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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
What is the benefit of 3rd generation GnRH antagonist structure?
Maintains high binding affinity, blocks GnRHR activation
26
Describe the mechanism of action of GnRH
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
27
Describe the mechanism of action of GnRH agonists
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
What is the mechanism of action of GnRH antagonists?
1. Binds to receptor 2. Blockage of receptor 3. No downstream effects
29
What are the diagnostic uses of Native GnRH?
Diagnostic tests: - Distinguish between 1° & 2° hypogonadism - Diagnose and treat hypogonadotrpic hypogonadism
30
What is hypogonadism?
Hypogonadism defined as impaired gonadal function with resultant decreased sex steroids
31
Where does primary hypogonadism start?
Primary hypogonadism starts in ovary/testes
32
What are the clinical consequences of primary hypogonadism?
low gonadal steroids | high LH & FSH
33
Where does secondary hypogonadism originate?
Secondary hypogonadism indicates problem in hyp/pituitary axis.
34
Why may LH/FSH levels be normal in secondary hypogonadism?
Normalish FHS/LH = gonadal failure due to ovaries or testes (lack of gonadal steroids)
35
What does high gonadotropin levels in secondary hypogonadism indicate?
High LH & FSH = hypothalamic dysfunction
36
What does low LH/FSH levels indicate in secondary hypogonadism?
low FSH/LH response = hypothalamus / pituitary gland.- levels vary during puberty
37
How is hypogonadism tested for?
IV GnRH administered or subcutaneously Plasma LH and FSH are measured at 0, 15, 30, 45 and 60 minutes
38
What disorders may cause gonadotropin deficiency?
- Large pituitary tumors - Endocrine deficiency - Hemochromatosis - Kallmann syndrome - Hyperprolactinemia - Amenorrhea - Anorexia nervosa - Starvation
39
How is delayed puberty classified in boys?
Boys, when testicular growth (volume >4 ml) has not started at 14yrs
40
Describe delayed puberty in girls
Girls, when breast development is not present at 13yrs or menarche did not occur 15-18 years of age
41
Why is it difficult to distinguish between HH and delayed puberty?
Difficult to distinguish between delayed puberty & HH ⇒ pre-pubertal pituitary is unresponsive
42
What are the clinical uses of GnRH analogues?
- IVF - Dysfunctional uterine bleeding - Precocious puberty - Hormone-dependent cancers Breast cancer Prostate cancer - Hirsutism and virilisation Endometriosis
43
Outline the normal mechanism of the HPG axis
Normal: pulsatile GnRH from hyp→ pit = LH/FSH release
44
How is HPG axis manipulated in IVF?
GnRH agonist administered to uncouple HPG axis - abolished endogenous gonadotrophin production ⇒ exogenous LH/FSH production to stimulate follicular growth
45
What are the effects of HPG manipulation in IVF?
Multiple follicles reach maturity Follicles monitored via US (>3 ~18mm) give hCG to trigger maturation and ovulation
46
Why is hCG administered in IVF instead of LH?
hCG used as has LH-like properties and has a longer half life (can collect oocytes 36hrs later)
47
Why do follicles have to be aspirated after 36 hrs in IVF?
If follicles are not aspirated after 36hrs they will all ovulate and will be lost
48
How are follicles aspirated in IVF?
Transvaginal egg collection to puncture follicle and aspirate oocyte into tubes passed onto embryologists
49
How are the eggs collected in IVF fertilised?
Eggs placed in culture and inseminated - fertilisation assessed next day
50
How are GnRH agonists used in IVF?
GnRH agonist + gonadotrophins used extensively for follicle growth stimulation in IVF
51
What are the benefits of using GnRH agonists in IVF?
Improved follicular recruitment ⇒ larger no. oocytes recovered (not in all patients) Prevent premature LH surge ⇒ lower cancellation rate Improvement in routine organisation
52
How are GnRH agonists used in pre-menopausal women to reduce breast cancer?
Premenopausal women → chemical castration (reduce oestrogen output)
53
Why are GnRH agonists used for breast cancer?
GnRHR present in breast cancer tissue (50-60%) Direct anti-proliferative effect of GnRHa in BCa cell lines
54
How common is Prostate cancer in men?
Prostate Cancer (PCa) is 2nd most frequent tumour in men
55
How androgen dependent is prostate cancer?
80% of PCa are androgen dependent
56
How can GnRH agonists aid in prostate cancer
GnRH agonist → desensitisation →↓↓ T (chemical castration) downside: “Flare-effect” results ↑T
57
What is a major consequence of cancer treatments in female fertility?
Large percentage develop POF due to follicular damage
58
How do cancer treatments affect female fertility?
Chemotherapeutic agents directly attack DNA in dividing and dormant germ cells
59
How can fertility be preserved during cancer treatment?
- Cryopreserve embryos or MII oocytes after IVF and before chemotherapy - Cryopreserve ovarian tissue for transplantation later
60
What is a major limitation of GnRH agonist use?
Temporary solution - symptoms can return
61
What side effects may present while using GnRH agonists?
- Reduced libido - Erectile dysfunction - Increased LDL / decreased HDL cholesterol - Insomnia - Headaches
62
Why is GnRH not tissue specific?
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
What is the consequence of chronic GnRH agonist treatment?
``` Chronic treatment (>6 months) Osteoporosis, Heart disease ```
64
What is the benefit of using GnRH antagonists for prostate cancer?
- No “flare” / microsurges | - Reduces testosterone to castrate levels by day 3
65
Name an example of GnRH antagonist used in prostate cancer
Degarelix ⇒ rapid & sustained reduction in Testo & PSA (prostate specific antigen) routinely used now in advanced prostate cancer
66
What are the advantages of GnRH antagonist use
- 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
What are the disadvantgaes of GnRH antagonist use?
- 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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