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FHB IV- Endocrinology > Endocrinology 4 > Flashcards

Endocrinology 4 Flashcards

1
Q

Discuss the structure, processing, and primary endocrine functions of AVP released from the posterior pituitary.

A

Slide 5

Nonapeptides
(9 amino acids)

Transcribed as a preprohormone

Prohormones:
AVP + neurophysin II,
OXY + neurophysin I

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2
Q

Describe the processing of AVP and OXY.

How many aa? (What type of peptides?)

How are they transcribed?

Describe their prohormone form.

A

Nonapeptides
(9 amino acids)

Transcribed as a preprohormone (signal, hormone, neurophysin, glycopeptide)

Prohormones:
AVP + neurophysin II,
OXY + neurophysin I

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3
Q

Is preprohormone pre-mRNA, gene, mRNA protein?

Prohormone?

A

mRNA -preprohormone
prohoromone- proteins (products after translation, processing and packaging of preprohormone =mRNA)

slide 6

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4
Q

Describe the Cell bodies located in paraventricular nucleus (PVN) and supraoptic nucleus (SON).

A

PVN has two types of cells: magnocellular and parvocellular. Only magnocellular neurons project to posterior pituitary.

Parvocellular PVN neurons that contain AVP project to median eminence and are important for regulating mood (anxiety)/stress.

AVP in magnocellular SON and PVN important for maintaining fluid balance.

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5
Q

When is the binding protein separated from prohormone?

A

Neurophysin is cleaved from the prohormone in the secretory granules during axonal transport.

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6
Q

Describe the target organs and mechanism of action for AVP released from the posterior pituitary including vasculature, kidney, and sympathetic nervous system.

A

Integration of signals that trigger AVP release from posterior pituitary. AVP
is stimulated by an increase in plasma osmolality and a decrease in blood
volume.

Small changes in plasma osmolality trigger AVP release prior to
thirst. Decreased blood volume sensitizes the system.

Blood loss greater than 10% and a decrease in mean arterial blood pressure triggers AVP release.

This is mediated by a increase in sympathetic
inputs, which releases magnocellular
neuronal inhibition.

slide 10

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7
Q

Describe/diagram the cellular mechanism of AVP vasoconstrictor effects.

(Is Actin and MLC active when phosphoryated or dephosphorylated?)

(If myosin phosphatase active will there be vasoconstriction or vasodilation?)

A

Cellular mechanism of AVP
vasoconstrictor effects.

AVP binds the V1 receptor in vascular smooth muscle
cells producing contraction and increasing vascular resistance.

DG = diacylglycerol. MLC = myosin light chain.

slide 11

actin and MLC active when P. (vasoconstriction)
vasodilation- when myosin phosphatase is active

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8
Q

Describe the cellular mechanisms of AVP water conservation.

What is the principal function of AVP?

To what does AVP bind? Where?

Which aquaporin channels are on basolateral/apical side?

A

Cellular mechanisms of AVP water conservation.

The principal function of AVP is to increase water reabsorption and conserve water.

AVP binds to V2 receptors in the principal cells of the distal tubule. PKA activation phosphorylates the water channel Aquaporin 2 (AQP2), which is then inserted into the membrane and allows increased water permeability. Water then
leaves the cell at the basolateral side through AQP3 and AQP4 channels.

Slide 12

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9
Q

List the primary etiologies and symptoms associated with diabetes insipidus.

How might AVP levels change? Why?

What is big clue to test for diabetes insip.?

A

Diabetes = excessive urine production

Etiology: 2 main causes
Decreased AVP release – most common defect
Hypothalamic or pituitary defect “central” due to trauma, cancer, or infectious disease.

Decreased renal responsiveness to AVP
Genetic: X-linked mutation in AVP type-2 receptor – 90% males
Acquired: lithium treatment, hypokalemia
AVP levels are normal

-hypokalemic chronic states- can interfere w countercurrent regulation going on in kidney
-AVP levels typically normal bc thirst mech. can compenstate for changes in plasma osmolality
(differential diagnosis- alter plasma osmolality and see what happens through water restriction)

have to water restrict to tell if diabetes insip. big clue is if they have to get up in middle of night to urinate (water restricted during the night…)

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10
Q

What can lithium cause? How?

A

Decreased renal responsiveness to AVP

mutation in AVP type-2 receptor

Acquired: lithium treatment
AVP levels are normal

Slide 14

also can have decreased renal responsiveness- most common reason in adults is acquired (lithium treatment prescribed for bipolar disease, enters through epithelial sodium channels but cant get out so accumulates inside cell and interferes w AVP abiity to traffic AQP2 channels) accumulation inside cell may either decrease AQP2 synthesis or increase lysosomal degradation of these channels

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11
Q

List the primary clinical presentation and etiology of Inappropriate Vasopressin Secretion (SIADH).

