1. The Women ’ s Clinic 婦產科中心 IVM/IVF in PCOS (PCO-Like Ovaries) Milton Ka Hong Leong MDCM DSc(McGill) FRCS(C) FRCOG FACOG FHKCOG Director, IVF Centre HK Sanatorium & Hospitals Specialist in Reproductive Medicine Adjunct Professor, Department Obstetrics & Gynecology McGill University,Montreal, CANADA

2. The Women ’ s Clinic 婦產科中心 PCOS Commonest endocrine disorder in women May be 80% anovulatory infertility? Ovulation induction required Most are clomiphene responsive Cumulative pregnancy rates lower than non-PCOS patients Balen 2002 2004

3. The Women ’ s Clinic 婦產科中心 PCOS Ovulation Induction: Low dose - reduced response Higher dose - over-response Leading to multiple pregnancies Higher risk OHSS

4. The Women ’ s Clinic 婦產科中心 PCOS and IVF IVF is an effective, may be preferred choice of therapy because of the problems associated with ovulation induction Significantly more oocytes Lower fertilization rate Dor et al, Homburg et al Kodama et al

5. The Women ’ s Clinic 婦產科中心 PCOS and IVF Pregnancies were comparable to non-PCOS patients Increased miscarriage rate FSH requirement leads to under or over response Higher cancellation rate Much higher chance of OHSS

6. The Women ’ s Clinic 婦產科中心 OHSS in IVF Prevalent Factors: Age -younger BMI - thinner PCOS PCO-like ovaries >10 follicles Ovarian volume > 10 cu mm LH/FSH > 2 Hyperandrogenism

7. The Women ’ s Clinic 婦產科中心 OHSS in IVF Preventive Measures Identify Risks - Low(er) FSH? No Help Use GnRh-ant - ? 50% Coasting E > 3000pg/ml but preg rate oocyte quality Cancel cycle - patient reluctant No hCG - use GnRH-a No transfer - cryo-preservation Albumin, hydroxyaethyl starch solution High Dose Progesterone, no Luteal hCG

8. The Women ’ s Clinic 婦產科中心 PCOS, OHSS and IVF Risk up 5-30 fold (6-30%) Estradiol >3000pg/ml # Follicles >20

9. The Women ’ s Clinic 婦產科中心 OHSS in PCOS Undergoing IVF Preventive Measures: Pre-treat with laparoscopic drilling Use GnRH-ant then GnRH-a to trigger Metformin (as short as 28 days) No Transfer, Cryopreservation Early Aspiration of Follicles - 2 operations Conversion to IVM IVM with and/or without stimulation

10. The Women ’ s Clinic 婦產科中心 Role of Metformin in PCOS Patients In Clomiphene responsive pts, no difference in LBR In Clomiphene resistant patients: Higher LBR when metformin added to Clomiphene to Laparoscopic drilling in IVF cases In IVF patients add metformin reduces OHSS

11. The Women ’ s Clinic 婦產科中心 Progress in IVM  Edwards 1965 : 1st in vitro matured oocyte  Veeck 1983 : 1st IVM pregnancy from an ovum derived from a  stimulated cycle  Cha et al. 1991 : the first pregnancy from in-vitro matured oocytes derived from a caesarean section donor  Trounson et al. 1994: IVM in women with PCOS  improvements in culture condition and transfer techniques have demonstrated that IVM is an effective treatment for women with PCO or PCOS.  In general, clinical pregnancy and implantation rates for infertile women with PCO or PCOS have reached approximately 30-35% and 10-15%, respectively, (Chian et al., 2004).

12. The Women ’ s Clinic 婦產科中心 IVM/IVF in PCOS

13. The Women ’ s Clinic 婦產科中心 Advantages of IVM No/minimal stimulation: less OHSS less long term effect safety factor – cancer patients Flexible start time, no preparation Cancer patients no theoretical and actual risk (esp br ca) can treat anytime

14. The Women ’ s Clinic 婦產科中心 IVM/IVF Best candidates under 35 PCOS or PCO-like ovaries To stimulate or not to stimulate, that is the question………………

15. The Women ’ s Clinic 婦產科中心 IVM/IVF vs IVF for PCOS Child TJ, et al,2002

16. The Women ’ s Clinic 婦產科中心 Over responders Risk of OHSS Treatment options a)Cancel cycle b)Coasting c)No embryo transfer d)Convert to IVM

17. The Women ’ s Clinic 婦產科中心 Over responders Prolonged Coasting Aim: To prevent hyperstimulation Practice: Coast till E2 ≤ 3000 pg/mL Sher, 1995Start when 30% follices > 15 mm Nilsson, 1999When 3 follicles > 17mm

