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Science of reproduction > GnRH analogues > Flashcards

GnRH analogues Flashcards

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1
Q

What does continuous low dose/single high dose of GnRH do?

A

Shuts down HPG axis

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2
Q

When would we need to shut down the HPG axis?

A
  • When we want to downregulate gonadotrophin secretion

- When gonadal inhibition is required i.e. ‘selective medical hypophysectomy’

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3
Q

When would we need to switch on the HPG axis?

A
  • When we want to upregulate gonadotrophin secretion

- When stimulation of gonads required

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4
Q

How do native GnRH/synthetic GnRH act?

A

binds to receptor, stimulates cellular response and signalling pathways (it’s similar to endogenous GnRH)

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5
Q

How do GnRH agonists act?

A

Mimics pulsatile GnRH functions: switching on HPG axis, same response as native GnRH but after a while it’s shut down because it just stays there and the receptor becomes desensitized, no downstream response

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6
Q

How do GnRH antagonists act?

A

Blocks the receptor by binding to it - Inhibition of GnRH functions and shutting down of HPG axis

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7
Q

What is the structure of native/synthetic GnRH?

A
  • same primary sequence as endogenous GnRH
  • Decapeptide
  • Pulsatile mode of delivery&raquo_space; switches on the HPG axis
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8
Q

Why are GnRH analogues used?

A

GnRH t1/2 in circulation is 2-4 mins so:

  • To increase potency & duration of GnRH → analogues created ⇒ agonists or antagonists
  • To manipulate the HPG axis in clinical practice - IVF, Hormone responsive cancers, endometriosis
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9
Q

Which amino acids of the GnRH are highly conserved?

A

Amino acids: 1-4 and 9-10

They’re important for GnRHr binding and activation

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10
Q

What shape does the GnRH take after synthesis and folding?

A

horse-shoe configuration

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11
Q

Which amino acids are important for receptor binding AND activation

A

Amino acids 1-3

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12
Q

Which amino acids are important for receptor binding ONLY?

A

Amino acids 8-10

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13
Q

Which amino acid is the most variable across species?

A

Amino acid 8

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14
Q

Which amino acids are usually substituted in GnRH antagonists?

A

Amino acids 1-3 are usually substituted by D amino acids

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15
Q

How are GnRH agonists made?

A
  • Substitution of 6 Gly by D-amino acids

* Replacement of Gly-NH2 by NH2-ethylamide binding to Pro (pos 9/10) to enhance affinity for receptor

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16
Q

Which amino acid is substituted in agonists and antagonists and why?

A
  • 6 Gly is substituted in all agonists and antagonists by D-aa’s
  • The substitutions help avoid proteolytic cleavage
  • This stabilises conformation and enhances activity
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17
Q

What substitutions happened in the different generation of antagonists?

A
  • 1st generation replaced His & Trp at pos 2 & 3, but low suppressive activity
  • 2nd generation potency increased by D-aa substitution in pos 6 but anaphylaxis due to histamine release
  • 3rd generation replaced D-Arg by D-ureidoalkayl aa
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18
Q

Where do all antagonists have substitutions?

A
  • all antagonists have substitutions in pos 1-3 and pos 10

- There’s more substitutions compared to agonists

19
Q

What is the mechanism of GnRH/synthetic GnRH?

A
  1. Binds to receptor
  2. Activation of signalling
  3. Stimulation of gonadotropin synthesis and secretion
  4. Dissociation of GnRH from GnRHR
  5. GnRHR will be responsive to the next GnRH pulse
20
Q

What is the mechanism of GnRH agonists?

A
  1. Binding to the receptor
  2. Activation of signalling
  3. Stimulation of the gonadotropin synthesis and secretion
  4. The agonist remains on the receptor, the Gs and Gq pathways become uncoupled from GnRHR – desensitisation occurs (NOT classical desensitisation)
  5. GnRHR non-responsive to GnRH
21
Q

What is the mechanism of GnRH antagonists?

A
  1. Binding to receptor
  2. Blockage of receptor
  3. No downstream effects
22
Q

What are the clinical uses of native GnRH?

A
  • In the case of gender reassignments and sex change, analogues are used to shut down the HPG axis so other hormones cab be administered
  • Diagnostic tests
  • To treat hypogonadotropic hypogonadism
  • To
23
Q

How is native GnRH used in diagnostic tests?

A
  • To distinguish between 1° & 2° hypogonadism
  • Blood test is taken, and GnRH levels are assayed

Test: GnRH is administered intravenously or subcutaneously and plasma LH and FSH are measured at 0, 15, 30, 45 and 60 minutes.
• Primary hypogonadism: High levels of LH/FSH
• Secondary hypogonadism: Low levels of LH/FSH

24
Q

What is the definition of hypogonadism?

A

Hypogonadism defined as impaired gonadal function with resultant decreased sex steroids

25
Q

What is the difference between primary and secondary hypogonadism?

A
  • 1∘ hypogonadism arises from gonadal failure – no gonado-stereo feedback so there’s a LH/FSH increase
  • 2∘ hypogonadism arises from abnormalities of hypo-pituitary axis: Gonads are functioning, but the hypothalamus and pituitary doesn’t work properly, downregulation of LH/FSH
26
Q

How is native GnRH used to treat hypogonadotropic hypogonadism?

