1. Does exogenous LH activity influence the outcome in IVF and not in ICSI cycles? Peter Platteau, Johan Smitz, Carola Albano, Per Sørensen Joan-Carles Arce and Paul Devroey Center for Reproductive Medicine, AZ-VUB, Brussels, Belgium Ferring Pharmaceuticals A/S, Copenhagen, Denmark

2. EISG 2002 European and Israeli Study Group Fertil Steril 2002 GnRH agonist daily/depot DAY 21 No Cyst E2<200pmol/L hCG OPU 32-42h 6 HP-hMG or rFSH Dose ↑↓ 1 ≥3 follicles ≥16mm and/or E2 ≥1000 pmol/L / foll ≥16mm

3. EISG: Overall Results HP-hMGrFSH Patients357336 Patients with IVF/ICSI344317 Primary endpoint (PP-population) Ongoing pregnancy85 (25%)71 (22%) European and Israeli Study Group Fertil Steril 2002

4. EISG 2002 26% 22% Gordon 2001 38% 28% Ng 2001 25% 20% Westergaard 2001 40% 34% 31% 26% Cochrane Review 2002: RCTs hMG vs rFSH Van Wely et al. 2002 0 1 2 3 4 5 6 Odds Ratio (95% C.I.) 1.26 (0.90-1.77) 1.32 (0.31-5.73) hMG rFSH 1.55 (0.56-4.30) 1.26 (0.83-1.92) 1.28 (1.00-1-64) Clinical Pregnancy N 727 68 40 379 Long Protocol

5. Cochrane Review 2002: RCTs hMG vs rFSH N% ICSI Clinical Pregnancy hMG rFSH Gordon 2001680% 38%28% Westergaard 200137925%40%34% EISG 200272764%26%22% Ng 200140100%25%20%

6. Pregnancy Rates IVF / ICSI IVFICSI HP-hMGrFSH P value HP-hMGrFSH P value Number of patients121112–237221– Clinical pregnancy42 (35%)22 (20%).00956 (24%)55 (25%)NS Ongoing pregnancy38 (31%)22 (20%).03749 (21%)50 (23%)NS Implantation rate21%15%.05412% NS

7. Baseline Characteristics IVFICSI HP-hMGrFSHHP-hMGrFSH Number of patients121112237221 Age (years)32 ± 4 30 ± 4 BMI (kg/m 2 )23 ± 3 Main cause of infertility Male factor Tubal factor Endometriosis Unexplained Other 20% 38% 7% 30% 6% 18% 38% 6% 33% 5% 92% 6% 0% 2% 0% 90% 6% 1% 3% 0% Duration of infertility (years)4 ± 3 4 ± 2 Number of previous cycles0.7 ± 1.20.9 ± 1.41.0 ± 1.41.1 ± 1.9 Baseline LH levels (IU/L)5.4 ± 3.05.6 ± 4.05.9 ± 5.46.1 ± 4.7

8. Follicle, Oocytes Retrieved, Fertilization Rate, Embryos Transferred: IVF / ICSI IVFICSI HP-hMGrFSH P value HP-hMGrFSH P value Number of patients121112–237221– Number of follicles ≥16mm on day of hCG 7.4 ± 3.88.0 ± 4.5NS8.4 ± 4.68.5 ± 5.7NS Number of oocytes retrieved 11.7 ± 7.114.1 ± 8.7.02213.4 ± 7.414.0 ± 8.4NS Fertilization rate (% of retrieved) 59% NS54%57%NS Number of embryos transferred 2.1 ± 0.92.1 ± 0.8NS2.2 ± 0.8 NS

9. Distribution of Patients according to LH Levels IU/L IVF

10. Ongoing Pregnancy Rates by hCG on Day 6 IUl/L ICSIIVF

11. Hypothesis: LH Activity Effects via Cumulus Cells IVF ICSI

12. Role of Cumulus Cells in Oocyte Viability and Early Development Animal Studies Mice, bovine and buffalo oocytes: removal of the cumulus before insemination is associated with reductions in cleavage rate, early embryo development and blastocyst formation Human Studies Protective effect of the cumulus on the oocyte against adverse environmental influences (Magier et al, 1990) Preincubation with intact cumulus before ICSI improves fertilisation and cleavage rate ( Hassan et al, 2001)

13. Conclusions A significantly higher ongoing pregnancy rate in IVF cycles was found in the HP-hMG group compared with rFSH No difference was observed in ICSI cycles between the HP-hMG and rFSH groups In the HP-hMG group, higher midfollicular hCG levels were associated with ongoing pregnancy, especially in IVF cycles

14. Future Directions Prospective multicenter randomized controlled trial to confirm these findings The role of cumulus cells in IVF cycles stimulated with different gonadotrophins