18. The Women ’ s Clinic 婦產科中心 IVM stimulation

19. The Women ’ s Clinic 婦產科中心 IVM/IVF in PCOS/PCO-Like Pts 2007 PCOSPCO-Like #810 Age26-35 (32.3) 29-38 (33.4) # Eggs178 (22.2) 126 (12.6) % matured/Fert73% 67.4% 76% 78.2% # ET21 (2.1) 14 (1.75) Pregnancies3 (37.5%) 5 (50%) % Implant4/21 (19%) 7/14 (50%)

20. The Women ’ s Clinic 婦產科中心 FSH Priming or Not?

21. The Women ’ s Clinic 婦產科中心 Du AL,et al,2005 Biological data and birth reports after in vitro maturation from unstimulated cycles in polycystic ovarian syndrome patients

22. The Women ’ s Clinic 婦產科中心 Natural cycle IVM results (McGill University)

23. The Women ’ s Clinic 婦產科中心 McGill Seoul Maria Sun Yat-sen HKSH Total No of cycles 35 128 13 17 193 Mean age 33.1 ± 3.4 29 35.1±4.4 Oocytes collected 284 1043 207 166 1700 Maturation rates(%) 226 (80%) 733(70.3%) 104(50.3%) 110(66.3%) 1173 (69%) Fertilizaiton rates(%) 188 (83%) 580(79.1%) 87(83.8%) 89(80.9%) 944 (80.5%) Embryo transferred 2.5 ± 8.6 4.0 ± 1.6 4.6 ± 2.5 2.3 ± 1.0 No of ET cycles 35 123 13 17 188 Clinical PR(%) 14(40%) 36(29.3%) 2(19.5%) 4(23.5%) 56 (29.8%) Natural cycle IVM (summary)

24. The Women ’ s Clinic 婦產科中心 FSH priming for obtaining more oocytes or enhancing oocyte maturation(Mikkelsen et al., 1999; 2001; Suikkari et al., 2000). However, the results were conflicting

25. The Women ’ s Clinic 婦產科中心 IVM stimulation

26. The Women ’ s Clinic 婦產科中心 Table. Number of oocytes obtained for in vitro maturation and rates of maturation, fertilization, cleavage and pregnancy in women in unstimulated and FSH-primed groups Mikkelsen AL et al,2001

27. The Women ’ s Clinic 婦產科中心 NO FSH + FSH P No of cycles 13 30 OPU day folic(mm) 6.4 ±0.7 8.1 ±1.9 <0.001 Oocytes collected 15.9 ±7.3 18.5 ±6.7 >0.05 No. of MTII 8.0 ± 3.9 11.1 ±5.2 0.065 No. of Fertilized 6.7 ±3.5 8.3 ±3.6 >0.05 Embryo transferred 4.6±2.5 4.6 ±2.0 >0.05 Clinical PR(%) 2(19.5%) 11(36.7%) 0.132 In-vitro maturation outcomes between the FSH-primed and no FSH treatment groups Sun Yat-sen University 2006

28. The Women ’ s Clinic 婦產科中心 Clinical variables and outcome of FSH-primed (Group A) and non-FSH-primed (Group B) (PCOS) Lin YH et al 2003

29. The Women ’ s Clinic 婦產科中心 IVF CENTRE (HKSH) data 2004-2005 FSH primedNon-stimulatedP No. of cycles2117 age35.0± 4.035.1 ±4.40.93 E2/HCG day(pg/ml)760.8 ± 816.2130.3 ± 129.50.06 No. of oocytes225166 MTII ooyctes(%)157 (69.8%)110 (66.3%)0.46 Fertilized (%)129 (82.2%)89 (80.9%)0.79 No. of embryos transferred/ET 2.6 ± 0.92.3 ± 1.00.32 PR29.8%(6/21)23.5%(4/17)0.73 IR12.7%12.8%0.99

30. The Women ’ s Clinic 婦產科中心 Conclusions PCOS poses as a problem in ovulation induction IVF may be treatment of choice for PCOS, but OHSS has to be controlled IVM/IVF can circumvent problems with ovulation induction Stimulated or not, it is safe, effective More studies have to be done, especially in follow-up of children IVM/IVF SHOULD BE TREATMENT OF CHOICE

31. The Women ’ s Clinic 婦產科中心 HCG priming or not ?

32. The Women ’ s Clinic 婦產科中心 How to improve pregnancy rate in IVM Dr Milton Ka Hong Leong MDCM DSC (McGill) FRCS(C) FRCOG FACOG FHKCOG Specialist in Reproductive Medicine Adjunct Professor,Department of Obstetrics & Gynecology McGill University

33. The Women ’ s Clinic 婦產科中心

34. The Women ’ s Clinic 婦產科中心 The advantages of IVM

35. The Women ’ s Clinic 婦產科中心 How to improve the pregnancy rate in IVM?

36. The Women ’ s Clinic 婦產科中心 The percentage of oocytes achieving maturation at 48 h was significantly higher in the HCG-primed group than in the non-HCG-primed group. Ooycte maturation was hastened in the HCG-primed group. There were no significant differences in the rates of ooycte fertilization and cleavage in these two groups. Chian RC,et al. 2000

