Hypothalamic-pituitary-gonadal axis I Flashcards
What is the HPG axis?
Hypothalamus-pituitary-gonad axis, the negative feedback loop that regulates sex-hormone production.
Describe the steps of the HPG axis.
- Hypothalamus releases GnRH to pituitary
- FSH and LH produced in anterior pituitary
- FSH and LH act on gonads
- Steroid hormones synthesized (oestrogen, progesterone, androgens)
- Steroid hormones exhibit negative feedback on pituitary and hypothalamus
Which neurones secrete GnRH from hypothalamus?
Parvocellular neurones
What is kisspeptin?
A hypothalamic peptide hormones that acts upstream of GnRH neurones and facilitates the release of GnRH, increasing gonadotrophin secretion by anterior pituitary
Where is kisspeptin expressed?
In the hypothalamus:
- Arcuate nucleus (AN)
- Anteroventral periventricular nucleus (APVN)
What is Kisspeptin synthesized as?
prepro-protein
-undergoes cleavage into active forms
Why is kisspeptin used in research?
Kp-54 used in clinical research because it crosses blood brain barrier
Kp-10 can’t cross barrier and so used in in vitro cell culture studies (cheaper to make 10 amino acid protein than 54 amino acid protein)
How is GnRH released from the hypothalamus?
in a pulsatile fashion from parvocellular neurones
What is GnRH synthesized as?
prepro-protein
- undergoes further cleavage into decapeptide
- secreted along with GAP protein (GnRH associated protein)
What does slow frequency pulse of GnRH secretion favour?
FSH secretion
What does rapid frequency pulse of GnRH secretion favour?
LH secretion
What does continuous release of GnRH result in?
Cessation of FSH and LH response
-shuts down HPG axis
Describe Synthetic GnRH.
- pulsatile administration
- used in stimulatory fashion in those with pubertal delay or failed to undergo puberty; or those with mutations in GnRH production/secretion
What are GnRH Analogues (agonists + antagonists)?
- single bolus administration
- used in inhibitory fashion (i.e. shuts down HPG axis for IVF stimulation and hormone dependent cancer treatments)
Agonists: binds GnRH receptor, INITIAL increase in GnRH activity, however shortly after they uncouple receptor from the G protein signalling, and there is shutdown of HPG axis
Antagonists: bind GnRH receptor and block receptor, inhibiting any activity
Describe the Structure of Gonadotrophins.
Heterodimeric peptides containing:
- common alpha subunit
- hormone specific beta subunit
- N-linked carbohydrate side chains
What is the Significance of N-linked carbohydrate side chains in gonadotrophins?
Important for biological function, and if gonadotrophin is de-glycosylated, it would cease to be active
What gives gonadotrophins their unique hormonal properties?
hormone specific beta subunit
How are alpha and beta subunits of gonadotrophins synthesized?
Alpha subunits synthesized in excess via constitutive secretion
Bets subunits synthesized in a limited fashion because it is GnRH dependent:
- slow GnRH pulse causes FSHβ expression
- fast GnRH pulse causes LHβ expression
How are the gonadotrophins released?
In a pulsatile fashion (due to pulsatile release of GnRH)
What are the Functions of LH on testis and ovaries?
Testis: stimulates Leydig cells for androgen (testosterone) synthesis
Ovaries
- stimulates theca cells for androgen synthesis
- stimulates corpus luteum for progesterone synthesis
- ovulation
What are the Functions of FSH on testis and ovaries?
Testis: stimulates Sertoli cells which convert androgens to oestrogens and also regulate spermatogenesis
Ovaries: stimulates granulosa cells for oestrogen synthesis (hence follicular maturation)
