GnRH analogues Flashcards
Continuous low-dose/single high-dose causes
(causes shutdown)
Downregulation of gonadotrophin secretion
- crucial when gonadal inhibition required i.e selective medical hypophysectomy
When you deliver GnRH in pulses this switches on the HPG Axis there is an..delete
Upregulation of gonadotrophin secretion
Crucial for when stimulation of gonads required
Native GnRH what is it
binds and cellular response - secretion of LH and FSH
Synthetically made GnRH (recombinant) made for clinical application
GnRH agonist will have similar effects to the native GnRH however,
this is shortlived.
GnRH antagonist, just binds and blocks the receptor so..
(inhibits from the get-go)
no downstream effects.
Why GnRH analogues?
- GnRH has a very short half life
- To increase potency & duration of GnRH → analogues created ⇒ agonists or antagonists
- Manipulate the HPG axis in clinical practice- IVF, Hormone responsive cancers, endometriosis
These bits are highly conserved in all mammals and most species and why are they important residues for GnRHR binding and activation?
They are important residues for GnRHR binding and activation
Mechanisms of action of GnRH and GnRH analogues
SUMMED UP
Hypogonadism defined as
impaired gonadal function with resultant decreased sex steroids
1° arises from?
arises from gonadal failure
To distinguish between 1° & 2° hypogonadism
2° hypogonadism arises from..
Hypogonadism arises from abnormalities of the hypo-pituitary axis.
Clinical uses of native GnRH
How is the diagnostic test carried out?
GnRH is administered intravenously or subcutaneously and plasma LH and FSH are measured at 0, 15, 30, 45 and 60 minutes.
Clinical uses of GnRH analogues
Delayed puberty
HH
IVF
Dysfunctional uterine bleeding
Precocious puberty
Hormone-dependent cancers
Breast cancer
Prostate cancer
Hirsutism and virilisation
Endometriosis
GnRH agonist + gonadotrophins used extensively for
follicle growth stimulation in IVF
What is the major benefits of using GnRH agonist + gonadotrophins for follicle growth stimulation in IVF
(x3)
- improved follicular recruitment larger no. oocytes recovered (not in all patients)
- prevent premature LH surge lower cancellation rate
- Improvement in routine organisation
GnRH agonists and Prostate Cancer
80% of PCa are androgen dependent
GnRH agonist → desensitisation →↓↓ T (chemical castration)
“Flare-effect” results ↑T
Micro-surges of T, LH & FSH with continued use
Co-administer with anti-androgens
GnRH agonists & fertility preservation – female cancers
To preserve fertility, we can either
Cryopreserve embryos or MII oocytes after IVF and before chemotherapy
Cryopreserve ovarian tissue for transplantation later
Large percentage develop Premature ovarian follicles due to follicular damage in chemo - how?
Chemotherapeutic agents directly attack DNA in dividing and dormant germ cells
Limitations of GnRH agonists
Temporary solution - symptoms can return
Side-effects -pseudo-menopause in women (with associated symptoms):
reduced libido, erectile dysfunction, increased LDL / decreased HDL cholesterol, insomnia, headaches
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
“Flare effect”
Chronic treatment (>6 months)
Osteoporosis, Heart disease
GnRH antagonists & prostate cancer
There are no..
Reduces _______ to castrate levels by day 3
The most commonly used treatment in advanced prostate cancer?
Specifically for Prostate Cancer:
No “flare” or micro-surges.
Reduces testosterone to castrate levels by day 3.
Degarelix –> rapid & sustained reduction in Testo & PSA (prostate specific antigen) routinely used now in advanced prostate cancer.
GnRH antagonists advantages
- 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.
GnRH antagonists disadvantages
- 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.