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Science of Reproduction > GnRH Analogues > Flashcards

GnRH Analogues Flashcards

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1
Q

What does a pulsatile GnRH release cause?

A

LH/FSH upregulation

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2
Q

What is the effect of continuous GnRH release on gonadotrophin release?

A

Continuous GnRH = LH/FSH cessation

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3
Q

What can be administered to upregulate LH/FSH?

A

GnRH

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4
Q

What is administered to downregulate gonadotropin release?

A

GnRH analogues

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5
Q

How can we shut down HPG axis?

A

Continuous low-dose / single high-dose of GnRH

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6
Q

When may gonadal inhibition be required?

A

Selective medical hypophysectomy

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7
Q

Describe the effects of GnRH agonists on HPG axis

A

GnRH agonists initially produce same cell response but GnRHR gets desensitised = no effect

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8
Q

How does GnRH antagonist work?

A

GnRH antagonist blocks GnRHR

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9
Q

Descrieb the structure of native GnRH

A

Synthetic GnRH- same primary sequence as endogenous GnRH

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10
Q

How is native GnRH administered?

A

Pulsatile mode of delivery🡪 Switching on

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11
Q

What is GnRH’s half life normally in circulation?

A

GnRH t1/2 in circulation is 2-4 mins

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12
Q

What is the purpose of GnRH analogues?

A

To increase potency & duration of GnRH → analogues created ⇒ agonists or antagonists

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13
Q

What is the role of GnRH analogues?

A

Manipulate the HPG axis in clinical practice- IVF, Hormone responsive cancers, endometriosis

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14
Q

How consistent is GnRH structure across species?

A

Highly conserved in all mammals - important residues for GnRHR binding and activation

1 a.a differentiates between them
substitution usually occurs at (Arg) pos.8

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15
Q

Describe the structure of GnRH post-translationally

A

Once post-translational modifications have occurred, GnRH takes a horseshoe configuration

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16
Q

Which regions of GnRH are most manipulated for administration?

A

N terminus and C terminus regions are most manipulated of peptide sequence to form (ant)agonists

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17
Q

How is GnRH manipulated to form GnRH agonists?

A

Straightforward to make agonist

  • Substitution of Gly by D-amino acids
  • Replacement of Gly-NH2 by NH2-ethylamide binding to Pro (pos 9/10)
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18
Q

How is GnRH agonist affinity to its receptor increased?

A

Replacement of glycine amide with ethylamide (at pos 10) enhances affinity for receptor

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19
Q

Where are the common substitutions of GnRH to form GnRH agonists?

A

Most substitutions among GnRH agonists proprietary brands is at position 6 and C terminus

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20
Q

What is the advantage of GnRH agonist substitutions?

A

Substitutions avoid proteolytic cleavage and enhance stability

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21
Q

How long did it take to form a GnRH antagonist?

A

30 years to make antagonist due to anaphylaxis that was occurring

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22
Q

What was the problem with the first generation GnRH antagonist created?

A

1st generation replaced His & Trp at pos 2 & 3, but low suppressive activity

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23
Q

Why was 2nd generation GnRH antagonist not the final product?

A

2nd generation potency increased by D-aa substitution in pos 6 but anaphylaxis by histamine release

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24
Q

Describe the manipulation to produce the 3rd generation GnRH antagonist

A

3rd generation replaced D-Arg by D-ureidoalkayl aa

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25
Q

What is the benefit of 3rd generation GnRH antagonist structure?

A

Maintains high binding affinity, blocks GnRHR activation

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26
Q

Describe the mechanism of action of GnRH

A
  1. Binds to receptor
  2. Activation of signalling
  3. Stimulation of gonadotropin synthesis and secretion
  4. Dissociation from GnRHR
  5. GnRHR responsive to next GnRH pulse
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27
Q

Describe the mechanism of action of GnRH agonists

A
  1. Binds to receptor
  2. Activation of signalling
  3. Stimulation of gonadotropin synthesis and secretion
  4. Desensitisation of GnRHR
  5. GnRHR non-responsive to GnRH
28
Q

What is the mechanism of action of GnRH antagonists?

A
  1. Binds to receptor
  2. Blockage of receptor
  3. No downstream effects
29
Q

What are the diagnostic uses of Native GnRH?

A

Diagnostic tests:

  • Distinguish between 1° & 2° hypogonadism
  • Diagnose and treat hypogonadotrpic hypogonadism
30
Q

What is hypogonadism?

A

Hypogonadism defined as impaired gonadal function with resultant decreased sex steroids

31
Q

Where does primary hypogonadism start?

A

Primary hypogonadism starts in ovary/testes

32
Q

What are the clinical consequences of primary hypogonadism?

A

low gonadal steroids

high LH & FSH

33
Q

Where does secondary hypogonadism originate?

A

Secondary hypogonadism indicates problem in hyp/pituitary axis.

34
Q

Why may LH/FSH levels be normal in secondary hypogonadism?

A

Normalish FHS/LH = gonadal failure due to ovaries or testes (lack of gonadal steroids)

35
Q

What does high gonadotropin levels in secondary hypogonadism indicate?

A

High LH & FSH = hypothalamic dysfunction

36
Q

What does low LH/FSH levels indicate in secondary hypogonadism?

A

low FSH/LH response = hypothalamus / pituitary gland.- levels vary during puberty

37
Q

How is hypogonadism tested for?

