the use of gnrh antagonists in gynaecology - a. el noury• (lhrh) gnrh discovery shally 1971 •...
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The Use of GnRH Antagonists in Gynaecology
AMR EL NOURY
TutorBianchi PG
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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 ?
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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
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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
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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
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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
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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.
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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.
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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.
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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
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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
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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
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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.
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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.
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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
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GnRH antagonists in Gynaecological disorders
• Fibroids• Endometriosis• PCOD• antitumour activity
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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
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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
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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.
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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
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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
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Thank You