Posterior pituitary and HPL axis (L4) Flashcards
Makeup of oxytocin and vasopressin
Both nonapeptides made first as preprohormones
Prohormones of OXY and AVP
Oxytocin + neurophysin I,
AVP + neurophysin II
Preprohormones of OXY and AVP
9 AAs, glycopeptide, signal peptide, and neurophysin
When is neurophysin cleaved from the peptide?
In the secretory granules during transport
What types of cells are located in the paraventricular nucleus?
Magnocellular and parvocellular
Which of the two cell types in the paraventricular nucleus projects to the posterior pituitary?
Magnocellular
What happens with the parvocellular cells in the PVN that contain AVP?
They project to the median eminence and other brain regions to regulate mood/stress
What is the purpose of magnocellular cells in the PVN and SON?
Maintaining body fluid homeostasis
AVP is stimulated by what two factors?
Increase in osmolality and decrease in fluid volume
Describe the sensitization of AVP neuron with blood volume loss.
Blood loss greater than 10% and a decrease in mean arterial pressure increases sympathetic neural input, releasing the inhibition on magnocellular cells
Cellular mechanism of AVP vasoconstrictor effects
AVP binds the V1 receptor in smooth muscle, activating PLC to make IP3 and DAG, increasing intracellular calcium concentration. This binds to the calmodulin in the cell, activating myosin light chain kinase, therefore increasing contractions
Cellular mechanism of AVP osmoregulation effects
Binds to V2 receptors in the distal tubules of the kidney, activating PKA and stimulating insertion of aquaporin 2 channels in the apical membrane. Water moves transcellularly and exits into the bloodstream through aquaporin 3 and 4 channels
What is the primary dysfunction in diabetes insipidus?
AVP defect
What is the most common etiology of diabetes insipidus?
Decreased AVP release due to hypothalamic trauma related to trauma, cancer, or infection.
What is the second, less common etiology of diabetes insipidus?
Decreased renal responsiveness to AVP. Can be genetic or acquired
Describe genetic diabetes insipidus.
X-linked; 90% in males. Mutation in AVP receptor
Describe acquired diabetes insipidus.
Nephrotoxicity from lithium treatment, hypokalemia
In the case of diabetes insipidus due to decreased responsiveness to AVP, what are the blood levels of AVP?
Normal
Primary clinical presentation of SIADH
Hyponatremia in the absence of edema
What percentage of patients have SIADH from primary pituitary dysfunction?
Only 33%
Other causes of SIADH (4)
CNS disorders (lesions, trauma, infections)
Lung diseases
Extrapituitary tumors
Low sodium: sodium loss due to lack of aldosterone will cause hypovolemia and increased AVP release
By what/where is oxytocin released?
Released by magnocellular neurons in the PVN and released in the posterior pituitary
Main function of oxytocin
Induction of smooth muscle contraction in the breast tissue and uterus
How is oxytocin regulated?
In a positive feedback loop
Mechanism of smooth muscle contraction stimulated by oxytocin
Oxytocin binds to GPCR, activating PLC to increase DAG and IP3, increasing the intracellular calcium concentration. This binds to calmodulin, and the calmodulin:Ca2+ complex activates myosin light chain kinase to induce smooth muscle contraction
How long is growth hormone releasing hormone?
44 amino acids long
Where is GHRH made and released?
In the arcuate nucleus
What is cleaved off of GHRH in the biosynthetic process?
GCTP (GHRH C-terminal peptide)
How long is somatostatin?
14 amino acids long
Where is somatostatin produced?
In the periventricular nucleus
What does somatostatin do?
Inhibits GHRH pulse frequency in the hypothalamus, and inhibits GH and TSH in the pituitary
What two types of somatostatin exist, and where are they each most dominant?
SS14 - pituitary
SS28 - intestine
Endopeptidases important in the biosynthetic processing of somatostatin
Furin, PC1, and PC2
What is the main goal of growth hormone?
To conserve protein (protein anabolic hormone)
Growth hormone is in the same family as what other hormone?
Prolactin
What are environmental activators and inhibitors of GH?
Activators: starvation, stress, exercise
Inhibitors: obesity, age, and high blood glucose
GH is mostly released when and in what fashion?
Pulsatile release; greatest during the nighttime
Many of the effects of GH are mediated through __
IGF-1
Primary actions of GH
Liver: release of IGF-1
Adipose: increase lipolysis/decrease glucose uptake
Skeletal muscle: increase protein synthesis
Indirect effects of GH
Mediated through IGF-1
- Cellular proliferation in visceral organs
- Bone/cartilage growth
IGF-1 is dependent on __
The presence of insulin
Defects in normal growth are often caused by __
defective IGF-1 release or signaling
GH excess etiology
20% caused by somatotrope tumor
Two syndromes caused by excess GH
Gigantism and acromegaly
When does gigantism occur?
Before closing of epiphysial plates in childhood
When is acromegaly usually diagnosed?
In middle age
Physical manifestations of acromegaly
Gradual enlargement of hands and feet; protruding of jaw, enlarged lips, tongue, and nose
Visceral manifestations of acromegaly
Possible increase in organ size
Most common cause of acromegaly
Pituitary adenoma
Etiology of Laron syndrome
No GH receptors, so no release of IGF-1
Treatment of Laron syndrome
IGF-1 supplementation
Blood hormone levels in Laron syndrome
Lack of IGF-1, normal to high GH due to lack of feedback
African pygmies
Partial lack of GH receptors, so some IGF-1 is released
Adult GH deficiency
Increased fat deposition, muscle wasting
How is prolactin unique?
It is not part of an endocrine axis; it uses a short-loop feedback system on hypothalamic dopamine. No unique stimulating factor from the hypothalamus
Inhibition of prolactin
Tonically inhibited by dopamine
Half-life of prolactin
20 minutes; not bound to any carrier proteins
Stimulus-secretion reflex
Prolacin is released in response to suckling
Physiologic effects of prolactin
Mammary development, breast differentiation, milk formation
Components of breast differentiation mediated by prolactin
Duct proliferation and branching
Glandular tissue development
Components of milk production mediated by prolactin
Synthesis of milk proteins (beta-casein and alpha-lactalbumin)
Synthesis of milk sugar: lactose
Synthesis of milk fats
What hormones can cause increase in prolactin release?
TRH and oxytocin
Estrogen and prolactin
Increases synthesis of prolactin and hyptrophies lactotrophs
Consequences of structural similarity of growth hormone and prolactin
If one of the hormone levels is really high, it can lead to non-specific binding and extra effects of the other hormone (e.g., high GH can lead to galactorrhea)
What percentage of pituitary adenomas are prolactinomas?
30-40%
Three symptoms of prolactinomas
Hyperprolactinemia
Galactorrhea
Reproductive dysfunction from GnRH inhibition
Sheehan’s syndrome
Caused by excessive blood loss/shock during birth
Partial pituitary destruction results, leading to lack of prolactin and other pituitary hormones
How must hormones be measured when evaluating anterior pituitary function?
In pairs; must evaluate simulating hormone and actual levels
Timing of hormone measurement
Must be correlated to the right time of day/age of the patient
Dexamethasone suppression test
Used typically to diagnose Cushing’s syndrome; dexamethasone inhibits ACTH release. If there is a corticotrophic adenoma, levels will not decrease
TRH challenge
(Review graph from lecture three)
Insulin-induced hypoglycemia should result in . . .
increased GH levels
Injection of IGF-1 should result in . . .
decreased GH levels
