recommended dosage of gnrh antagonist is too high presented by dr. milton leong, md dsc(mcgill)...

Recommended Dosage of GnRH Antagonist is Too High

Presented by

Dr. Milton Leong, MD DSc(McGill)

Director, IVF Centre

When Do I Use GnRH Antagonist in my IVF Practice?

Presented by

Dr. Milton Leong, MD DSc(McGill)

Director, IVF Centre

ACTION, STRUCTURE AND USE OF GnRH AGONISTS AND

ANTAGONIST

Action of GnRH agonists

LH + FSH

post-receptor-cascade

GnRH - receptor

GnRH

GnRH - agonistflare up effect

Downregulation

pituitary suppression

Structure of GnRH agonists

Modifications of natural GnRHto have GnRH agonistic properties

1 2 43 65 98 107

pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2

activation of the GnRH receptor

regulation of GnRHreceptoraffinity

regulation ofbiologic activity

Results of first application of GnRH-agonists in the long protocol

• 11 patients eligible for IVF• GnRH agonist s.c. (Buserelin) started at day

of menstruation or one day before• Ovarian stimulation started with HMG or

purified FSH when all ovarian follicles and the endometrial lining has disappeared on ultrasound (average: 15 days)

• One ongoing pregnancy achievedPorter et al., 1984

Analysis of protocols using GnRH agonists for ovarian stimulation

protocol cumulative

live birth rate p (compared to long protocol)

long protocol 55% -

gonadotropins without agonist 29% p = 0.0001

short or ultrashort protocol 17% p = 0.005

• 2893 patients for IVF

• long protocol superior to other protocols in IVF

Tan et al., 1994

Comparison: Mode of Actions

Antagonists Agonists

•Immediate onset of actions (shortens treatment durations)

•Prevents hormonal

withdrawal symptoms

•No recovery time of the pituitary

•long pre-treatment

•Hormonal (estrogen) withdrawal symptoms through desensitization of pituitary

•Recovery of the pituitary gonadotrophin secretion, after stopping the treatment takes about 2 weeks.

Meta-analysis of protocols using GnRH agonists for ovarian

stimulation• The long protocol is superior to the short

and ultra-short protocol

Daya, 1997

long versus short

long follicular vs. short

long luteal vs. short

long vs. ultrashort

long luteal vs. long follicular

depot vs. daily (long)

0.1 1 10

Action of GnRH antagonists

LH + FSH

post-receptor-cascade

GnRH - receptor

GnRH

GnRH - antagonistpituitary suppression

Structure of GnRH antagonistsname amino acid sequenceGnRH pGlu – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2

1st generation4F Ant NAc1,1Pro – D4FPhe – DTrp – Ser – Tyr – DTrp – Leu – Arg – Pro – GlyNH2

2nd generationNalArg NACD2Nal – D4lFPhe=pTrp – Ser – Tyr – DArg – Leu – Arg – Pro – GlyNH2

Detirelix NACD2Nal – D4ClPhe – pTrp – Ser – Tyr – DHarg(Et2) – Leu – Arg – Pro – DAlaNH2

3rd generationNalGlu NACD2Nal – D4C7Phe – D3Pal – Ser – Arg – DGlut(AA) – Leu – Arg – Pro – DAlaNH2

Antide NACD2Nal – D4ClPhe – D3Pal – Ser – Lys(Nic) – DDLys(Nic) – Leu – Lys(Isp)Pro – DAlaNH2

Org30850 NACD4ClPhe – D4ClPhe – DBal – Ser – Tyr – DLys – Leu – Arg – Pro – DAlaNH2

Ramorelix NACD2Nal – D4ClPhe – DTrp – Ser – Tyr – DSet(Rha) – Leu – Arg – Pro – AzaglyNH2

Cetrorelix NACD2Nal – D4ClPhe – D3Pal – Ser – Tyr – DCit – Leu – Arg – Pro – DAlaNH2

Ganirelix NACD2Nal – D4ClPhe – D3Pal – Ser – Tyr – DHarg(Et2) – Leu – Harg(Et2) – Pro – DAlaNH2

