1. Safety and efficacy of FSH drugs in ART for polycystic ovarian disease M. Aboulghar Cairo, Egypt

2. Safety of FSH

3. Urinary and recombinant gonadotrophins are being used for many years with 100% safety record concerning transmission of infection and with no serious allergic reaction.

4. The only risk of the use of both types of FSH is the development of OHSS. This is not uncommon complication in PCO patients as those patients are particularly liable to OHSS.

5. Ovarian stimulation for PCOS patients is associated with complications. Under- and over-stimulation are relatively common (Urman 2004).

6. Polycystic ovaries and OHSS: a systematic review (Tummon et al 2005) 10 studies were included with PCOS and available data on OHSS. 10 studies were included with PCOS and available data on OHSS. Combined OR for OHSS was 6.8 (CI 4.9 – 9.6) Combined OR for OHSS was 6.8 (CI 4.9 – 9.6) There is a significant consistent relation between PCOS and OHSS. There is a significant consistent relation between PCOS and OHSS.

7. How can we prevent OHSS in PCOS? Smaller dose of FSH Smaller dose of FSH Close monitoring. Close monitoring. Coasting Coasting Use of GnRH antagonist as a protocol of stimulation or to prevent OHSS in hyperstimulated patients. Use of GnRH antagonist as a protocol of stimulation or to prevent OHSS in hyperstimulated patients. Small dose of hCG 5000 IU. Small dose of hCG 5000 IU.

8. Efficacy of FSH in ART for PCOS

9. Outcome IVF in PCO and controls matched for age, cause of infertility and stimulation protocol (MacDougall et al 1993) PCONon PCOP N76 NS FSHSmaller doseHigher doseS E2HigherLowerS OocytesMoreLessS FRLessMoreS PR25.4%23%NS OHSS10.5%ZeroS

10. Outcome of IVF in women with US finding of polycystic ovaries (Engmann et al. 1999) 191 women 46 (PCO by US) 145 matched (normal ovary by US) Long GnRHa protocol 97 IVF cycles332 IVF cycles More follicles More oocytes More embryos Less follicles Less oocytes Less embryos Equal fertilization, cleavage, miscarriage rates Odds of achieving pregnancy within 3cycles were 69% higher in PCO Odds of achieving live birth in 3cycles were 82% higher in PCO

11. During simple ovulation induction for PCOS patients, hMG, urinary FSH, and recombinant FSH appear to be equal in achieving pregnancy (Van Wely et al 2003)

12. A meta-analysis of outcomes of IVF in PCOS and a matched non PCOS group (Heijnen 2006) 458 PCOS patients (From 9 studies) Rotterdam criteria 694 non PCOS patients. Significantly more oocytes retrieved in PCOS (OR = 3.4, 95% CI = 1.7 – 5.1) 793cycles1116 cycles No significant difference between mean number of fertilized oocytes No significant difference in PR (OR = 1.0 95% CI = 0.8 – 1.3) OHSS was rarely reported.

13. Oocyte quality in patients with severe ovarian hyperstimulation syndrome. (Aboulghar et al 1997; Fabregues 2004) Significantly more oocytes Significantly more oocytes Significantly lower FR Significantly lower FR Similar number and quality of available embryos Similar number and quality of available embryos Similar implantation and pregnancy rates. Similar implantation and pregnancy rates.

14. We will present the results of the first prospective randomized study in the world literature comparing highly purified FSH with recombinant FSH for IVF/ICSI in PCOS patients. (Aboulghar et al Fertil Steril, in press).

15. Declaration of conflict of interest This randomized study was sponsored in part by IBSA Institute Biochimique SA This randomized study was sponsored in part by IBSA Institute Biochimique SA

16. Study design: A prospective randomized study of IVF/ICSI for patients with PCOS comparing recombinant FSH (Gonal F, Merk-Serono) and highly purified urinary FSH (Fostimon, IBSA). A prospective randomized study of IVF/ICSI for patients with PCOS comparing recombinant FSH (Gonal F, Merk-Serono) and highly purified urinary FSH (Fostimon, IBSA). A sample size of 42 women in each arm is sufficient to detect a difference of 10% in oocyte maturity to ensure a power of 80% based on the oocyte maturity in our study (Aboulghar et al. 1997). A sample size of 42 women in each arm is sufficient to detect a difference of 10% in oocyte maturity to ensure a power of 80% based on the oocyte maturity in our study (Aboulghar et al. 1997).

