The Use of GnRH Antagonists in Gynaecology
AMR EL NOURY
TutorBianchi PG
Introduction
• (LHRH) GnRH discovery Shally 1971• Knowledge of LH effect on pregnancy outcome
and problem of premature LH surge• GnRH agonists
– Problems:• usually long duration of treatment• flare up effect
• GnRH - Antagonists– Avoid problems of GnRH agonists ?
Types of GnRH antagonists• There are several types• Decapeptides• First Generation
– ( Histamine release & severe allergy )
• Second generation– ( allergy and gel formation)
• Third Generation– ( well tolerated)
– Cetrorleix (Asta Medica)– Ganirelix (Organon)
Marketapproval
Hexapeptides, Heptapetides
PROLEU ARGGLYTYRSERTRPHISPyro-Glu
1 2 3 4 5 6 7 8 9 10
GnRH
Decapeptide
GLYNH2
Chemical composition
GLYNH2
GLY PROPyro-Glu
HIS TRP SER TYR LEU ARG
GnRH Agonists
GLYNH2D.AIA-NH2
ARGD.hArg(Et2)
GanirelixCetrorelix
PROGLY
GnRH Antagonists
D.hArg(Et2)
Pyro-GluAc-D-Nal(2)
HISD.Phe(4CI)
TRPD/PAL
SER TYR LEU
1 2 3 4 5 6 7 8 9 10
Mode of Action: GnRH AgonistsGnRH Agonist-chronic adminstration
/ suppressionGnRH Agonist-Initial phase:
stimulation
X
Loss of receptors (down regulation)
native GnRH excluded from receptorbinding (desensitization)
Cell membrane
Receptor
nRHG
gonisa t
Increased LH/FSH
initial flare up
Mode of Action: GnRH Agonists
X
Loss of receptors (down regulation)
native GnRH excluded from receptorbinding (desensitization)
G nRH Agonist-chronic adminstration/ suppression
Increased L H/FSH
initial flare up
G nRH Agonist-Initial phase:stim ulation
Cell membrane
Receptor
Immediate decrease inLH , FSH
No initia l flare up
Mode of Action: GnRHAntagonists
XXXX
Com petitive binding
Mode of action
Median serum hormone concentration during
Ganirelix treatment
01234567
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time (days)
IU/L
FSH LH Oestradiol
Oberye et al. Fertil Steril 1999 Dec:72(6):1001-5.
Effect of different doses of Ganirelix on serum LH
00 .5
11 .5
22 .5
33 .5
4
0.0625(n=31)
0.125(n=65)
0.25(n=69)
0.5(n=69)
1(n=65)
2(n=30)
d a ily G a n ire lix d o s e (m g )
Seru
m L
H le
vel (
IU/L
)
L H
The ganirelix dose-finding study group. Hum Reprod 1998 Nov :13(11):3023-31.
Plasma LH values
Plasma LH values in 2 mg and 3 mg cetrorelix
0
1
2
3
4
5
D -2 D -1 D 0 D 1 D 2 D 3 D 4
days relative to cetrorelix injection
LH
IU/L
2 mg3 mg
Cetrorelix
Olivennes et al. Hum Reprod 1998 Sep :13(9) :2411-4.
Dosages in Assisted ReproductionDosages in Assisted Reproduction
Single dose protocol : Cetrorelix
Multiple dose protocol : Cetrorelix or Ganirelix
Multiple daily doseHCG
E2>400pg/ml
HMG or rFSH
Luteal phaseLuteal support
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
single
Effect of GnRH Antagonists on Follicular Phase
• Stop follicular growth• Normal follicular rescue
• after terminal half life time of GnRH antagonist• with appropriate administration of gonadotrophins
• Transient decrease in E2 (related to dose)• Decrease in total number of follicles• No decrease in number of mature oocytes• GnRH receptors found only after the LH
surge
Effect of GnRH Antagonist on Luteal Phase
• Less impaired with antagonist than agonist• still needs luteal phase supplementation• P4 & E2 higher in cultured granulosa cells from
women treated with antagonists > agonists• Withholding luteal supplementation did not
exclude pregnancy in some studies• No impact on luteal phase when hormonal support
is given
Multicentre trial of the European Orgalutran Study Group (ganirelix)
Ganirelix BuserlinMedian duration of analouge 5 26
Median total rFSH 1500 Iu 1800 IU
Incidenceof LH rise > 10IU/L
2.8% 1.3%
Mean follicular number > 11mm
10.7 11.8
Mean number of oocytesretrieval
9.1 10.4
Fertilization rate 62.1% 62.1%
On going pregnancy rate 20.3% 25.7%Borm and Mannaerts TheEuropean Orgalutran Study Group. Hum Reprod 2000 Jul;15(7):1490-8.
Ovarian hyperstimulation syndrome (OHSS)
• WHO grade III 0.6% ( 2/346)Felberbaum et al. Hum Reprod 2000 May;15(5):1015-20
• WHO grade II-III GnRH antagonist(3.5%)Agonist (11.1%)
Olivennes et al. Fertil Steril 2000 Feb:73(2):314-20.
• WHO grade III GnRH antagonist (1.8%)Agonist (5.6%)
• Overall incidence GnRH antagonist (2.4%)Agonist (5.9%)
Borm and Mannaerts. The European Orgalutran Study Group. Hum Reprod 2000 Jul;15(7):1490-8.
Advantages and disadvantages
• Lower incidence of OHSS• Less days of gonadotrophin stimulation• Lower number of ampoules• Mild headache on day of injection• Mild local injection reaction around 5%• No increased risk of miscarriage• No evidence of teratogenicity
GnRH antagonists in Gynaecological disorders
• Fibroids• Endometriosis• PCOD• antitumour activity
GnRH antagonist & Fibroids
0%
20%
40%
60%
80%
100%
0 1 2 3 4
months of treatment
5 mg b.d s.c for 2 dasys, then 0.8 mg daily s.c for 4.4 months
Fibroid
Gonzalez et al, 1997
GnRH antagonist & Fibroids
0%20%40%60%80%
100%
d0 14 d 21 28fibroid
days after starting GnRH antagonists
60 mg depot cetrorelix
Reduction in fibroid volume
fibroidgood responders
Felberbaum et al, 2000
GnRH Antagonists and tumour
• GnRH receptors ( and GnRH antagonist effect) demonstrated in human malignant tumours, breast, ovary, endometrium and prostate
• inhibits the release of Insulin like growth factor and cell growth
• potential use in IVF, prior to chemotherapy in women wishing to become pregnant in the future.
Conclusion I
• Third generation GnRH antagonists have been evaluated in clinical studies
• Act by competitive blockage with GnRH• Effective in immediate suppression of LH
surge• Avoid initial flare up effect• Can be used in single or multiple dose
protocols
Conclusion II• Favourable outcome compared to agonists• Low complication rate• Well tolerated• Reduce duration of treatment and total
number of gonadotrophin stimulation and cost
• Rapid significant reduction in fibroid size• Potential use in endometriosis and tumours• GnRH antagonists may replace the agonist
in gynaecology
Thank You