A

attach a pump to the individual, GnRH is administered in pulses to activate the HPG axis

27
Q

How is native GnRH used to diagnose delayed puberty?

A
  • Difficult to distinguish between delayed puberty & HH ⇒ pre-pubertal pituitary is unresponsive to GnRH
28
Q

Symptoms of delayed puberty in boys and girls?

A
  • Boys, when testicular growth (volume >4 ml) has not started at 14yrs
  • Girls, when breast development is not present at 13yrs or menarche did not occur 15-18 years of age
29
Q

What are the common clinical uses of GnRH analogues?

A

• IVF – most common use

• To treat hormone-dependent cancers
o Breast cancer
o Prostate cancer

30
Q

What are other clinical uses of GnRH analogues?

A
  • Dysfunctional uterine bleeding
  • Precocious puberty
  • Hirsutism and virilisation
  • Endometriosis
31
Q

How is the HPG axis manipulated in IVF?

A
  • continuous GnRH agonist release, the HPG axis is shut down, dominant follicle isn’t selected.
  • Allows the IVF clinic to add exogenous FSH for the ovaries, multiple follicles recruited instead of one.
32
Q

How is the growth of follicles tracked in IVF?

A
  • Ultrasound is used to track the growth, amount and size of the follicles.
  • Once follicles have reached required size, ovulation is triggered by administering hCG (it has a longer half-life, and it can bind to the LH receptor)
33
Q

What happens if you don’t shut down the HPG axis in IVF?

A

If you don’t shut down HPG axis:

  • all of the follicles might get ovulated and then they’re lost
  • There’s also feedback that counteracts what you’re trying to do
34
Q

When are oocytes in IVF retrieved?

A

After 36 hours of final maturation, oocytes are retrieved – ovulation happens if you’re too late.

Ultrasound probe and a needle is used for this.

Needle is used to puncture the follicles and the fluid in the follicles is aspirated.

Oocytes also get taken out with the fluid.

35
Q

What happens after oocyte retrieval?

A

IVF takes place – sperm added to the oocytes. They then looked out for fertilisation.

After a few days, embryos are loaded in a capital with a drop of culture media. Via ultrasound guidance it’s inserted into the uterus and expelled from the capital

36
Q

What is used for follicle growth in stimulation and why?

A

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

There’s major benefit:
• improved follicular recruitment&raquo_space;> larger no. oocytes recovered (not in all patients)
• prevent premature LH surge&raquo_space;> lower cancellation rate
• Improvement in routine organisation

37
Q

How are GnRH agonists used to treat breast cancer?

A
  • Premenopausal women → GnRH agonists are used for chemical castration (reduce oestrogen output)
  • GnRHR present in breast cancer tissue (50-60%) - direct anti-proliferative effect of GnRHa in BCa cell lines
38
Q

How are GnRH agonists used to treat prostrate cancers?

A
  • 80% of prostate cancer (PCa) are androgen dependent
  • GnRH agonist → desensitisation →↓↓ T (chemical castration)
  • “Flare-effect” (initial activation of LH/FSH by the agonist) results ↑T&raquo_space; can be harmful
  • Micro-surges of T, LH & FSH with continued use
  • Co-administer with anti-androgens (usually androgen receptor antagonists) – they prevent defects of testosterone
39
Q

Why are GnRH agonists given to female cancer patients?

A

• Large percentage develop POF (premature ovarian failure) in cancer patients due to follicular damage
o Chemotherapeutic agents directly attack DNA in dividing and dormant germ cells

  • Use GnRH agonists before chemotherapy as a fertility preservative to minimise damage
  • By shutting down follicular activity it makes the follicles resistant to the damages - but this doesn’t guarantee fertility
40
Q

What are the limitations of GnRH agonists in cancer treatment?

A
  • Temporary solution - symptoms can return in the case of cancers
  • Side-effects: pseudo-menopause in women, reduced libido, erectile dysfunction, increased LDL / decreased HDL cholesterol, insomnia, headaches
  • Extra pituitary sites of GnRH receptors in animals – might affect these other sites too, we’re not sure how
  • “Flare effect” with prostate cancers
• It's a chronic treatment (>6 months)
o Osteoporosis (due to lack of oestrogen), Heart disease (due to changes in the serum lipids)
41
Q

Why are GnRH antagonists used to treat prostrate cancers?

A
  • No “flare” or micro-surges.
  • Reduces testosterone to castrate levels by day 3.
  • 1st antagonist Abarelix withdrawn due to systemic allergic reaction.
  • Degarelix&raquo_space; rapid & sustained reduction in Testo & PSA (prostate specific antigen) routinely used now in advanced prostate cancer.
42
Q

What are the advantages of GnRH antagonists in cancer treatment?

A

• Rapid action (= rapid pain relief) – 4-6hrs post administered.
• Rapid reversal of symptoms
• Shorter treatment regime compared to 7-10 days for pituitary down-regulation with agonists.
• No “flare effect”.
• Dose-dependent.
o Can get partial pituitary-gonadal inhibition.
o Can adjust level of hypogonadism as desired.

43
Q

What are the disadvantages of GnRH antagonists in cancer treatment?

A
  • Limited licenses available for wider use – only used for specific cases
  • 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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