GnRH analgoues Flashcards
Describe the mode of GnRH action- continuous vs pulsatile
Continuous low-dose/single high-dose- Shutting down:
Downregulation of gonadotrophin secretion
When gonadal inhibition required i.e. ‘selective medical hypophysectomy’
Pulsatile mode of delivery- Switching on:
Upregulation of gonadotrophin secretion
When stimulation of gonads required
Native GnRH vs GnRH analogues
Native GnRH binds to GnRH receptor and produces downstream effects resulting in secretion of gonadotrophins such as FSH and LH
GnRH agonists bind to the GnRH receptor and initially produces downstream effects but then the receptor becomes desensitised with no downstream effects
The GnRH antagonist blocks the receptor from the beginning so there is no LH/FSH production at all
Mimicking pulsatile GnRH functions- switching on HPG axis
Inhibition of GnRH functions and shutting down of HPG axis
Structure of native GnRH
Switches on HPG axis, decapeptide with amide attached at C terminus
synthetic/native GnRH has same primary sequence as endogenous GnRH
chain on 10 amino acids starting with glutamine ending with glycine ending with nh2
Why use GnRH analogues
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- IVF, Hormone responsive cancers, endometriosis
GnRH structure manipulation
The structure of GnRH is highly conserved in all mammals and most species- important residues for GnRH binding and activation
4,4,2
N shaped structure of 10 amino acids
left side: pglu, his, trp—- D amino acid substitutions here are present in antagonists
middle section: Ser, tyr, gly, leu—- in this area d amino substitutions enhance activity and stability
right side: Arg,Pro, Gly, NH2. The Arg part is most variable across species. The right side is for receptor binding only
How to make GnRH agonists
to make agonist
Substitution of Gly by D-amino acids
Replacement of Gly-NH2 by NH2-ethylamide binding to Pro (pos 9/10)
ll agonists & antagonists have substitution of Gly with D-aa at position 6 stabilises conformation & enhances activity
Stages of making GnRH antagonist and why it took 30 years
30 years to make antagonist!
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 by histamine release
3rd generation replaced D-Arg by D-ureidoalkayl aa
This maintains high binding activity and blocks GnRHr activation
How can native GnRH be used in clinical diagnostic tests
Test: GnRH is administered intravenously or subcutaneously and plasma LH and FSH are measured at 0, 15, 30, 45 and 60 minutes.
Hypogonadism defined as impaired gonadal function with resultant decreased sex steroids
To distinguish between 1° & 2° hypogonadism
Diagnostic tests
Hypogonadism defined as impaired gonadal function with resultant decreased sex steroids
To distinguish between 1° & 2° hypogonadism
Hypogonadotrophic hypogonadism (HH) to diagnose and treat
Delayed puberty
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
Difficult to distinguish between delayed puberty & HH ⇒ pre-pubertal pituitary is unresponsive
Clinical uses of GnRH analogues
IVF (hCG also required for final maturation- ovulatory process mimic
Oocytes retrieval)
Dysfunctional uterine bleeding Precocious puberty Hormone-dependent cancers Breast cancer Prostate cancer Hirsutism and virilisation Endometriosis
GnRH agonists and IVF
GnRH agonist + gonadotrophins used extensively for follicle growth stimulation in IVF
Major benefit:
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 breast cancer
Premenopausal women → chemical castration (reduce oestrogen output)
GnRHR present in breast cancer tissue (50-60%)
Direct anti-proliferative effect of GnRHa in BCa cell lines
GnRH agonists and prostate cancer
Prostate Cancer (PCa) is 2nd most frequent tumour in men in West
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 and fertility preservation in female cancer patients
Last 20 years survival rates for young women > 80-90%
Large percentage develop POF due to follicular damage
Chemotherapeutic agents directly attack DNA in dividing and dormant germ cells
To preserve fertility either
Cryopreserve embryos or MII oocytes after IVF and before chemotherapy
Cryopreserve ovarian tissue for transplantation later
Administer adjuvant therapy to minimise gonadal damage?
Before chemotherapy, GnRH agonists on their own result in pre-menopause and fertility
If GnRH agonist and FSH are administered together, follicles are protected with normal oestrogen production- retained ovarian function
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 anatagonists in cancer
Prostate Cancer
No “flare” or micro-surges.
Reduces testosterone to castrate levels by day 3.
1st antagonist Abarelix withdrawn due to systemic allergic reaction.
Degarelix rapid & sustained reduction in Testo & PSA (prostate specific antigen) routinely used now in advanced prostate cancer.