17. Protocol of treatment We used our routine long GnRHa protocol (Aboulghar et al.2008) We used our routine long GnRHa protocol (Aboulghar et al.2008) Start dose of FSH was 2-3 ampoules depending on age and weight of patient, from day 6 of stimulation, adjustment could be done. Start dose of FSH was 2-3 ampoules depending on age and weight of patient, from day 6 of stimulation, adjustment could be done. Frequency of E2 assays depended on the number of follicles, and the rate of growth. Frequency of E2 assays depended on the number of follicles, and the rate of growth. Triggering ovulation when follicle reaches 18 mm (according to our routine protocol). (Aboulghar et al.2008) Triggering ovulation when follicle reaches 18 mm (according to our routine protocol). (Aboulghar et al.2008)

18. In case of risk of OHSS, coasting was performed according to our coasting protocol (Mansour et al 2005). We stopped FSH treatment when the lead follicle reached 15-16 mm and waited until E2 level dropped to 3000 pg/ml or less, then a dose of 10,000 hCG was given.

19. Indication for IVF/ICSI FostimonGF Male factor73.8%61.9%NS Tubal factor14.3%21.4%NS Failure of ovulation induction 12.9%18.7%NS

20. Patients’ characteristics FostimonGF Age28.29±4.0427.36±3.50NS Period of infertility 5.03±3.605.77±3.42NS BMI29.80±4.7429.90±4.65NS

21. Ovarian stimulation data FSH dose and durationFostimon GF p Start FSH dose (Ampoules) 2.71±0.46 2.67±0.47 NS Mean Total ampoules29.98±9.17 28.29±7.95 NS Days of stimulation11.05±2.59 11.21±2.82 NS Days of coasting1.88±0.96 1.80±0.77 NS

22. Coasting Done in 16 patients in fostimon Done in 16 patients in fostimon Done in 20 patients in Gonal F Done in 20 patients in Gonal F 15 patients:one day 15 patients:one day 13 patients:two days 13 patients:two days 7 patients:three days 7 patients:three days 1 patient:four days 1 patient:four days

23. Fostimon GF p Retrieved oocytes17.1±8.66 13.83±7.07 0.064 NS Mature Oocytes12.8±7.78 10.45±5.69 0.106 NS Fertilized oocytes9.52±6.78 6.76±5.44 0.043 Fertilization rate74.5±20.14 62.96±24.2 0.021 Top quality embryos2.79±0.55 2.18±0.95 0.021 Good quality embryos2.64±0.85 2.19±0.75 0.060 NS Outcome in both groups

24. Fostimon GF p Patients with frozen embryos 28 (66.7%) 14 (33.3%) 0.006 Total n of cryo embryos 20796 No. of embryos transferred 2.88±0.552.80±0.51NS Frozen embryos per patient 4.9±6.42.57±4.5 0.015 * Positive BHCG 26 (63.4%) 24 (58.5%) NS Clinical pregnancies 21 (50%) 22 (50.2%) NS Ongoing pregnancies 19 (45.2%) 20 (47.6%) NS Outcome in both groups

25. In the current study, 84 patients of IVF/ICSI were performed for one or more of these indications in a single large center during the relatively short period of 8 months, denoting that the indication for IVF/ICSI in PCOS patients in not uncommon.

26. In previous studies on IVF/ICSI for PCOS (Urman et al 2004) Small dose of FSH for fear of OHSS High FSH dose for fear of cancellation High cancellation rate was reported Due to

27. In the present study only 2 cycles out of 84 cycles were canceled due to poor response. In the present study only 2 cycles out of 84 cycles were canceled due to poor response. Coasting used liberally in 36 out of 84 patients (42.8%) in our study and without affecting the clinical pregnancy rate which was 50%. Coasting used liberally in 36 out of 84 patients (42.8%) in our study and without affecting the clinical pregnancy rate which was 50%.