A-75998 NACD2Nal – D4ClPhe – D3Pal – Ser – NMeTyr – DLys(Nic) – Leu – Lys(Isp) – Pro – DAlaNH2

Azaline B NACD2Nal – D4ClPhe – D3Pal – Ser – Aph(atz) – DAph(atz) – Leu – Lys(Isp) – Pro – DAlaNH2

Antarelix NACD2Nal – D4ClPhe – D3Pal – Ser – Tyr – DHcit – Leu – Lys(Isp) – Pro – DAlaNH2

Two possible antagonist protocols

• multiple dose protocol

- Cetrotide® 0.25mg

• single dose protocol

- Cetrotide® 3mg

The single dose antagonist protocol compared to the long luteal protocol

• Inclusion criteria– Age: 18 - 39 years

– Normal menstrual cycle (range: 24 - 35 days) with an intraindividual variation of max. ± 3 days

– No more than 3 IVF procedures

– Normal uterus and at least one functioning ovary

• Exclusion criteria– Severe endometriosis (AFS III/IV)

– PCO syndrome

Olivennes et al., 2000


Cetrotide® Triptorelin 95% CI

no of patients undergoing oocyte pick-up (% of treated patients)

113 (98.3) 36 (92.3) -0.4 to -12.5

stimulation length (d) 9.4 1.4 10.7 1.7 -1.9 to -0.7

no of ampoules 24.3 7.4 35.6 15.1 -14.2 to -7.2

estradiol on day of hCG (pg/ml) 1.786 808 2549 1.194 -1.042 to -368

total no. of oocytes retrieved 9.2 5.1 12.6 7.4 -5.6 to -1.3




no. of embryos obtained 5.4 3.5 7.5 4.9 - 3.7 to - 0.6

no. of mature/metaphase II oocytes

7.2 4.9 10.3 7.4 - 5.3 to - 1.2

rate of OHSS (%) 3.5 11.1 - 18.4 to 3.2

OHSS patients requiring hospitalisation (%)

1.8 5.6 - 11.7 to 4.1




clinical pregnancy rate/oocyte pick up (%)

22.6 28.2 - 23.9 to 12.3

miscarriage rate (%) 15.4 (4/26) 27.3 (3/11) - 41.6 to 17.9

ectopic pregnancy rate (%)

7.7 (2/26) - (0/11) -

ongoing pregnancy rate/oocyte pick up (%)

18.3 23.1 - 20.2 to - 8.9

ongoing pregnancy rate/embryo transfer (%)

21.2 27.3 - 22.9 to 11.0


The multiple dose antagonist protocol compared to the long luteal

protocol Cetrotide® Buserelin p number of patients 188 85 - age (years) 31.9 3.7 31.6 3.8 n.s. days of analogue treatment 5.7 2.3 26.6 3.2 < 0.001

number of patients who got hCG (%)

181 (96.3) 77 (90.6) n.s.

number of gonadotropin ampoules 23.6 8.5 25.6 7.6 < 0.01

days of gonadotropin treatment 10.6 2.3 11.4 1.8 < 0.01

estradiol on day of hCG (pg/ml) 1625 836 2082 1049 < 0.01

Albano et al., 2000

n.s. not significant

The multiple dose antagonist protocol compared to the long luteal

protocol

Cetrotide® Buserelin p no. of patients 188 85 - no. of patients with pick-up 178 77 - no. of cumulus oocyte complexes per patient 8.0 4.9 10.6 6.6 < 0.01

no. of 2 PN oocytes per patient 4.5 3.3 6.0 4.1 = 0.01 no. of cleaved embryos (% of 2 PN)

671 (89.5) 345 (79.9) -

- excellent (n, % of all) 235 (35.0) 94 (28.1) - - good (n, % of all) 321 (47.8) 154 (44.6) - - fair (n, % of all) 115 (83.5) 67 (78.8) - no. of embryos per transfer 2.2 0.6 2.2 0.6 n.s.

