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SoR > Lecture 9: GnRH Analogues > Flashcards

Lecture 9: GnRH Analogues Flashcards

1
Q

What are GnRH analogues?

A
  • GnRH agonists
  • GnRH antagonists
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2
Q

Clinically, how can we shut down the HPG axis?

A
  • Continuous low-dose/single high-dose =SHUTTING DOWN
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3
Q

What do we see when the HPGF axis is shut down?

A
  • Down-regulation of gonadotrophin (LH/FSH) secretion
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4
Q

When is it useful to shut down the HPG axis?

A
  • When gonadal inhibition is required i.e. ‘selective medical hypophysectomy’ or shutting down ovaries for IVF
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5
Q

Clinically, how can we switch on the HPG axis?

A
  • Pulsatile mode of delivery
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6
Q

What is characterised by the switching on of the HPG axis?

A

Up-regulation of gonadotrophin secretion

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7
Q

When may we switch the HPG axis on?

A
  • When stimulation of gonads is required
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8
Q

What is the rational of using GnRH or its analogues?

A
  • To either switch on or switch off the HPG axis
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9
Q

How do GnRH antagonists, native GnRH and GnRH agonists work?

A

1- Binds to GnRHR
2- Cell response = secretes LH/FSH

1- Bind and block GnRHR
- Competitive inhibitor of the GnRHR - compete with GnRH for the same receptor

1- Bind to GnRHR
2- Initial response = FSH/LH secretion
3- After a while, shut down of HPG axis

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10
Q

What are the characteristics of native GnRH?

A
  • Synthetic GnRH - same primary sequence as endogenous GnRH
  • Deca-peptide (Glycinamide group at position 10)
  • Pulsatile mode of delivery = switching on
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11
Q

Why do we need GnRH analogues?

A
  • GnRH t1/2 in circulation is 2-4 mins
  • To increase potency & duration of GnRH → analogues created ⇒ agonists or antagonists
  • Manipulate the HPG axis in clinical practice- useful in IVF, Hormone responsive cancers, endometriosis
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12
Q

What is the structure of GnRH?

A
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13
Q

What sequence is highly conserved in all mammals and most species?

A
  • AA in positions 1-4 & 9-10 & Amide group
  • Important residues for GnRHR binding & Activation
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14
Q

Describe the function of each section of the GnRH structure?

A
  • Horseshoe conformation after undergoing transcribing translation and protein folding.
  • Position 6: Agonist formation when Glycine undergoes D-AA substitution
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15
Q
  • What are D-Amino Acids?
A
  • Stereoisomers of L-AA
  • E.g. D-Arg is the stereoisomer of L-Arg
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16
Q

How are GnRH agonists synthesised?

A
  • Substitution of Gly by D-amino acids (Position 6)
  • Replacement of Gly-NH2 by NH2-ethylamide binding to Pro (pos 9/10) for increased stability and resistance to proteolytic cleavage.
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17
Q

Give 2 examples of GnRH agonists

A
  1. Lupron: D Leu substituted + NEt
    = 10 fold increase in GnRH activity (10x more potent than endogenous GnRH and 10x more GnRHR activity)
  2. Buserelin: Most popular agonist used in IVF; D Ser sub + Net
    = 100x increase in GnRH activity
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18
Q

What is the advantage of NEt substitution in positions 9/10?

A
  • Allows GnRH agonist to avoid proteolytic cleavage
  • exogenous injection = higher risk of digestion by proteases and thus risk of being broken-down.
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19
Q

History of GnRH antagonists creation and how are they made now?

A
  • 1st gen replaced His & Trp at pos 2 & 3, but low suppressive activity
  • 2nd gen potency increased by D-aa substitution in pos 6 but anaphylaxis by histamine release
  • 3rd gen replaced D-Arg by D-ureidoalkayl aa
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20
Q

What were the issues with the 1st and 2nd gen of GnRH antagonists?

A
  • 1st: low suppressive activity - function of antagonist is to suppress!!
  • 2nd gen: Many patients had anaphylactic reactions thus withdrawn from market
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21
Q

Give examples of GnRH antagonists and where the changes in the structures are

A
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22
Q

What is the aim of antagonists?

A
  • To maintain high binding affinity
  • And block GnRHR activation
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23
Q

Mechanisms of action of GnRH and GnRH analogues

A
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24
Q

Describe the desensitisation of the GnRHR?

A
  • The sustained agonist exposure to GnRHR
  • Downstream pathways of the receptor are uncoupled
    = Shut down of HPG axis
  • reversible
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25
Q

Clinical uses of native GnRH

A
  • To diagnose & treat HH
26
Q

What is 1° hypogonadism? What do these individuals present with?

