the use of gnrh antagonists in gynaecology - a. el noury• (lhrh) gnrh discovery shally 1971 •...

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