HPG axis Flashcards

1
Q

history of kisspeptin in?

A
  • 1996: kiss 1 gene discovered
    -2001 :peptide products identified and de- orphan used
  • 2003: gatekeeper of puberty role
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2
Q

function of kisspeptin (Kiss1)?

A
  • controls synthesis and secretion of GnRH in GnRH neurons upstream of GnRH
    -dependent on hypothalamic expression expression - ARC and AVPV (species dependent)
  • expression regulated by gonadal steriods- region express ER, PR.
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3
Q

Kisspeptin structure?

A
  • prepro- kisspeptin
  • kisspeptin - 54 (metastin)
  • kisspeptin 10 : cheaper to make bind to ligands more easily
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4
Q

kisspeptin receptor (GPR54/KISS1R) and puberty

A
  • expressed on GnRH neurons
    -Kisspeptin/KISS1R system is a component trigger of puberty
    -inactivating mutations of KISS1R and kisspeptin = failure to undergo spontaneous puberty
    -activating KISS1R mutations can lead to precocious puberty
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5
Q

How does KISS1 regulate GnRH secretion - mouse model

A
  • hypothalamic explants from mice shown kisspeptin administration stimulates GnRH synthesis and secretion.
    -kisspeptin neurons send projections to GnRH neurons, and binding to KISS1R expressed on GnRHneurons.
  • A bolus of kisspeptin correlates with a peak of LH secretion.
  • Sexual dimorphic responses - cyclical differences.
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6
Q

what manner is GnRH synthesised?

A

pulsatile

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7
Q

GnRH structure

A
  • decapeptide (10 AAs)
    -GAP - GnRH associated protein
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8
Q

How does GnRH pulsatility determine the secretion of FSH or LH?

A
  • GnRH is secreted in pulses from hypothalamus every 30- 120 min
  • GnRH pulse stimulates a pulse of LH and FSH secretion from the pituitary
  • pulse frequency determines if FSH or LH is released
  • Slow = FSH beta transcription favoured = FSH
    -rapid = LH beta transcription favoured = LH
  • continuous release results in no response
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9
Q

What is the GnRH pulse generator(extrinsic mouse model)?

A
  • clarkson et al (2017) found evidence for identity of the GnRH pulse generator in mice to be a subpopulation of arcute nucleus kisspeptin neuron (ARN)
  • inhibition of ARN in the mid caudal region of the arcute nucleus suppressed pulsatile LH secretion( extrinsic model)
    =>intrinsci mode said that the pulse generator is the subpopulation of neurones of GnRH themselves.
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10
Q

What is the mode of GnRH action?

A
  1. GnRH binding to GnRH receptor
    2.signal transduction
  2. gonadotrophin gene expression , gonadotrophin synthesis , gonadotrophin secretion
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11
Q

structure of gonadotrophin hormone: LH, FSH (and hCG)

A
  • glycoprotein hormones, heterodimeric, pulsatile
  • alpha unit is common in both LH an dFSH but beta unit varies between the two giving them different properties
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12
Q

structure of gonadotrophin receptors

A

G protein coupled receptor
No carboxyl tail - lack of rapid desensitisation of receptor

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13
Q

What is the function of FSH?

A

testes : regulation of sertoli cell metabolism
ovaries : follicular maturation , granulosa cell estrogen synthesis

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14
Q

What is the function of LH?

A

testis: stimulation of leydig cell androgen synthesis
ovaries : theca cell androgen synthesis, ovulation, progesterone production of corpus luteum

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15
Q

Where in the male gonad is LH and FSH produced?

A
  1. leydig cells: LHR expressed - testosterone production
  2. sertoli cells: FSHR expressed on - test->DHT
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16
Q

Where in the female gonad is LH and FSH produced?

A
  1. theca cells : LHR expression -> testoterone
    2.Granulosa cells : FSHR expression -> estrogen
    testosterone => estrogen by aromatase
17
Q

What inhibits FSH secretion?

A
  • inhibin = inhibits FSH by direct negative feedback to anterior pituitary
    -Inhibin A and B isoforms
  • males: isoform inhibin B
    -females : A/B depending on cycle