A
  • arises from gonadal failure
  • primary gonadal failure -> Gonads produce little or no steroids = little or no steroidal feedback.
  • Individuals with 1° hypogonadism present with low levels of gonadal steroids & NORMAL TO ↑ levels of FSH/LH.
27
Q

What is 2° hypogonadism

A
  • arises from abnormalities of hypo-pituitary axis
  • hypothalamic or pituitary failure -> downregulation /shutdown of gonadotrophin release = ↓gonadal function -> gonads produce ↓ or no steroids = ↓ or no steroidal feedback.
  • Individuals with 2° hypogonadism present with ↓ levels of gonadal steroids & ↓ levels of FSH/LH.
28
Q

Give an example of using native GnRH for a diagnostic test

A
  • To diagnose and treat Hypogonadotrophic Hypogonadism (HH)
  • To distinguish between 1° & 2° hypogonadism
  • Test: GnRH is administered intravenously or subcutaneously and plasma LH and FSH are measured at 0, 15, 30, 45 and 60 minutes
    -> High FSH/LH = 1°
    -> Low FSH?LH = 2°
29
Q

What is Hypogonadism?

A
  • Hypogonadism = impaired gonadal function with resultant decreased sex steroids
30
Q

How is HH treated using native GnRH?

A
  • Pump attached to patient -> GnRH provided in a pulsatile manner
31
Q

What is the issue with diagnosing HH?

A
  • Difficult to distinguish between delayed puberty & HH because pre-pubertal pituitary is unresponsive
32
Q

Characteristics of delayed puberty

A
  • Boys: testicular growth (volume >4 ml) has not started at 14yrs
  • Girls: breast development is not present at 13yrs or menarche did not occur 15-18 years of age
33
Q

Clinical uses of GnRH analogues

A
  • IVF
  • Hormone-dependent cancers: BC & PC
  • Dysfunctional uterine bleeding
  • Precocious puberty
  • Hirsutism & virilisation
  • Endometriosis
34
Q

How is the HPG axis manipulated in IVF?

A

1 - Continuous administration of GnRH agonist/antagonist = HPG axis shuts down
2 - Exogenous administration of gonadotrophins
= stimulates follicular growth + recruits astral follicles
3 - Follicles tracked -> 3x 16-18mm in size = ready for oocyte retrieval
4- Administration of hCG
5- 36-48hrs later - oocytes retrieved

35
Q

How is the HPG axis manipulated in IVF?

A

1 - Continuous administration of GnRH agonist/antagonist = HPG axis shuts down
2 - Exogenous administration of gonadotrophins
= stimulates follicular growth + recruits astral follicles
3 - Follicles tracked -> 3x 16-18mm in size = ready for oocyte retrieval
4- Administration of hCG
5- 36-48 hrs later - oocytes retrieved

36
Q

What are we trying to achieve during IVF when shutting down the HPG axis?

A
  • Take control of ovaries to stimulate them to recruit multiple oocytes
  • thus we shut down HPG axis to allow this ovary control
37
Q

How long does it take to see the effects of GnRH agonists vs antagonists during IVF?

A
  • Agonists: 1-2 weeks
  • Antagonists: 7 days
38
Q

How are follicles tracked during IVF?

A
  • The size of the follicles are tracked (ultrasound)
  • Blood E2 levels tracked
  • At least 3 Follicles that are 16-18mm in size => oocyte retrieval
39
Q

What is the significance of administering hCG during IVF?

A
  • Triggers final maturation of the oocytes
  • Thus, triggers ovulation
40
Q

Why is oocyte retrieval done within 36-48 hours?

A
  • Later than this, ovulation takes place
  • Thus, loss of oocytes
41
Q

Why do we use hCG in IVF?

A
  • LH-like properties
  • Longer half-life than LH
  • More stable than LH in its recombinant form
  • Can bind & activate LHR => replaces LH in order to trigger ovulation
41
Q

Why do we use hCG in IVF?

A
  • LH-like properties
  • Longer half-life than LH
  • More stable than LH in its recombinant form
  • Can bind & activate LHR => replaces LH in order to trigger ovulation
42
Q

Steps in IVF?

A

1- Oocyte retrieval: Ultrasound guidance- ultrasound probe attached to aspirator needle which punctures follicle & drains follicular fluid & oocyte (collected in tube)
2- IVF: oocytes in culture media & insemination of oocytes approved to move onto next stage
3- Embryo transfer

43
Q

How long do we culture the resulting embryo in IVF?

A

5 days
- day 0 to day 5 (after which is transferred to uterus)

44
Q

What stage are the majority of oocytes in?

A
  • MII
  • Some MI -> leave for a few hours -> MII stage
45
Q

What is used to stimulate follicle growth in IVF?

