L71: Posterior Pituitary and HPL Axis Flashcards
How is Oxytocin/Vasopressin(AVP) synthesized and processed?
Preprohormone (signal peptide, hormone, neurophysin, glycopeptide) -> processed and cleaved -> Neurophysin and Hormone are stored in vesicles
Which neurophysin molcules are associated with AVP and OXY?
OXY: Neurophysin I
AVP: Neurophysin II
What are hte 2 types of cells in the PVN?
MAgnocellular and Parvocellular
Only magnocellular project to posterior pituitary
Where are the cell bodies that secrete AVP?
PVN and SON
Where do the parvocellular PVN neurons project to ?
HAve AVP and project to median eminence to regulated mood
What are the AVP in magnocellular SON and PVN important for?
Maintaining fluid balance
What’s another name for AVP?
ADH: antidiuretic hormone
What stimulates release of AVP from the posterior pituitary?
Increase in plasma osmolality
Decrease in blood volume
Blood loss greater than 10% and decrease in mean arterial BP -> AVP release by decreased sympathetic tone (release neuronal inhibition)
How does AVP carry out its vasocontrictor effects?
Binds V1 receptor in vascular smooth muscle -> contraction -> increase vascular resistance
PLC/DAG/IP3 pathway
What is the principal funciton of AVP?
Increase water reabsorptionand conserve water
How does AVP conserve water?
Binds to V2 receptors in the principal cells of distal tubule -> PKA activation -> phosphorylate AQP2 -> insert into membrane -> increased water permeability
What is Diabetes Insipidus?
Defect in AVP causing excessive urine production
Due to:
Decreased AVP release (most common): hypothalamic or pituitary defect from trauma, cancer, disease
Decreased renal responsiveness to aVP: Genetic mutation in V2 receptor, or acquired via Li tx or hypokalmeia (Note: AVP levels are normal in these case)
Where is oxytocin released by?
MAgnocellular neurons from PVN
What is the function of oxytocin?
Smooth muscle cell contraction in breast and uterus
positive feedback loops
What is pitocin?
synthetic oxytocin used to induce labor
How does oxytocin signal on target tissues?
OXY binds to GPCR -> activate PLC signaling pathway > increase intracellular calcium -> Ca2+ binds Calmodulin -> activate myosin light chain kinase-> phosphorylate myosin filament-> smooth muslce contraction
Where is GHRH produced and what does it do?
Arcuate nucleus: stimulates GH from the anterior pituitary
How is GHRH synthesized and processed?
Preprohormone -> cleave signal peptide-> prohormone -> processing to form GHRH and C term peptide-> processing to active form
Where is Somatostatin produced and what does it do?
Periventricuar nucleus;
Inhibits GHRH pulse frequency at the hypothalamus
Inhibit GH and TSH release in pituitary
What are the dominant forms of somatostain in the intestines and the brain?
SS28: intestines
SS14: Brain
What is growth hormone?
Produced from somatotrope cells in anterior pituitary
Protein anabolic hormone-> conserve protein
What increases GH levels?
Stress, exercise, starvation
What causes GH levels to decrease?
Age, high blood glucose, obesity
How is GH released?
Pulsatile release mostly at night
How are most of hte downstream target organ effects of GH mediated?
Through IGF-1 (somatomedins) made in the liver
WHat stimulates GH release?
GHRH, Dopamin, NE/Epi, Amino acids, Thyroid Hormone
What inhibits GH release?
Somatostatin, IGF-1, glucose, FFAs
Describe the action of GH on peripheral tissues
GHRH stimulates GH release from posterior pituitary -> GH act on liver-> stimulate IGF-1 :
Direct GH Effects:
Liver: IGF-1
Adipose tissue: increased lipolysis and decreased glucose uptake
Skeletal Muscle: Increase protein Syntehsis
Indirect GH Effects: via IGF-1
What are the direct physiological effects of GH?
Direct actions promote lean body mass (inc protein and dec adiposity), mobilize glucose stores, increase plasma glucose
Targets: Liver,Adipose tissue, Muscle
What are the indirect effects of GH?
Stimulated by IGFs-> cellular differentiation in visceral organs and bone/cartilage growth => increase organ size and linear growth
IGF actions are DEPENDENT on INSULIN (GH stimultion of IGF is decreased in starvation states)
What does GH need to mediate its effects through IGF-1?
INSULIN
How is IGF-1 important for growth?
Peaks during critical growth periods -> defects in normal growth patterns usually due to defective IGF-1 receptors or signaling
What results with a somatotrope tumor?
GH Excess -> Acromegaly, Gigantism
What is Gigantism?
Somatotrope tumor that occurs before closing of epiphyseal plate during childhood -> leads to increased long bone growth and extreme height
What is acromegaly?
Diagnosed in middle age
Enlarged hands and feed (arthritis)
changes in facial features (protruding lower jaw, enlarged lips, tongue, nose)
Increased organsize
usually due to pituitary adenoma
What happens with GH deficiency?
Dwarfism (children)
Adults: Increased fat deposition, muscle wasting
What is Laron Syndrome?
Genetic defect in GH receptor -> no IGF-1 production -> plasma GH levels are normal-high due to lack of feedback
Tx: IGF-1 to prevent dwarfism
What is African Pygmy?
Partial defect in GH receptor->some IGF-1 response
Plasma GH levels normal but no pubertal increase in IGF-1
What is unique about prolactin?
Made by lactotropes which are not part of endocrine axis -> short feedback loop on hypothalamic dopamine
No stimulating factor from hypothalamus
How is prolactin regulated?
Tonically inhibited by dopamine from the arcuate nucleus
How is prolactin transporte din blood?
Not bound to serum protein
What sitmulates release of prolactin?
Suckling-> stimulus secretion reflex
Also by TRH and OXY
What are the physiological effects of prolactin?
Mammary gland development
Breast differentiation
Milk production
How does estrogen affect prolactin?
Increase prolactin synthesis and lactotrope hypertrophy
What is the consequence of the similarity between GHa nd prolactin?
Nonspecific binding of either receptor when one is produced in excess
Example: Excess GH -> GH binding to PRL receptor -> galactorrhea
What causes prolactin excess and what does it cause?
Prolactinomas: hyperprolacinemia, galactorrhea, reproductive dysfunction (prolactin inhibits GnRH release)
What is Sheehan’s Syndrome?
Prolactin Deficiency due to excessive blood loss/shock during childbirth -> causes partial pituitary destruction
How do you evaluate anterior pituitary function?
Measure hormone in pairs (ex: ACTH + Cortisol)
Measure at appropriate time or longitudinally (take into account circadian rhythm and age)
Stimulation/Inhibition test to test feedback and pitutiary function (Ex: TRH challenge)
Predict Neg Feedback Effects (Ex: insulin induced hypoglycemia should lead to inc GH levels; Administered IGF-1 should lead to decreased GH levels)
What stimulates GH?
GHRH Dopamine NE/EPi (Exercise, stress) Amino acids Thyroid hormone
What inhibits GH?
IGf-1
High glucose
Obesity (high FFas)
