act on the distal tubules?
It binds V2 receptors in the principle cells of the distal tubules
What happens on binding of AVP to principle cells?
Activates PKA to phosphorylate Aquaporin 2 (AQP2) which is inserted into the membrane and allows water to be reabsorbed
What is diabetes insipidus?
AVP defect
What are the two main causes of diabetes insipidus?
Decreased AVP release (most common)
Decreased renal responsiveness to AVP (AVP levels are normal in these cases)
What can cause decreased AVP release?
hypothalamic or pituitary defect due to trauma, cancer, infection, etc.
What can cause decreased renal responsiveness to AVP?
Genetic: X-linked mutation in AVP2 receptor (90% males)
Acquired: lithium treatment, hypokalemia
What is the clinical presentation of SIADH?
hyponatremia in the absence of edema
What is the etiology of SIADH?
SIADH due to a primary pituitary disorder only accounts for 33% of patients
What are some other factors that can result in SIADH?
CNS disorders, lung disease, extrapituitary tumors, low sodium (results in low blood volume which will stimulate AVP release even with a decreased blood osmolality)
What is oxytocin released by, and where are their cell bodies located?
released by magnocellular neurons with cell bodies located in the PVN
Where is oxytocin released?
axon terminals in the posterior pituitary
What is the function of oxytocin?
smooth muscle contraction in the breast and uterus
What kind of feedback is oxytocin release regulated by?
positive feedback loops
What is a synthetic oxytocin and what is it used for?
Pitocin –> used to induce labor
What does OXY bind to and what signaling does it induce?
binds to GPCR and activates PLC signaling which increases intracellular Ca
How big is GHRH, where is it produced, and what does it do?
44AA, produced in the arcuate nucleus, stimulates GH release from the anterior pituitary
How is GHRH processed?
Produced as a preprohormone, signal peptide cleaved to give GHRH and a c-terminal peptide GCTP, which is then later processed to give the active form of GHRH
How big is somatostatin and what does it do?
14AA produced in the PeVN
What does somatostatin do?
Inhibition of GHRH pulse frequency at the level of the hypothalamus
Inhibits GH and TSH release from the anterior pituitary
How is somatostatin processed, and what/where are the 2 main forms?
the endopeptidases Furin, PC1, and PC2 are responsible for the processing of SS28 and SS14.
SS28 predominates in the intestines
SS14 predomintaes in the brain
What is growth hormone released by?
Somatotrope cells (anterior pituitary)
What is the overall goal of GH?
Protein conservation
What increases GH?
Stress, exercise, starvation
What decreases GH?
aging, high blood glucose, obesity
When is GH mostly released?
at night, in a pulsatile fashion
What are the stimulators of GH?
GHRH, dopamine, norepi/epi, AA (protein building), TH
What are inhibitors of GH?
somatostatin, IGF-1, glucose (hyperglycemia), FFA (obesity)
Where does IGF-1 inhibit GH?
in the pituitary
What does GH do?
GH acts on the liver to stimulate IGF-1 (stimulaiton is insulin dependent), on adipose tissue ti increase lipolysis and decrease glucose uptake, and on skeletal muscle to increase protein synthesis
What do the direct effects of GH promote?
stimulated by hypoglycemia and exercise, GH promotes lean body mass (increased protein, decreased adiposity), mobilization of glucose stores, and increased plasma glucose levels
What are the indirect effects of GH mediated by?
IGFs
What are IGF functions dependent on?
Insulin
What are the actions of IGF?
stimulate cellular proliferation in visceral organs and bone/cartilage growth
What is GH excess a result of?
somatotrope tumor (20%)
What can excess GH result in?
Gigantism - rare, occurs before closing of epiphyseal plate in childhood - increases long bone growth resulting in extreme height
acromegaly - diagnosed in middle age, gradual enlargement of hands and feet leading to arthritis, facial changes, increased organ size - usually due to a pituitary adenoma
What can a GH deficiency result in?
Dwarfism (children) and Adult GH deficiency
What are the two dwarfism syndromes, and what are their main features?
Laron syndrome: genetic defect in GH receptor, and thus no IGF. Treatment with IGF-1 can prevent dwarfism
-plasma GH levels are normal to high, due to no negative feedback
African pygmy: partial defect in GH receptor and thus some IGF response
-plasma levels of GH are normal, but no pubertal increase of IGF-1 during puberty
What is adult GH deficiency?
characterized by increased fat deposition, muscle wasting
What does prolactin do?
breast differentiation
duct proliferation and branching
glandular tissue development
synthesis of milk protein: beta-casein and alpha-lactalbumin
synthesis of milk sugar: lactose
synthesis of milk fats in epithelial cells
How is prolactin unique?
lactotropes are not part of an endocrine axis as there is no unique hypothalamic stimulator. There is a short-loop feedback on hypothalamic dopamine (from arcuate nucleus)
What is prolactin tonically inhibited by?
Dopamine
How is prolactin found in the blood?
It is not bound to serum proteins and thus has a lifespan of about 20 minutes
how is prolactin stimulated?
suckling or TRH or OXY
What does estrogen do in regards to prolactin?
Estrogen increases prolactin synthesis and lactotrope hypertrophy
What is similar between GH and prolactin?
similar structure, come from the same family of peptides
What can result from prolactin excess?
prolactinomas are 30-40% of all pituitary adenomas
results in hyperprolactinemia, galactorrhea, and reproductive dysfunction (as prolactin inhibits GnRH release)
What can result from prolactin deficiency?
Sheehans syndrome: a result of blood loss at birth, can result in partial pituitary destruction
How would you evaluate anterior pituitary function?
measure hormones in pairs
measure at an appropriate time or longitudinally
stimulation/inhibition tests to assess feedback and pituitary function
- dexamethasone suppression test
- TRH challenge
predict negative feedback effects
