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Gynaecology
AMR EL NOURY
Tutor
Bianchi 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 ?
Second generation
( allergy and gel formation)
Third Generation
( well tolerated)
Market
approval
Hexapeptides, Heptapetides
1
PyroGlu
PyroGlu
Ac-DPyroNal(2)
Glu
2
HIS
Decapeptide
5
6
TRP
SER
TYR
Chemical composition
GLY
LEU
ARG
PRO
10
GLY
NH2
GnRH
HIS
TRP
SER
TYR
GLY
LEU
ARG
PRO
GLY
NH2
D.hArg
ARG
(Et2)
PRO
D.AIA
GLY
-NH2
NH2
GnRH Agonists
D.Phe
HIS
(4CI)
D/PA
TRP
L
SER
TYR
D.hArg
GLY
(Et2)
LEU
GnRH Antagonists
2
Cetrorelix
Ganirelix
7
10
GnRH
agonist
Receptor
Cell membrane
Increased LH/FSH
initial flare up
Mode of action
Re ce ptor
Ce ll me mbrane
Increa se d L H/FSH
initial flare up
LH
Oestradiol
7
6
IU/L
5
4
3
2
1
0
1
9 10 11 12 13 14 15
Time (days)
Oberye et al. Fertil Steril 1999 Dec:72(6):1001-5.
LH
4
3 .5
3
2 .5
2
1 .5
1
0 .5
0
0 .0
5
62
(n
1
=3
5
.1 2
(n
5
=6
)
5
0 .2
(n
9
=6
)
0 .5
6
n=
9)
1(
6
n=
5)
2(
3
n=
0)
d a ily G a n ir e lix d o s e ( m g )
The ganirelix dose-finding study group. Hum Reprod 1998 Nov :13(11):3023-31.
Plasma LH values
4
3
2 mg
3 mg
2
1
0
D -2
Cetrorelix
D -1
D0
D1
D2
D3
D4
: Cetrorelix
: Cetrorelix or Ganirelix
E2>400
pg/ml
HCG
HMG
or
rFSH
Luteal phase
support
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
single
26
1500 Iu
1800 IU
2.8%
1.3%
10.7
11.8
9.1
10.4
62.1%
62.1%
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
GnRH antagonists in
Gynaecological disorders
Fibroids
Endometriosis
PCOD
antitumour activity
Fibroid
20%
0%
months of treatment
100%
80%
60%
40%
20%
0%
fibroid
d0
14 d
21
28
fibroid
good responders
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
Thank You