A

IV GnRH administered or subcutaneously Plasma LH and FSH are measured at 0, 15, 30, 45 and 60 minutes

38
Q

What disorders may cause gonadotropin deficiency?

A
  • Large pituitary tumors
  • Endocrine deficiency
  • Hemochromatosis
  • Kallmann syndrome
  • Hyperprolactinemia
  • Amenorrhea
  • Anorexia nervosa
  • Starvation
39
Q

How is delayed puberty classified in boys?

A

Boys, when testicular growth (volume >4 ml) has not started at 14yrs

40
Q

Describe delayed puberty in girls

A

Girls, when breast development is not present at 13yrs or menarche did not occur 15-18 years of age

41
Q

Why is it difficult to distinguish between HH and delayed puberty?

A

Difficult to distinguish between delayed puberty & HH ⇒ pre-pubertal pituitary is unresponsive

42
Q

What are the clinical uses of GnRH analogues?

A
  • IVF
  • Dysfunctional uterine bleeding
  • Precocious puberty
  • Hormone-dependent cancers
    Breast cancer
    Prostate cancer
  • Hirsutism and virilisation
    Endometriosis
43
Q

Outline the normal mechanism of the HPG axis

A

Normal: pulsatile GnRH from hyp→ pit = LH/FSH release

44
Q

How is HPG axis manipulated in IVF?

A

GnRH agonist administered to uncouple HPG axis - abolished endogenous gonadotrophin production

⇒ exogenous LH/FSH production to stimulate follicular growth

45
Q

What are the effects of HPG manipulation in IVF?

A

Multiple follicles reach maturity

Follicles monitored via US (>3 ~18mm) give hCG to trigger maturation and ovulation

46
Q

Why is hCG administered in IVF instead of LH?

A

hCG used as has LH-like properties and has a longer half life (can collect oocytes 36hrs later)

47
Q

Why do follicles have to be aspirated after 36 hrs in IVF?

A

If follicles are not aspirated after 36hrs they will all ovulate and will be lost

48
Q

How are follicles aspirated in IVF?

A

Transvaginal egg collection to puncture follicle and aspirate oocyte into tubes passed onto embryologists

49
Q

How are the eggs collected in IVF fertilised?

A

Eggs placed in culture and inseminated - fertilisation assessed next day

50
Q

How are GnRH agonists used in IVF?

A

GnRH agonist + gonadotrophins used extensively for follicle growth stimulation in IVF

51
Q

What are the benefits of using GnRH agonists in IVF?

A

Improved follicular recruitment
⇒ larger no. oocytes recovered (not in all patients)

Prevent premature LH surge
⇒ lower cancellation rate

Improvement in routine organisation

52
Q

How are GnRH agonists used in pre-menopausal women to reduce breast cancer?

A

Premenopausal women → chemical castration (reduce oestrogen output)

53
Q

Why are GnRH agonists used for breast cancer?

A

GnRHR present in breast cancer tissue (50-60%)

Direct anti-proliferative effect of GnRHa in BCa cell lines

54
Q

How common is Prostate cancer in men?

A

Prostate Cancer (PCa) is 2nd most frequent tumour in men

55
Q

How androgen dependent is prostate cancer?

A

80% of PCa are androgen dependent

56
Q

How can GnRH agonists aid in prostate cancer

A

GnRH agonist → desensitisation →↓↓ T (chemical castration)

downside: “Flare-effect” results ↑T

57
Q

What is a major consequence of cancer treatments in female fertility?

A

Large percentage develop POF due to follicular damage

58
Q

How do cancer treatments affect female fertility?

A

Chemotherapeutic agents directly attack DNA in dividing and dormant germ cells

59
Q

How can fertility be preserved during cancer treatment?

A
  • Cryopreserve embryos or MII oocytes after IVF and before chemotherapy
  • Cryopreserve ovarian tissue for transplantation later
60
Q

What is a major limitation of GnRH agonist use?

A

Temporary solution - symptoms can return

61
Q

What side effects may present while using GnRH agonists?

A
  • Reduced libido
  • Erectile dysfunction
  • Increased LDL / decreased HDL cholesterol
  • Insomnia
  • Headaches
62
Q

Why is GnRH not tissue specific?

A

Extra pituitary sites of action? (e.g. oocyte, embryo, uterus) in animals - humans??

GnRHR present on these sites – role in implantation?
Inadvertently administered during pregnancy

63
Q

What is the consequence of chronic GnRH agonist treatment?

A 
Chronic treatment (>6 months)
Osteoporosis, Heart disease
64
Q

What is the benefit of using GnRH antagonists for prostate cancer?

A
  • No “flare” / microsurges

- Reduces testosterone to castrate levels by day 3

65
Q

Name an example of GnRH antagonist used in prostate cancer

A

Degarelix ⇒ rapid & sustained reduction in Testo & PSA (prostate specific antigen) routinely used now in advanced prostate cancer

66
Q

What are the advantages of GnRH antagonist use

A
  • Rapid action (rapid pain relief) 4-6hrs post administered.
  • Rapid reversal
  • Shorter treatment regime
  • No “flare effect”
  • Dose-dependent
  • Partial pituitary-gonadal inhibition
  • Can adjust level of hypogonadism as desired
67
Q

What are the disadvantgaes of GnRH antagonist use?

A
  • Limited licenses available for wider use
  • More expensive than agonists
  • Need higher dose than agonist 100mg/month versus 3-5mg
  • Competitive inhibitor, therefore less effective over time

Science of Reproduction (32 decks)

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