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Science of Reproduction > GnRH > Flashcards

GnRH Flashcards

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1
Q

What is the role of GnRH?

A 
Master controller of reproduction 
Roles include: 
- Neuroendocrine - HPG
- Paracrine (placenta/gonads)
- Autocrine (prostate/breast cancer)
- Neurotransmitter (Regions of the brain)
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2
Q

Describe the structure of GnRH

A

Gene located on chromosome 8
23 isoforms in vertebrates - GnRH I / GnRH II most common
Pre-prohormone

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3
Q

Describe the cleavage steps of GnRH

A

Cleavage steps = from 69 aa to Mature GnRH (10aa) and GAP

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4
Q

What is the role of the GAP peptide?

A

GAP peptide co-secreted with GnRH, unknown function

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5
Q

Where is GnRH located in embryonic period?

A

Originate outside CNS, in medial olfactory placode

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6
Q

Where do GnRH containing cells migrate for GnRH release?

A

Nasal region 🡪 brain 🡪 medio-basal hypothalamus

GnRH-producing cells migrate through nasal system into forebrain
Numerous genes involved

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7
Q

What is a placode?

A

Area of thickening of embryonic epithelial later where organ / structure later develops

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8
Q

What are the possible disorders of incorrect GnRH neurone migration?

A

Kallmann Syndrome

Hypogonadotropic Hypogonadism

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9
Q

How does Hypogonadotropic Hypogonadism occur due to incorrect GnRH migration?

A

Hypogonadotropic Hypogonadism due to regulatory gene mutations

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10
Q

Give examples of known gene mutations causing Hypogonadotropic Hypogonadism

A 
KAL1
FGFR1, FGF8
PROK2, PROKR2, 
NELF
CHD7
GNRH1, GNRHR
GPR54
TAC3, TAC3R
NKB/NK3R
WDR11
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11
Q

What causes kallman syndrome?

A

Mutation in KAL-1 gene
Premature termination of migration
⇒ anosmia & hypogonadotrophic hypogonadism

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12
Q

Which cells are responsible for GnRH production?

A

Parvocellular system (medial preoptic nucleus & arcuate nucleus) produce GnRH

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13
Q

How is GnRH prepared for release?

A

GnRH processed + packaged into storage granules

Transported down axons to external zone of median eminence

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14
Q

Where is GnRH released?

A

GnRH released in synchronized pulses from GnRH nerve endings into hypophyseal portal system

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15
Q

How often is GnRH released?

A

Rhythmic pulses- every 30-120 minutes – “circhoral pulses”

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16
Q

What generates GnRH pulses?

A

collection of hypothalamic neurons producing endogenous secretory rhythms

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17
Q

What is the half life of GnRH?

A

GnRH t1/2 2-4 minutes

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18
Q

What does GnRH release cause?

A

GnRH stimulates synthesis and secretion of gonadotrophins.

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19
Q

What is the significance of GnRH pulse release?

A

Differential frequency + amplitude alters pattern of FSH and LH secretion, therefore impact gonadal response
Determines dimerisation of subunits and glycosylation

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20
Q

Describe the structure of the GnRHr

A

G-protein-coupled receptor (GPCR)

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21
Q

How many types of GnRHr are there?

A

Two variants Type I and II GnRHR
Type 1 - full length
Type 2 - missense truncation (humans)

22
Q

Where is the GnRHr expressed?

A

Expressed on gonadotroph cells of anterior pituitary

23
Q

What is the role of the GnRHr?

A

GnRH-R = regulatory molecule

Transduces GnRH action (to stimulate synthesis and release of gonadotrophins).

24
Q

Which tissues is GnRH receptors found in?

A

GnRH receptors are found in tissues like human anterior pituitary, breast, placenta and gonads and certain tumour cell lines

25
Q

What are gonadotrophins?

A

Glycoproteins with α & β chains

26
Q

Describe the structure of gonadotrophins

A

α-chains identical in FSH & LH

β-chains unique & confer biological actions

27
Q

Which gonadotrophin is favoured slow GnRH expression?

A

Slow frequency / low amp GnRH pulse ⇒ ⇧FSHb gene expression

28
Q

Which gonadotrophin does a rapid GnRH frequency favour?

A

Fast frequency GnRH pulse ⇒ ⇧LHb transcription

29
Q

Which signalling pathway is activated by GnRH?

A

MAP Kinase pathway via Gq and Gs activation

30
Q

What is a major sign that ovulation has occurred?