A

Primary clinical presentation: hyponatremia (low sodium plasma levels) in the absence of edema.

Etiology –
SIADH due to primary pituitary disorder only accounts for 33% of patients.

Other causes:
CNS disorders – lesions, infections, trauma
Lung disease – infections
Extrapituitary tumors
Low sodium: sodium loss due to lack of aldosterone will cause hypovolemia (low blood volume).
AVP is triggered by low blood volume and will be secreted despite the decrease in plasma
osmolality.

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12
Q

Explain the processing, and primary endocrine functions of OXY and discuss how OXY is regulated.

What is oxytocin released by? Where?
Main function?

How is it regulated?

What will stimulate oxytocin release? What will inhibit oxytocin release?

A

Oxytocin is released
by magnocellular neurons whose cell bodies are located in the PVN. It is
released at axonal terminals in the posterior pituitary.

Its main function
is to induce smooth muscle cell contraction in the breast and uterus.

OXY release is regulated by positive feedback loops.
“pitocin” = synthetic oxytocin used to induce labor.

Slide 16
(stretch of cervix/end of pregnancy and suckling of lactating breast will stimulate PVN and SON to post. pituitary to release OXY)
(Fear, pain, noise and fever will inhibit release)

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13
Q

What is pitocin?

A

“pitocin” = synthetic oxytocin used to induce labor.

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14
Q

Explain the structure, processing, of OXY.

What kind of receptor does it bind? Discuss signaling pathway.

A

Slide 17

Oxytocin signaling in
target tissues.

OXY binds to G proteincoupled
receptors and activates PLC signaling pathways (and IP3) which increases intracellular calcium.

Calcium binds calmodulin
(CaM) and the Ca2+:CaM
complex activates myosin
light chain kinase to
phosphorylate myosin
filaments and initiate
smooth muscle contraction.
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15
Q

Draw an HPL axis for GHRH.

A

Slide 19

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16
Q

Describe the structure of GHRH.

Where is it produced?

What does it act on?

A

44 amino acid peptide

Produced in the arcuate nucleus

Stimulates growth hormone (GH) from the anterior pituitary

17
Q

Describe the structure of somatostatin.

What is its role? Where does it act?

A

28 or 14 amino acid peptide

Inhibitor of GHRH at the level of the hypothalamus

Inhibits GH and TSH in pituitary

SS28 – made by D cells in stomach and duodenum (Furin)

SS14 made in hypothalamus (PVN) and pancreatic delta cells (PC1/PC2).

SS14 and SS28 have identical C termini

18
Q

Describe SS28. Where is it made? What does it do?

SS14?

Which enzymes are involved?

A

SS28 – made by D cells in stomach and duodenum (Furin)

SS14 made in hypothalamus (PVN) and pancreatic delta cells (PC1/PC2).

Inhibitor of GHRH at the level of the hypothalamus

Inhibits GH and TSH in pituitary

19
Q

Describe the physiological relationship between GHRH and somatostatin.

A

Somatostatin modulates GHRH pulsatility (decreased frequency) in hypothalamus.

Somatostatin inhibits GH release in pituitary

Slide 23

20
Q

Show how plasma levels of somatostatin and GHRH and GH will align.

A

Slide 24

High somatostatin- low GHRH and GH (and vice versa)

21
Q

When is GH mostly released?

A

Pulsatile release – mostly during the night (sleep)

Slide 25

22
Q

Describe the function of IGF-I in relation to GH signaling and list the downstream physiological targets of IGF-I.

A

Many downstream target organ effects of GH are mediated through Insulin-like growth factor I (IGF-I) (somatomedins).

GH stimulates IGF-I production in the liver -insulin dependent

IGF-I inhibits GH

IGF-I mimics insulin in muscle, but not liver and adipose due to lack of receptors

23
Q

When is IGF-I the highest?

A

IGF-I peaks during critical growth periods –

highest during puberty

24
Q

Describe the direct effects of GH (adipose tissue, liver, muscle).

A

adipose tissue- decreased glucose uptake, increased lipolysis, decreased adiposity

liver- increased RNA synthesis, increased protein synthesis, increased glucoenogensis, increased IGFBP, increased IGFs (these will stimulate IGF production)

muscle-
decrease glucose uptake, increased amino acid uptake, increased preotein synthesis, increased lean body mass

Direct action of GH promotes lean body mass -
increased protein and decreased adiposity. Direct effects mobilize glucose stores and increase
plasma glucose levels. GH is stimulated by hypoglycemia and exercise. Indirect effects of GH
are mediated by IGFs, which stimulate cellular proliferation in visceral organs, and
bone/cartilage growth. IGF actions are dependent on insulin because GH stimulation of IGF
is markedly decreased in starvation states.

25
Q

Describe the indirect effects of GH.

