1. Recommended Dosage of GnRH Antagonist is Too High Presented by Dr. Milton Leong, MD DSc(McGill) Director, IVF Centre

2. When Do I Use GnRH Antagonist in my IVF Practice? Presented by Dr. Milton Leong, MD DSc(McGill) Director, IVF Centre

3. ACTION, STRUCTURE AND USE OF GnRH AGONISTS AND ANTAGONIST

4. Action of GnRH agonists LH + FSH post-receptor-cascade GnRH - receptor GnRH GnRH - agonist flare up effect Down regulation pituitary suppression

5. Structure of GnRH agonists Modifications of natural GnRH to have GnRH agonistic properties 12436598107 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH 2 activation of the GnRH receptor regulation of GnRH receptor affinity regulation of biologic activity

6. 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 achieved Porter et al., 1984

7. Analysis of protocols using GnRH agonists for ovarian stimulation 2893 patients for IVF long protocol superior to other protocols in IVF Tan et al., 1994

8. Comparison: Mode of Actions AntagonistsAgonists 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.

9. 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) 0.1 110

10. Action of GnRH antagonists LH + FSH post-receptor-cascade GnRH - receptor GnRH GnRH - antagonist pituitary suppression

11. Structure of GnRH antagonists

12. Two possible antagonist protocols multiple dose protocol - Cetrotide ® 0.25mg single dose protocol - Cetrotide ® 3mg

13. 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

14. The single dose antagonist protocol compared to the long luteal protocol Olivennes et al., 2000

15. The single dose antagonist protocol compared to the long luteal protocol Olivennes et al., 2000

16. The single dose antagonist protocol compared to the long luteal protocol Olivennes et al., 2000

17. The multiple dose antagonist protocol compared to the long luteal protocol Albano et al., 2000 n.s. not significant

18. The multiple dose antagonist protocol compared to the long luteal protocol Albano et al., 2000 n.s. not significant

19. The multiple dose antagonist protocol compared to the long luteal protocol: significant reduction of OHSS Albano et al, 2000 Oliveness et al, 2000 Felberbaum et al, 2000 Diedrich K et al, 2000 Frydman R. et al, 2000 StudyCetrotide ® groupAgonist group Phase III2/181 (1.1%)Buserelin ® : 5/77 (6.5%) Phase III(1.8%)Triptorelin ® : (5.6%) Phase III2/346 (0.6%)N.A. Phase IIIb10/859 (1.2%)N.A. Phase IIIb2/192 (1.1%)N.A.

20. Estradiol drop following administration of Cetrotide ® 3 mg 20 0 400 800 1200 1600 Day 0Day 1Day 2Day 3Day 4Day 5Day 6 Days after Cetrotide ® 3mg [pg/ml] 0 5 10 15 [mm] E2 value Lead Follicle according to: Olivennes, 2001

21. Mean number of Cetrotide ® 0.25 mg ampoules in the multiple dose protocol average: 6.3 injections

22. 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

23. 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

24. 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

25. Cetrorelix 0.125mg Flexible Dose Trial Methods: 1.FSH LH E 2 on day 2 2.U/S on day 3, start Gonal-F 225IU/day 3.Stimulation day 4, check E 2 LH U/S

26. Cetrorelix 0.125mg Flexible Dose Trial Treatment Criteria 1.LH > 1.5IU/L 2.Leading follicle = 15mm diameter Cetrorelix 0.125mg/day given until day of HCG injection Monitor by E 2 LH U/S everyday

27. Cetrorelix 0.125mg Flexible Dose Trial RESULTS

28. Age Distribution Mean = 36.6 (range 29-44)

29. BMI Distribution Mean = 21.8 (range 19-30)

30. Cetrorelix Start Cycle Day FSH 225 Units/day SC starts on day 3

31. # Days Cetrorelix Used Mean = 2.2 days (range 1-3)

32. LH and Cetrorelix 0.125mg/day Range mIU/ml Pre 1.2 - 7.8 Day 1 post 0.9 - 4.9 Day HCG 1.8 - 6

33. Clinical Data Age BMI 36.6 (29-44) 21.8 (19-30) 15 40yr Ova # per OPU %MT II % Fertilization 9 (1-16) 77% 74.4% Transfer # embryos Pregnancy rate Implantation rate 2.6 40yr 60% 40yr 25.4% (16/63)

34. 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

35. 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

36. THE FIRST GLOBAL CHINESE CONFERENCE ON REPRODUCTIVE MEDICINE 14 th – 15 th December 2002, Hong Kong