HPG axis Flashcards
history of kisspeptin in?
- 1996: kiss 1 gene discovered
-2001 :peptide products identified and de- orphan used - 2003: gatekeeper of puberty role
function of kisspeptin (Kiss1)?
- 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.
Kisspeptin structure?
- prepro- kisspeptin
- kisspeptin - 54 (metastin)
- kisspeptin 10 : cheaper to make bind to ligands more easily
kisspeptin receptor (GPR54/KISS1R) and puberty
- 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
How does KISS1 regulate GnRH secretion - mouse model
- 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.
what manner is GnRH synthesised?
pulsatile
GnRH structure
- decapeptide (10 AAs)
-GAP - GnRH associated protein
How does GnRH pulsatility determine the secretion of FSH or LH?
- 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
What is the GnRH pulse generator(extrinsic mouse model)?
- 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.
What is the mode of GnRH action?
- GnRH binding to GnRH receptor
2.signal transduction - gonadotrophin gene expression , gonadotrophin synthesis , gonadotrophin secretion
structure of gonadotrophin hormone: LH, FSH (and hCG)
- glycoprotein hormones, heterodimeric, pulsatile
- alpha unit is common in both LH an dFSH but beta unit varies between the two giving them different properties
structure of gonadotrophin receptors
G protein coupled receptor
No carboxyl tail - lack of rapid desensitisation of receptor
What is the function of FSH?
testes : regulation of sertoli cell metabolism
ovaries : follicular maturation , granulosa cell estrogen synthesis
What is the function of LH?
testis: stimulation of leydig cell androgen synthesis
ovaries : theca cell androgen synthesis, ovulation, progesterone production of corpus luteum
Where in the male gonad is LH and FSH produced?
- leydig cells: LHR expressed - testosterone production
- sertoli cells: FSHR expressed on - test->DHT