37. The Women ’ s Clinic 婦產科中心 Stimulation protocol Best candidates : women under 35 years of age who have polycystic-like ovaries  Stimulate or not  With or without HCG priming

38. The Women ’ s Clinic 婦產科中心 Chian RC,et al. 2000

39. The Women ’ s Clinic 婦產科中心 Chian RC,et al. 2000

40. The Women ’ s Clinic 婦產科中心 Is ICSI essential for IVM?

41. The Women ’ s Clinic 婦產科中心  Reports of insemination of human in vitro-matured oocytes are scarce.  In the study by Barnes et al. (1996), 43% of mature oocytes from normal ovaries and 26% of in vitro matured oocytes from PCOS women fertilized after insemination.  The reason for poor fertilization rates after standard insemination has been thought to depend on altered characteristics of zona pellucida as a result of the longer culture time before insemination.

42. The Women ’ s Clinic 婦產科中心 Comparison of outcomes between IVM-IVF and IVM-ICSI in all patients without hormonal priming Viveca Hum Reprod 2005

43. The Women ’ s Clinic 婦產科中心 Comparison of outcomes between IVM-IVF and IVM-ICSI in women with presumed ovulatory, regular cycles Viveca Hum Reprod 2005

44. The Women ’ s Clinic 婦產科中心 Ooycte-secreted factors enhance oocyte developmental competence during IVM

45. The Women ’ s Clinic 婦產科中心 Hussein TS,et al.2006

46. The Women ’ s Clinic 婦產科中心 Hussein TS,et al.2006

47. The Women ’ s Clinic 婦產科中心 Hussein TS,et al.2006

48. The Women ’ s Clinic 婦產科中心 Hussein TS,et al.2006

49. The Women ’ s Clinic 婦產科中心 Selection Method

50. The Women ’ s Clinic 婦產科中心

51. The Women ’ s Clinic 婦產科中心 Natural IVF with IVM (Seoul Maria) Group1: Succeed to collect oocytes from Leading Follicle Group2: Failed to collect ooyctes from Leading Follicle

52. The Women ’ s Clinic 婦產科中心 Distribution of Patients according to LF size at HCG injection (N=128)

53. The Women ’ s Clinic 婦產科中心 Proportion of OPU from a leading follicle in groups classified by the size of follicles at HCG injection (N=128)

54. The Women ’ s Clinic 婦產科中心 Comparison of Outcomes in IVF/M, IVM and COH

55. The Women ’ s Clinic 婦產科中心 REGISTRY We have already set up a registry to collectively gather information so that we can prove natural cycle or minimally stimulated cycle IVF with or without IVM can be an acceptable alternate, or even the preferred method. We would like to invite anyone and everyone to join in so we can reach a significant number faster, for patients’ sake A registry will speak louder than rhetoric Register through: http//www.ivf.com.hk, or c/o Dr Milton Leong, www.clinic@netvigator.com until we get our specific website up

56. The Women ’ s Clinic 婦產科中心 IVM Registry ART center Patient's IVF# Wife age Husband age Indication (pcos=1,cancer=2,tubal=3,endometriosis=4,unexplained=5, male factor=6,others=7) Gn used or not (1= natural cycle,2= Gn used) HCG used or not (1=used,0=no used) No. of ooyctes collected No. of Matured No. of fertilized No. of cleaved ET day( D2/D3/D4/D5) No. of embryos transferred Pregnancy (clinical PR =1 ) Multiple pregnancy (2/3/4) Abortion % Pregnancy outcome (if known)

57. The Women ’ s Clinic 婦產科中心 REGISTRY Register through: http://www.ivf.com.hk or email clinic@netvigator.com At least get in touch Once our website is launched you will be contacted Then join us for this worthwhile project

58. The Women ’ s Clinic 婦產科中心 Registry’s Current Member Groups Milton Leong, IVF Centre, Hong Kong Yoshiharu Morrimoto, Namba IVF, Osaka, Japan J-H Lim, Maria Fertility Hospital, Seoul and Beijing Ri-Cheng/SL Tan, McGill Centre for Reproductive Medicine, Montreal, Canada XY Liang, Suen Yat-sen University, Guangzhou, China JY Liu, Nanjing University, China YY Cao, University of Anhui, China JK Chen, Tsingtao IVF, China Everyone’s Welcome to Join! Thank you.

59. The Women ’ s Clinic 婦產科中心 We are friends let’s join hands Our goal is to provide the safest cost- effective treatment to our patients. Above all this should be provided with the least stress - physically, mentally and financially. Thank you for listening.