HPG axis

Question 1

history of kisspeptin in?

Answer 1

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

Question 2

function of kisspeptin (Kiss1)?

Answer 2

• 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.

Question 3

Kisspeptin structure?

Answer 3

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

Question 4

kisspeptin receptor (GPR54/KISS1R) and puberty

Answer 4

• 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

Question 5

How does KISS1 regulate GnRH secretion - mouse model

Answer 5

• 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.

Question 6

what manner is GnRH synthesised?

Answer 6

pulsatile

Question 7

GnRH structure

Answer 7

• decapeptide (10 AAs)
  -GAP - GnRH associated protein

Question 8

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

Answer 8

• 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

Question 9

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

Answer 9

• 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.

Question 10

What is the mode of GnRH action?

Answer 10

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

Question 11

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

Answer 11

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

Question 12

structure of gonadotrophin receptors

Answer 12

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

Question 13

What is the function of FSH?

Answer 13

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

Question 14

What is the function of LH?

Answer 14

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

Question 15

Where in the male gonad is LH and FSH produced?

Answer 15

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

Question 16

Where in the female gonad is LH and FSH produced?

Answer 16

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

Question 17

What inhibits FSH secretion?

Answer 17

• 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