28. Dose of FSH and BMI FostimoneGF Mean starting dose2.71±0.52.67±0.5 BMI29.8±4.829.9±4.6 We noted that the use of small dose of FSH in patients with high BMI frequently result in high cancellation rate

29. The study reported a high clinical pregnancy rate, 21 pregnancies (50%) in Group A and 22 pregnancies (50.23%). However, the study also reported very high multiple pregnancies, 9 out of 22 in Group A and 11 out of 22 in Group B.

30. The difference in the mean fertilized oocytes, fertilization rate, top quality embryos and number of cryopreserved embryos could possibly be explained by the difference in the FSH isoform composition of commercial gonadotrophin preparations. The difference although statistically significant did not reflect on the clinically important pregnancy rate. However, FSH isoform composition is usually considered to have negligible effect on clinical outcome (Andersen et al 2004)

31. On the other hand, the distribution of FSH isoforms in human-derived products may have a higher average glycosylation as compared to the recombinant ones. Thus the urinary product may possibly provide some balancing to the excessive activity of granulosa cells of PCOS, which could result in some clinical benefits (Sharron et al 2007).

32. During fresh cycles, the best available embryos were selected for transfer in both groups. The significantly more cryopreserved embryos in the urinary FSH group may possibly make a difference in the pregnancy rate between both groups after embryo transfer of frozen-thawed embryos.

33. The multiple pregnancy is extremely high in the present study and our policy of transferring between two and three embryos should be in the future restricted to a maximum of two embryos transferred. The final solution to the problem of multiple pregnancy will be achieved by single embryo transfer (Gelbaya et al 2009)

34. Our study has shown that IVF/ICSI in PCOS patients, even with high BMI can be managed safely with minimal occurrence of OHSS and with an excellent pregnancy rate. Both highly purified and recombinant FSH produce similar pregnancy rates.

35. Conclusions IVF/ICSI results in excellent pregnancy rate in PCOS patients. IVF/ICSI results in excellent pregnancy rate in PCOS patients. There is a high risk of OHSS in PCOS which could be minimized by proper preventive methods. There is a high risk of OHSS in PCOS which could be minimized by proper preventive methods. Although highly purified FSH resulted in a significantly higher fertilization rate, higher number of fertilized oocytes and higher number of top quality and frozen embryos as compared to recombinant FSH, yet there was no difference in clinical or ongoing pregnancy rates. Although highly purified FSH resulted in a significantly higher fertilization rate, higher number of fertilized oocytes and higher number of top quality and frozen embryos as compared to recombinant FSH, yet there was no difference in clinical or ongoing pregnancy rates.

36. This study has shown that ovarian stimulation for IVF/ICSI in PCOS patients can result in excellent pregnancy rates and if carefully managed and precautions to prevent OHSS are taken, the high risk of OHSS could be avoided to a great extent.

37. As clinical pregnancy rate is not significantly different between both groups, the cost of medicine may play a role in the choice of FSH product.

38. The Egyptian IVF-ET Center Clinical directors: M. Aboulghar, M. D. G. Serour, M. D. - Clinical associates: Y. Amin, M. D. M. Sattar, M. D. A. Ramzy, M. D. L. Mansour, M. D. M. Metwally, M. D. H. Aboulghar, M. D. M. Aboulghar, M. D. H. Al Inany, M. D. A. Abou-Setta, M. D. - Andrology: I. Fahmy, M. D. A. El-Gindy Scientific director & Program manager: Ragaa Mansour, M. D., Ph. D. - Embryology and micromanipulation S. Mansour, M. D. A. Kamal, M. D. A. Mostafa, M. D. N. Tawab, B.Sc. G. Afifi, B.Sc. M. Hammam, B.A. - Cytogenetics H. Fayek, Ph. D. A. Abdel-Razek, M. D. A. Amer, B.Sc. A. Khalil, Ph. D. A. Naser, Ph. D. O. Kamal, B.S. S. Mostafa - Cryobiology and Andrology D. Saad, B.Sc. Y. Demery, B.Sc. A. Barakat, B.Sc. M. Serour, B.Sc. N. Salah, B.Sc. H. Fanous, B.Sc. A. Mohamed, B.Sc.