A
  • GnRH agonist
  • Gonadotrophins
46
Q

Benefits of using GnRH agonists(& exogenous gonadotrophins) during IVF

A
  • improved follicular recruitment = larger no. oocytes recovered (not in all patients)
  • prevent premature LH surge (i.e. no shut down -> LH surge= ovulation of follicles) = lower cancellation rate
  • Improvement in routine organisation
46
Q

How are GnRH agonists used in breast cancer treatment?

A

Bc cells= E2 dependent -> shut down of HPG axis = shut down of E2 production -> growth of BC due to E2 ceased

  • In premenopausal women -> GnRHa causes chemical castration (due to reduced E2 output)
  • GnRHR present in BC tissue (50-60%) = direct anti-proliferative effect of GnRHa in BCa cell lines
47
Q

What is chemical castration?

A
  • using drugs to stop sex hormone production
48
Q

How are GnRH agonists used in prostrate cancer treatment?

A
  • 80% of PCa are androgen-dependent
  • GnRH agonist → desensitisation →↓↓ T (chemical castration)
  • Takes 7-10 days
  • “Flare-effect” = ↑T (∵ ↑ FSH/LH initially, before it shuts down)
  • Micro-surges of T, LH & FSH with continued use
  • THUS co-administer GnRHa with anti-androgens (blocks AR & prevents T from activating its receptor = prevent flare effect)
49
Q

Why do a large % of BC patients develop premature ovarian failure (POF)?

A
  • ∵ follicular damage
  • Chemotherapeutic agents directly attack DNA in dividing and dormant germ cells
50
Q

How can we use GnRH agonists for fertility preservation in BC patients?

A

-Administer GnRHa to minimise gonadal damage

To preserve fertility either :
- Cryopreserve embryos or MII oocytes after IVF & before chemotherapy
- Cryopreserve ovarian tissue for transplantation later

51
Q

Characteristics of the study that suggested how to preserve fertility in BC patients

A
  • Xu et al (2011) Nature Medicine 17:1562-63
  • Study in mice
  • In humans, this method was mainly refuted
52
Q

Limitations of GnRHa?

A
  • Temporary solution - symptoms can return
  • Side-effects: pseudo-menopause (hot flashes, insomnia, ↓ libido) in women (with associated symptoms): ↓ libido, erectile dysfunction, ↑LDL/↓HDL cholesterol, insomnia, headaches
  • Extra pituitary sites of action (e.g. oocyte, embryo, uterus) in animals, thus extra affects as GnRHR in others so may cause other unwanted affects
  • “Flare effect” - before providing relief
  • Chronic treatment (>6 months): Osteoporosis(E2 maintains bone density), Heart disease (HDL/LDL levels)
53
Q

GnRH antagonists & their affects in prostate cancer treatment

A
  • No “flare” or micro-surges.
  • ↓ testosterone to castrate levels by day 3.
54
Q

2 examples of GnRH antagonists used in PC treatment

A
  • Abarelix (1st antagonist) withdrawn ∵ systemic allergic reaction (anaphylactic reaction).
  • Degarelix -> rapid & sustained ↓ in Testo & PSA (prostate-specific antigen), used only in special causes of advanced prostate cancer.
55
Q

Are agonists mainly used or antagonists for P cancer treatment?

A
  • GnRH Agonists
56
Q

Time it takes for GnRH agonists to apply their effects in PC treatment vs antagonists?

A
  • Agonists: 7-10 days
  • Antagonists: 3 days
57
Q

Advantages of GnRH antagonists

A
  • Rapid action (= rapid pain relief) – 4-6hrs post administered.
  • Rapid reversal
  • Shorter treatment regime compared to 7-10 days for pituitary down-regulation with agonists.
  • No “flare effect”.
  • Dose-dependent:
    - Partial pituitary-gonadal inhibition.
    - Can adjust level of hypogonadism as desired.
58
Q

Disadvantages of GnRH antagonists

A
  • Limited licenses available for wider use (highly controlled treatment regime)
  • More expensive than agonists.
  • Need ↑ dose than agonist 100mg/month versus 3-5mg/month (need ↑ levels of GnRHa ∵ competitive inhibitor).
  • Competitive inhibitor, ∴ ↓ effective over time (once effect seen i.e. once R blocked, nothing more can be done, that is as good as an effect as possible).
59
Q

How do we use native GnRH to diagnose primary/secondary hypogonadism?

A
  • 1° hypogonadism: GnRH test administered (functional pituitary & hypothalamus) -> primary gonadal failure & no steroid production/feedback, you should expect to see an ↑ FSH/LH response.
  • 2° hypogonadism: GnRH test (difficult to distinguish between hypothalamic & pituitary disorders using GnRH test alone). Key observation = ↓ FSH/LH response. The exact nature of the secondary hypogonadism (hypothalamic or pituitary) is usually confirmed using other clinical diagnostic measures (e.g. assays of other pituitary stimulating hormones; neuroimaging etc.).

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