A

presence / formation of the corpus luteum is a good indicator of ovulation

31
Q

Describe ovulation in DKO(ERK1/2-/-) mice

A

Anovulatory
Follicles weren’t making it past antral follicle stage…no ovulation

LHβ expression is decreased

32
Q

What is the essential pathway for LHb expression in mice?

A

ERK-MAPK activation is essential for LHβ transcription and translation

33
Q

What were the effects of ERK-MAPK absence in mice?

A

Transcription / Translation: Absence of ERK caused drastic reduction in LH expression in females

No effect on FSH production.

34
Q

Outline the proposed mechanism of LHb expression via ERK_MAPK

A
  1. GnRH binds to GnRHR
  2. Triggers downstream signalling via Gs and Gq pathways
  3. PKA and PKC upregulated
  4. Undergo diverging ERK1/2 pathways
  5. Upregulation of EGR (early growth response) factor
  6. Results in upregulation of LHβ
35
Q

What is the consequence of ERK-MAPK blockade?

A

When ERK pathway is blocked there is a subsequent downregulation in LHβ expression

36
Q

What is CREB?

A

cAMP response element binding protein - binds on FSHbr

37
Q

What is essential for CREB activity?

A

CREB activity requires cyclic AMP

38
Q

What is ICER?

A

A protein that inhibits cAMP dependent pathways

39
Q

How does ICER affect FSHb expression?

A

ICER inhibits CREB binding to response element on FSHβ gene

=> downregulates FSH expression

40
Q

How does the menstrual cycle affect GnRH pulsatility?

A

GnRH pulses change frequency during menstrual cycle

41
Q

How does GnRH pulsatility vary during menstrual cycle?

A

Early Follicular phase
– pulses slow (every 90-120mins) »FSH

Mid-late F phase
– pulse freq increases (every hr.) »LH

After ovulation
– pulses slow (every 3-5h) »FSH production

End of luteal phase
– increase GnRH pulse secretion » FSH

42
Q

How is GnRH negative feedback stopped?

A
  1. Follicular phase: FSH secretion = Increase in estrogen levels
  2. -ve feedback resulting in FSH decline = DF selection (due to follicle expressing LHr)
  3. Switch from FSH pulses to LH pulses
  4. E2 levels continue to rise: 48hr sustained high level E2 expression reaching threshold of 300pg/mL
  5. Switch to +ve feedback – rapid pulses
  6. LH surge - ovulation
43
Q

Describe the gonadal steroid feedback on LH in rhesus monkey males

A

Testosterone from Leydig cells reduces LH secretion (Rhesus monkey experiments)

44
Q

How is FSH affected by steroid feedback in males?

A

Inhibin ↓FSH secretion from pituitary

Activin ↑FSH secretion from pituitary

45
Q

Describe the HPG control of sperm production

A
  1. Hypothalamus secretes GnRH
  2. Stimulates synthesis + secretion of FSH & LH
  3. LH binds to LHr stimulating testosterone production from Leydig cells
  4. FSH binds to FSHr on Sertoli cells + stimulates production of Sertoli cell proteins e.g. inhibin B, activin, ABP, and transferrin
  5. Inhibin B + activin feedback to pituitary, regulating LH/FSH production and secretion
46
Q

How does sperm mature?

A

Maturation of sperm to spermatid occurs in epididymis through contributions from prostate and seminal vesicle.

47
Q

Describe the -ve feedback of gonadal steroids in females?

A

Progesterone & low plasma oestrogen ⇒ -ve feedback

Net effect = reduced LH & FSH

48
Q

How is +ve feedback of gonadal steroids produced in females?

A

High sustained (48h) plasma [E2] = enhanced LH & FSH ⇒ +ve feedback

49
Q

How do gonadal steroids affect GnRH release?

A

P4 ↓GnRH pulse freq

E2 ↓GnRH pulse amplitude

50
Q

Where are the proposed sites of steroid feedback?

A

Either anterior pituitary or hypothalamus
E2 & P4 receptors on anterior pituitary and hypothalamus

Inhibin receptors found only in pituitary

51
Q

How is steroid feedback proposed to occur in the anterior pituitary?

A

Direct regulation of GnRHR
- Hormones directly regulating FSH / LH to decrease/increase their sensitivity to GnRH pulses

Plenty of receptors of E2, P4 and inhibins here via GnRH receptor regulation

52
Q

How is steroid feedback proposed in the hypothalamus?

A

Directly affecting GnRH neurones
Indirectly: changing activity of neural systems that influence GnRH release
e.g. ovarian hormones

Science of Reproduction (32 decks)

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