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The Use of GnRH Antagonists in

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 ?

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)

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

Mode of Action: GnRH Agonists


GnRH Agonist-Initial phase:
stimulation

GnRH Agonist-chronic adminstration


/ suppression

GnRH

agonist
Receptor
Cell membrane

Increased LH/FSH

Loss of receptors (down regulation)

initial flare up

native GnRH excluded from receptor


binding (desensitization)

M ode of Action: GnRH Agonists


G nR H Agonist-Initial phase:
stim ulation

G nRH Agonist-chronic adminstration


/ suppression

Mode of action

Re ce ptor
Ce ll me mbrane

Increa se d L H/FSH

Loss of rec eptors (dow n regulation)

initial flare up

native GnRH exclude d from receptor


binding (desensitization)

M ode of Action: GnRH


Antagonists
Com petitive binding

Imme diate de crease in


LH , FSH
N o initia l flare up

Median serum hormone concentration during


Ganirelix treatment
FSH

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.

Effect of different doses of Ganirelix on


serum LH
Serum LH level (IU/L)

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

Plasma LH values in 2 mg and 3 mg cetrorelix


5
LH IU/L

4
3

2 mg
3 mg

2
1
0
D -2

Cetrorelix

D -1

D0

D1

D2

D3

D4

days relative to cetrorelix injection

Olivennes et al. Hum Reprod 1998 Sep :13(9) :2411-4.

Dosages in Assisted Reproduction


Dosages in Assisted Reproduction

Single dose protocol

: Cetrorelix

Multiple dose protocol

: Cetrorelix or Ganirelix

E2>400
pg/ml

HCG

Multiple daily dose

HMG

or

rFSH
Luteal phase
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 Buserlin
Median duration of analouge

26

Median total rFSH

1500 Iu

1800 IU

Incidenceof LH rise > 10


IU/L
Mean follicular number > 11
mm
Mean number of oocytes
retrieval
Fertilization rate

2.8%

1.3%

10.7

11.8

9.1

10.4

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


5 mg b.d s.c for 2 dasys, then 0.8 mg daily s.c for 4.4
months
100%
80%
60%
40%

Fibroid

20%
0%

months of treatment

Gonzalez et al, 1997

GnRH antagonist & Fibroids


Reduction in fibroid volume

100%
80%
60%
40%
20%
0%

fibroid
d0

14 d

21

28

fibroid
good responders

days after starting GnRH


antagonists
60 mg depot cetrorelix

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