HPG axis

Question 1

What is key in the HPG axis?

Answer 1

• Negative and positive feedback

Question 2

Give a brief summary of feedback in the HPG

Answer 2

• 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

Question 3

Where are the GnRH neurones in the hypothalamus expressed?

Answer 3

GnRH neurones in the hypothalamus are expressed in 2 locations:

• arcuate nucleus
• the medial preoptic nucleus

Question 4

What is the hypophyseal portal system?

Answer 4

• 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

Question 5

What happens after GnRH is made in the hypothalamus?

Answer 5

• The neurones synthesis and secrete GnRH

- It makes it way from the medial eminence to the anterior pituitary by hypophyseal portal system

Question 6

What is kisspeptin?

Answer 6

• ‘gatekeeper of puberty’
• Controls synthesis and secretion of GnRH in GnRH neurons.
• Upstream of GnRH.

Question 7

Where is kisspeptin expressed?

Answer 7

In the hypothalamus in:

• The arcuate nucleus (ARC)
• The anteroventral periventricular nucleus (AVPV)

Question 8

What is the kisspeptin gene?

Answer 8

Kiss1

Question 9

What is the kisspeptin receptor?

Answer 9

GPR54/KISS1R

Question 10

What is kisspeptin expression regulated by?

Answer 10

Gonadal steroids - oestrogen and progesterone

Question 11

What is kisspeptin initially synthesised as?

Answer 11

A prepro-protein

Question 12

How is the original prepro-protein modified to become kisspeptin?

Answer 12

• 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)

Question 13

Which kisspeptin is used in in-vivo studies?

Answer 13

• Kp-54

- crosses the blood brain barrier easily

Question 14

Which kisspeptin is used in in-vitro studies?

Answer 14

Kp-10

• very active ligand of the GPR54 receptor
• cheaper to make

Question 15

Where is the kisspeptin receptor expressed?

Answer 15

On GnRH neurones

Question 16

What can inactivating mutations of KISS1R and Kisspeptin do?

Answer 16

Lead to failure to undergo spontaneous puberty

Question 17

What does early activation of KISS1R lead to?

Answer 17

precocious puberty

Question 18

How does KISS1 regulate GnRH secretion?

Answer 18

• 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

Question 19

How is GnRH mediated by sex steroids?

Answer 19

• 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

Question 20

What does the LH surge do?

Answer 20

• 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

Question 21

Where is GnRH synthesised and secreted from?

Answer 21

• Synthesised and secreted from specialised neurons of hypothalamus- GnRH neurons.
• Secreted in a pulsatile fashion - pulse generator orchestrated.

Question 22

What does GnRH do?

Answer 22

• It stimulates the synthesis and secretion of pituitary gonadotrophin hormones (LH and FSH) from the pituitary

Question 23

What is the structure of GnRH?

Answer 23

• Initially synthesised as a prepro-protein

- It’s then cleaved into a 10 amino acid protein and GAP (GnRH associated protein)

Question 24

How is GnRH secreted?

Answer 24

In pulses from hypothalamus every 30 - 120 mins

Question 25

What do slow pulses of GnRH do?

Answer 25

Slow pulses favour FSH-beta transcription and FSH release

Question 26

What do fast pulses of GnRH do?

Answer 26

Fast pulses favour LH-beta transcription and LH release

Question 27

What does continuous release of of GnRH do?

Answer 27

Leads to cessation of response - HPG axis shuts down

Question 28

What is the GnRH pulse generator?

Answer 28

- 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

Question 29

What is the mode of GnRH action?

Answer 29

- 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

Question 30

What are the gonadotrophin hormones?

Answer 30

LH, FSH and hCG

Question 31

What is the structure of FSH and LH?

Answer 31

- 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

Question 32

What is the structure of gonadotrophin receptors?

Answer 32

- 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

Question 33

Where does FSH act?

Answer 33

- On the testis: regulates the Sertoli cell metabolism | - On the ovaries: matures follicles and acts on the granulosa cells for oestrogen synthesis

Question 34

Where does LH act?

Answer 34

- 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

Question 35

What are steroid hormones?

Answer 35

- Progesterone - Oestrogens: Oestradiol and oestrone - Androgens: Androstenedione, testosterone and dihydrotestosterone

Question 36

Describe male gonadal steroid production.

Answer 36

- 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

Question 37

Describe female gonadal steroid production

Answer 37

- 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

Question 38

What does the corpus luteum express and produce in the luteal phase?

Answer 38

- Expressed both LH and FSH in the luteal phase | - Produces both progesterone and oestrogen

Question 39

What is inhibin?

Answer 39

- A peptide hormone - A heterodimer - Has 2 isoforms: A and B - Made in the gonads

Question 40

What does inhibin do?

Answer 40

It inhibits FSH secretion via direct negative feedback to the anterior pituitary

Question 41

What isoform of inhibin do men and women produce?

Answer 41

- Males only make inhibin B | - With females the inhibin depends on the menstrual cycle