Albano et al., 2000

n.s. not significant

The multiple dose antagonist protocol compared to the long luteal protocol:

significant reduction of OHSS

Albano et al, 2000Oliveness et al, 2000

Felberbaum et al, 2000Diedrich K et al, 2000

Frydman R. et al, 2000

Study Cetrotide® group Agonist group

Phase III 2/181 (1.1%) Buserelin ® : 5/77 (6.5%)

Phase III (1.8%) Triptorelin ® : (5.6%)

Phase III 2/346 (0.6%) N.A.

Phase IIIb 10/859 (1.2%) N.A.

Phase IIIb 2/192 (1.1%) N.A.

Estradiol drop following administration of Cetrotide® 3 mg

20

0

400

800

1200

1600

Day 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6

Days after Cetrotide ®

3mg

[pg/

ml]

0

5

10

15

[mm

]

E2 value

Lead Follicle

according to: Olivennes, 2001

Mean number of Cetrotide® 0.25 mg ampoules in the multiple dose

protocol

0

5

10

15

20

25

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

number of injections

patie

nts (

%) average: 6.3 injections

Possibilities to individualize the multiple dose protocol

• To avoid a premature LH rise the administration of cetrotide® 0.25 mg on day 6 of stimulation should be the standard procedure

• Using the standard procedure, a mean of 6.3 injections are necessary

• This is in accordance with the package size of 7 ampoules cetrotide® 0.25 mg per patient

Possibilities to individualize the multiple dose protocol

• Individualized administration of Cetrotide® 0.25 mg can be done– According to follicle size:

only if leading follicle is 14 mm

• Thereby, the multiple dose protocol can also be adapted to patients with a lower response

Cetrorelix 0.125mg Flexible Dose Trial

Selection Criteria:

1. Previous over-suppression with agonist

2. Previous poor response

3. Previous LH surge if no agonist


Methods:

1. FSH LH E2 on day 2

2. U/S on day 3, start Gonal-F 225IU/day

3. Stimulation day 4, check E2 LH U/S


Treatment Criteria

1. LH > 1.5IU/L

2. Leading follicle = 15mm diameter

• Cetrorelix 0.125mg/day given until day of HCG injection

• Monitor by E2 LH U/S everyday


RESULTS

Age Distribution

0

1

2

3

4

5

6

7

<32 33-36 37-40 >40

Mean = 36.6 (range 29-44)

BMI Distribution

01

23

45

67

89

10

<20 20 21 22 >25

Mean = 21.8 (range 19-30)

Cetrorelix Start Cycle Day

0

1

2

3

4

5

6

7

8

5 7 9 11 13 15 17 19 21 23 25

FSH 225 Units/day SC starts on day 3

# Days Cetrorelix Used

01234567

89

10

1 2 3 4

Mean = 2.2 days (range 1-3)

LH and Cetrorelix 0.125mg/day

1.20.9

1.82.4

2.12.5

4.9

6

7.8

0

1

2

3

4

5

6

7

8

pre day 1post

dayHCG

Range mIU/ml

• Pre 1.2 - 7.8

• Day 1 post 0.9 - 4.9

• Day HCG 1.8 - 6

Clinical Data

•Age

•BMI

36.6 (29-44)

21.8 (19-30)

15<40yr 5>40yr

•Ova # per OPU

•%MT II

•% Fertilization

9 (1-16)

77%

74.4%

•Transfer # embryos

•Pregnancy rate

•Implantation rate

2.6 <40yr 4.8 >40yr

60%<40yr 40% >40yr

25.4% (16/63)

The GnRH Antagonists

Conclusions:

1. Why treat 100% of patients when we are trying to prevent 5-10% LH surge

2. Avoid over-suppression and poor response

3. Effective in preventing LH surge

4. Reduction of hyper-stimulation

5. Lower costs

Flexible dose GnRH Antagonist

• 1. To use the lowest effective dosage• 2. 0.125mg/day may be adequate• 3. Starting date may be adjusted• 4. Criteria for dose and commencement to

be better defined

• 5. Some may not need suppression• 6. Future individual FSH GnRH-antagonist

dose

THE FIRST GLOBAL CHINESE CONFERENCE

ON REPRODUCTIVE MEDICINE

14th – 15th December 2002, Hong Kong

recommended dosage of gnrh antagonist is too high presented by dr. milton leong, md dsc(mcgill)...

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