Lecture 8: GnRH

Question 1

What is GnRH?

Answer 1

• Master controller of reproduction

Question 2

When was GnRH discovered?

Answer 2

• 1971

Question 3

Which chromosome contains the gene that codes for GnRH?

Answer 3

• chromosome 8

Question 4

How many isoforms of GnRH in vertebrates?

Answer 4

• 23

Question 5

Is GnRH conserved across vertebrates?

Answer 5

• Highly conserved
• 1 AA substitution max otherwise conserved across species

Question 6

Which GnRHs are present in vertebrates?

Answer 6

• GnRH I (GnRH) (classical GnRH)
• GnRH II

Question 7

What are the roles of GnRH in physiology?

Answer 7

• Neuroendocrine - HPG
• Paracrine (because GnRHRs present in placenta/gonads)
• Autocrine (Rs prostate/breast cancer)
• Neurotransmitter (has affects on other regions of the brain)

Question 8

What is the structure of GnRH?

Answer 8

• Peptide
• Pre-pro hormone
  -> Proteolytic cleavage => Mature GnRH & GnRH associated protein (GAP)
• GnRH is a decapapetide (10 AA long)
• GAP peptide- co-secreted with GnRH - unknown function (no ongoing research on GAP)

Question 9

Where do GnRH neurones originate?

Answer 9

• They do not originate in Hypothalamus -> have to migrate there:

Embryonic period:
- Originate outside CNS, in medial olfactory placode
- Cells migrate:
- Nasal region -> brain -> medio-basal hypothalamus
- Numerous genes involved

Question 10

What is the Placode region?

Answer 10

Placode=area of thickening of the embryonic epithelial later from which the organ/structure later develops.

Question 11

Migration of GnRH neurones

Answer 11

Question 12

What may occur if migration of GnRH neurones goes wrong?

Answer 12

• Results in Hypogonadotrophic Hypogonadism (HH)

Question 13

Which genes regulate GnRH neurone migration and thus known mutations in them cause HH?

Answer 13

-KAL1 (main one),
FGFR1, FGF8, PROK2, PROKR2, NELF, CHD7,
GNRH1, GNRHR, GPR54, TAC3, TAC3R, NKB/NK3R, WDR11

Question 14

What is a consequence of a mutation in KAL-1 gene?

Answer 14

= Kallmann Syndrome
- Premature termination of migration
-> anosmia (inability to smell because GnRH neurones are still in olfactory region) & hypogonadotrophic hypogonadism

Question 15

Gross anatomy of Parvocellular system

Answer 15

Question 16

How is GnRH released?

Answer 16

• GnRH is processed & packaged into storage granules
• transported down the axons to external zone of median eminence
• GnRH released in synchronized pulses from GnRH nerve endings into hypophyseal portal system

Question 17

How often is GnRH released?

Answer 17

• every 30-120 mins
  via rhythmic pulses “circhoral pulses”

Question 18

How is GnRH released in a pulsatile fashion?

Answer 18

• Via the GnRH Pulse generator

Question 19

What is the GnRH pulse generator?

Answer 19

• collection of hypothalamic neurons producing endogenous secretory rhythms
• sub-population of kisspeptin neurones in the arcuate nucleus

Question 20

What is the half life of GnRH?

Answer 20

• GnRH t1/2 2-4 minutes

(very short)

Question 21

What does GnRh stimulate?

Answer 21

• synthesis and secretion of gonadotrophins

Question 22

Is the differential frequency and amplitude of GnRH significant?

Answer 22

• Yes
• alter pattern of FSH and LH secretion, therefore impact gonadal response

Question 23

What is a slow pulse of GnRH responsible for?

Answer 23

• Up-regulation of FSH release

Question 24

What is a fast pulse of GnRH responsible for?

Answer 24

• Up-regulation of LH release

Question 25

Describe the GnRH receptor

Answer 25

- G-protein-coupled receptor (GPCR) - Two variants: Type I and II GnRHR - Resistant to desensitisation (some exceptions) - Mainly expressed on gonadotroph cells of anterior pituitary

Question 26

What are the two variants of GnRHR?

Answer 26

- Type 1- full length - Type 2 - missense truncation ( in humans)

Question 27

What is a missense truncation?

Answer 27

- mRNA for GnRH receptor 2 is expressed and transcribed - but actual receptor protein is not available due to missense truncation

Question 28

How is GnRHR resistant to desensitisation?

Answer 28

- C-terminal tail absence

Question 29

What is the significance of the absence of a c-terminal tail?

Answer 29

- Evolutionary benefit - Absence = renders GnRHR resistant to desensitation (via C-terminal) (in the classical sense) - overexposure to ligand - receptor is desnesitised. This process occurs by C-terminal tail being phosphorylated and receptor is then internalised into the cell (classical desensitisation of a receptor in cell biology)

Question 30

Are GnRH neurones only located in the anterior pituitary?

Answer 30

- No! (cell lines of breast etc shown below containing GnRH neurones)

Question 31

How does GnRH regulate Gonadotrophin production?

Answer 31

Rhythm & pulsatility of GnRH - Relative rates of gene expression for α/β - Determines dimerisation of subunits - Determines glycosylation

Question 32

What is the structure of gonadotrophins?

Answer 32

- Glycoproteins with α & β chains - α-chains identical in FSH & LH - β-chains unique & confer biological actions

Question 33

What does changing GnRH pulse frequency and amplitude cause?

Answer 33

- Switching between FSH and LH synthesis AND secretion. - Slow frequency or low amp GnRH pulse ⇒ ⇧FSHb gene expression - Fast frequency GnRH pulse ⇒ ⇧LHb transcription

Question 34

Describe GnRH and gonadotrophin patterns in MALESH

Answer 34

- GnRH pulses: constant frequency every 2hr - Amplitude varies throughout the day = normal in males

Question 35

Describe GnRH and gonadotrophin patterns in FEMALES

Answer 35

- Higher frequency GnRH pulse (every 30min) = favours LH secretion - Lower frequency/amplitude GnRH pulse (every 90-120min) = favours FSH synthesis and secretion

Question 36

How does GnRH differentially regulate FSH and LH production?

Answer 36

- ERK signalling