Hypothalamic pituitary gonadal axis Flashcards
Why is the HPG axis important?
Necessary for sustaining fertility
Describe the transport of GnRH from the Hypothalmus to Ant.Pituitary
GNRH is secreted by GnRH neurons in the acrutate nucleus and GnRH makes its way through the median eminenceto the anterior pituitary and this is made possible by the hypophyseal portal system (network of blood vessels that connects the hypothalmus to the anterior pituitary)
How is GnRH produced?
Kisspeptin (KISS1) gene and its peptides (Kisspeptins) were discovered in in 1996-2001
-It functions as the ‘gatekeeper of puberty’
-Controls synthesis and secretion of GnRH in GnRH neurons.
Upstream of GnRH.
-It acts on the GPR54 receptor
- It is expressed in the hypothalmus, ARC and AVPV (species dependent).
Its expression is regulated by gonadal steroids - Regions express ER, PR.
Describe the structure of Kisspeptin?
Kisspeptin is produced by proteolytic cleavage of the KISS-1 gene into Kp-14, Kp-13 and Kp-10
What triggers puberty?
KISS1R de-orphanised in 2001, physiological relevance to reproduction identified in 2003 - human and rodent discovery.
Expressed on GnRH neurons.
The 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?
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 GnRH neurons.
A bolus of Kisspeptin correlates with a peak of LH secretion.
Sexual dimorphic responses - cyclical differences
To monitor GnRH activity we measure LH. LH mimics what GnRH does – we don’t measure GnRH directly due to ethical reasons GnRH is the hypophyseal circulation
Describe Kisspeptin-mediated regulation of GnRH
In rodents, 2 populations of Kisspeptin expressing and secreting neurons in the arcuate and AVPV have been documented
refer to useful diagram on slide 12 of lecture
Sex steroids produced from gonads negatively feedback into the hypothalmus- this is mediated by the KISS-1 neurons in the arcuate nucleus, this in turn reduces GnRH secretion and LH&FSH secretion.
Kisspeptin neurons in the AVPV however, are responsive to E2 and P4, mediating the change in GnRH secretion to set up the LH surge and increasing responsiveness that mediates ovulation. This appears to be clear in rodents, however in sheep and primates this is not so clear.
In sheep, two populations of Kisspeptin neurons are found in the arcuate nucleus, however in humans and primates, just kisspeptin neurons that respond to negative feedback have been identified to date.
In what manner is GnRH secreted?
Synthesised and secreted from specialised neurons of hypothalamus- GnRH neurons.
Secreted in a pulsatile fashion - pulse generator orchestrated (Collection of neurones that stimulate the pulsatility)
Stimulates the synthesis and secretion of pituitary gonadotrophin hormones - LH and FSH.
Describe the structure of GnRH
GnRH is also synthesised from a preproprotein
It undergoes proteolytic cleavage into GnRH and GAP
Describe the pulsatility of GnRH
Evidence obtained through Rhesus monkeys suggested:
GnRH is secreted in pulses from hypothalamus every 30-120min
A GnRH pulse stimulates a pulse of LH and FSH secretion from the pituitary
Pulsatile GnRH secretion is vital for stimulation of synthesis and secretion of LH/FSH
Slow frequency pulse favours FSHb transcription and FSH release, rapid pulse frequency favours LHb transcription and LH release
Continuous release results in cessation of response
What is the GnRH pulse generator?
Studies provided evidence for the identity of the GnRH pulse generator in mice:
A sub-population of Arcuate Nucleus Kisspeptin Neurons (ARNKISS)
Inhibition of ARNKISS in the mid-caudal region of the arcuate nucleus suppressed pulsatile LH secretion
ARNKISS were all found to exhibit intermittent periods of synchronized electrical activity which had a near perfect correlation with pulsatile LH secretion.
Describe the mode of GnRH action
GnRH binding to GnRHR
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Signal transduction
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gonadotrophin gene expression
gonadotrophin synthesis
gonadotrophin secretion
What are the structural similarities in the Gonadotrophin hormones: LH, FSH (and hCG)
LH & FSH are glycoprotein hormones, they are Heterodimeric and released in a pulsatile manner
LH & FSH share a common alpha subunit but differ in the beta subunit
There are differences in the number of residues and the point of which sequences are attached
What is the structure of the gonadotrophin receptors?
The receptors have have an extracellular region, a transmembrane region and an intracellular region.
They have a large extracellular reigion where the gonadotrophins bind
Describe the function of the gonadotrophin FSH
Follicle-stimulating hormone (via FSHR)
* Testis:
- regulation of Sertoli cell metabolism
* Ovary:
- follicular maturation
- granulosa cell estrogen synthesis