A

kidney, pancreas, intestine, islets, parathyroids, skin, connective tissue

increased protein synthesis
increased RNA synthesis
increased DNA synthesis
increased cell size and number
increased organ size, increased organ function

see chart slide 30

26
Q

What are GH stimulators? Inhibitors?

A

GH hormone stimulator- GHRH, dopamine, NE/E (exercise/stress), amino acids (protein building), thyroid hormone

GH inhibitor -somatostatin, IGF-I, glucose (hyperglycemia), free fatty acids (obesity)

Increased by stress, exercise, starvation.

Decreased with aging, high blood glucose, obesity.

27
Q

Describe the consequences of GH excess.

A

GH Excess – somatotrope tumor (20%)
Gigantism – extremely rare, occurs before closing of epiphyseal plate during childhood.
Long bones
**Xq26 microduplications – genetic basis for early onset gigantism (now called X-LAG).

Acromegaly – usually diagnosed in middle age
Gradual enlargement of hands and feet – leads to arthritis
Changes in facial features – protuding lower jaw, enlarged lips, tongue, and nose.
Possible increased organ size
Most often caused by pituitary adenoma
**mutations in GPR101 identified in adult patients

28
Q

Describe the consequences of GH deficiencies.

A

Dwarfism (children): related to GH
Laron Syndrome –
genetic defect in GH receptor – no production of IGF-I. Treatment with IGF-I can prevent dwarfism
Plasma GH levels are normal to high (lack of feedback).
African Pygmy
Partial defect in GH receptor – some IGF-I response.
Plasma levels of GH normal – no pubertal increase in IGF-I.

Adult GH deficiency 
Caused by pituitary tumor/surgery or treatment (76%)
Increased fat deposition, muscle wasting
Reduced bone density, risk of fractures
Higher LDL, Triglicerides
29
Q

Describe the physiological effects of prolactin.

What effect does dopamine have?

How does it travel in serum?

Half life?

When is it released?

A

Physiological effects:
- Mammary gland development
- Breast differentiation:
(Duct proliferation and branching and Glandular tissue development)

Milk production

  • Synthesis of milk proteins: beta-casein and alpha-lactalbumin
  • Synthesis of milk sugar: lactose
  • Synthesis of milk fats in epithelial cells

Prolactin is unique:
Lactotropes are not part of an endocrine axis – short loop feedback on hypothalamic dopamine; no unique stimulating factor from hypothalamus

Prolactin is tonically inhibited by dopamine – early antihypertensive drugs inhibit dopamine —- increased prolactin (galactorrhea)

Prolactin is not bound to serum proteins – half-life = 20 min.

Prolactin is released in response to suckling “stimulus-secretion reflex”

30
Q

Explain how the release of prolactin from the pituitary is regulated.

A

Slide 38

31
Q

Describe the structure of prolactin. (compare to GH)

What are the implications for high levels?

A

Slide 39

Sequence alignment and structure of growth hormone (b) and prolactin (a).

The structural similarity can result in non-specific binding of the GH or prolactin receptor when one of the hormones is produced in excess.

Example: High levels
of GH can result in GH binding to the PRL receptor and causing galactorrhea.

32
Q

Explain the consequences and causes associated with prolactin excess and/or deficiencies.

A

Prolactin Excess
Prolactinomas – 30-40% of all pituitary adenomas.
Hyperprolactinemia
Galactorrhea – milk production or discharge from breast
Reproductive dysfunction - prolactin inhibits GnRH release

Prolactin Deficiency
Sheehan’s Syndrome
Occurs as a result of excessive blood loss/shock during childbirth
Partial pituitary destruction
Usually affects other pituitary cell types – loss of axillary and pubic hair

33
Q

Describe the evaluation of anterior pituitary function.

How must hormones be measured?

Explain stimulation/inhibition tests to assess feedback and pituitary function. Give example. What should Insulin-induced hypoglycemia result in?

What should administration of IGF-I result in?

A

Hormones must be measured in pairs
Example: ACTH and Cortisol

Hormones must be measured at appropriate time or longitudinally

Stimulation/inhibition tests used to assess normal feedback and pituitary function
Example:
Insulin-induced hypoglycemia should result in?
Increased GH levels
Administration of IGF-I should result in?
Decreased GH levels

34
Q

What are defects in normal growth patterns the result of?

A

Defects in normal growth patterns are often the result of defective IGF-I receptors or signaling.

35
Q

During starvation, why would GH be active?

A

GH in other cell types is promoting protein syn. in muscle and lipolysis in adipose tissue. promotes gluconeogenesis in liver (mobilizing glucose) and through lipolysis mobilizes FFA for substrates to make more glucose. counteracting actions of insulin… (during starvation you WANT this…you want to be able to mobilize glucose into the blood!)

get as much glucose to brain as you can. but don’t want to promote growth - so if you’re starving you wont produce insulin and these effects wont happen.

GH will not simulate IGF1 in liver in absence of insulin.

FHB IV- Endocrinology (17 decks)

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