HPG axis Flashcards
What is key in the HPG axis?
- Negative and positive feedback
Give a brief summary of feedback in the HPG
- Hypothalamus releases GNRH
- that affects gonadotroph cells which release FSH and LH
- They act on the gonads and then release steroid hormones (progesterone, oesterone, tostesterone)
- The hormones feedback to the pituitary and hypothalamus
- In men feedback is always negative, in women it’s mostly negative except for when there’s a LH surge
Where are the GnRH neurones in the hypothalamus expressed?
GnRH neurones in the hypothalamus are expressed in 2 locations:
- arcuate nucleus
- the medial preoptic nucleus
What is the hypophyseal portal system?
- Network of blood vessels that connect the hypothalamus and the anterior pituitary.
- It allows GnRH to move to the gonadotroph cells in the anterior pituitary
What happens after GnRH is made in the hypothalamus?
- The neurones synthesis and secrete GnRH
- It makes it way from the medial eminence to the anterior pituitary by hypophyseal portal system
What is kisspeptin?
- ‘gatekeeper of puberty’
- Controls synthesis and secretion of GnRH in GnRH neurons.
- Upstream of GnRH.
Where is kisspeptin expressed?
In the hypothalamus in:
- The arcuate nucleus (ARC)
- The anteroventral periventricular nucleus (AVPV)
What is the kisspeptin gene?
Kiss1
What is the kisspeptin receptor?
GPR54/KISS1R
What is kisspeptin expression regulated by?
Gonadal steroids - oestrogen and progesterone
What is kisspeptin initially synthesised as?
A prepro-protein
How is the original prepro-protein modified to become kisspeptin?
- It undergoes proteolytic cleavage (makes kisspeptin 54)
- cthen undergoes more cleavage to be made into different types of kisspeptin (kp-14, kp-15, kp-10)
Which kisspeptin is used in in-vivo studies?
- Kp-54
- crosses the blood brain barrier easily
Which kisspeptin is used in in-vitro studies?
Kp-10
- very active ligand of the GPR54 receptor
- cheaper to make
Where is the kisspeptin receptor expressed?
On GnRH neurones
What can inactivating mutations of KISS1R and Kisspeptin do?
Lead to failure to undergo spontaneous puberty
What does early activation of KISS1R 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.
- May be differences due to the fact mice are a different species
How is GnRH mediated by sex steroids?
- Sex steroids made the by the gonads
- Sex steroids mediate their negative feedback via the kisspeptin neurones on the arcuate nucleus
- This cases GnRH to be downregulated and the expression of LH and FSH is also downregulated
What does the LH surge do?
- Switch the negative feedback to positive
- The positive feedback is mediated via the kisspeptin neurones in the AVPV
- This leads to the upregulation of GnRH
Where is GnRH synthesised and secreted from?
- Synthesised and secreted from specialised neurons of hypothalamus- GnRH neurons.
- Secreted in a pulsatile fashion - pulse generator orchestrated.
What does GnRH do?
- It stimulates the synthesis and secretion of pituitary gonadotrophin hormones (LH and FSH) from the pituitary
What is the structure of GnRH?
- Initially synthesised as a prepro-protein
- It’s then cleaved into a 10 amino acid protein and GAP (GnRH associated protein)
How is GnRH secreted?
In pulses from hypothalamus every 30 - 120 mins
What do slow pulses of GnRH do?
Slow pulses favour FSH-beta transcription and FSH release
What do fast pulses of GnRH do?
Fast pulses favour LH-beta transcription and LH release
What does continuous release of of GnRH do?
Leads to cessation of response - HPG axis shuts down
What is the GnRH pulse generator?
- A sub-population of Arcuate Nucleus Kisspeptin Neurons (ARNKISS)
- ARNKISS exhibit intermittent periods of synchronized electrical activity which had a near perfect correlation with pulsatile LH secretion.
- Inhibition of ARNKISS in the mid-caudal region of the arcuate nucleus suppressed pulsatile LH secretion
- However this study was done in mice
What is the mode of GnRH action?
- GnRH binds to its receptor
- That leads to signal transduction
- That leads to expression of LH and FSH beta genes and the production of FSH and LH
What are the gonadotrophin hormones?
LH, FSH and hCG
What is the structure of FSH and LH?
- They are both glycoprotein hormones and have a sugar residue attached
- They are heterodimeric: made of an alpha and a beta sub-unit held together by a disulphide bond
- FSH and LH have the same alpha subunit but the beta subunit is different gives them their distinct properties and function
- The type of glycosylation also gives them their unique properties
What is the structure of gonadotrophin receptors?
- Characterised by their large extracellular region with the amide part: this is where FSH and LH bind
- Are transmembrane
- Have an intracellular part which contains the -COOH tail
Where does FSH act?
- On the testis: regulates the Sertoli cell metabolism
- On the ovaries: matures follicles and acts on the granulosa cells for oestrogen synthesis
Where does LH act?
- On the testis: stimulates androgen synthesis in the Leydig cells
- On the ovaries: stimulates androgen synthesis in theca cells
- causes ovulation
- causes progesterone production of the corpus luteum
What are steroid hormones?
- Progesterone
- Oestrogens: Oestradiol and oestrone
- Androgens: Androstenedione, testosterone and dihydrotestosterone
Describe male gonadal steroid production.
- In the region between tubules (the interstitial region) the Leydig cells express LH receptor.
- Through this receptor LH modulates the production of androgens (DHEA, testosterone etc)
- Inside the tubules are Sertoli cells. Sertoli cells have FSH receptors
- FSH modulates Sertoli cell metabolism which is crucial for spermatogenesis. It is also needed for concentration of testosterone turning into DHT
Describe female gonadal steroid production
- Theca cells are on the lining of the mature antral follicle and they express LH receptors
- LH binding to the LHr produces testosterone/androstenedione.
- Cells that surround the oocyte are granulosa cells and they express FSH receptors
- FSH/FSHr binding modulates the conversion of the androgens made in the theca cells into oestrogens through the help of aromatase
What does the corpus luteum express and produce in the luteal phase?
- Expressed both LH and FSH in the luteal phase
- Produces both progesterone and oestrogen
What is inhibin?
- A peptide hormone
- A heterodimer
- Has 2 isoforms: A and B
- Made in the gonads
What does inhibin do?
It inhibits FSH secretion via direct negative feedback to the anterior pituitary
What isoform of inhibin do men and women produce?
- Males only make inhibin B
- With females the inhibin depends on the menstrual cycle
