IVM is ready as a treatment for PCOS patients Dr. Milton Leong MDCM DSc (McGill) Director, IVF Center, HKSH Adjunct Professor, OBS-GYN, McGill University

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

PCOS Ovulation Induction: Low dose - reduced response Higher dose - over-response Leading to multiple pregnancies Higher risk OHSS

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

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

PCOS, OHSS and IVF Risk up 5-30 fold (6-30%) Estradiol >3000pg/ml # Follicles >20

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

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). Since Cha et al. (1991) reported the first pregnancy from in-vitro matured oocytes derived from a caesarean section donor, fertilization, embryo development and pregnancy by immature human oocytes matured in-vitro have been successfully achieved in women with polycystic ovary syndrome (PCOS) (Trounson et al., 1994; Cha and Chian, 1998). Recent improvements in culture condition and transfer techniques have demonstrated that immature oocyte retrieval followed by IVM is an effective treatment for women with polycystic ovaries (PCO) or polycystic ovarian syndrome (PCOS)-related infertility because there are numerous antral follicles within the ovaries in this group of patients. 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., 2004a, b).

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

IVM is a useful treatment ,particularly for women with pcos The majority of other groups have also reported low rates of success when performing ivm for women with normal ovaries.

IVM/IVF vs IVF for PCOS Child TJ, et al,2002 For women with pcos who required assisted conception, IVM is a promising alternative to conventional IVF treatment. Child TJ, et al,2002

IVM-IVF in POS 210 cycles 1883 oocytes 56% maturation 83% fertilization Pregnancy rate 31% fresh 32% frozen-thawed 50/56 pregnancies delivered Miscarriage 11% OHSS 0% A. Fukuda et al, Fertility & Sterility 2008

Ovulation trigger LH surge induced by GnRH agonist achieves identical clinical outcome as HCG in in vitro maturation, in vitro fertilization and embryo transfer (IVM-IVF)

GnRHa v.s. HCG in IVF-IVF used in PCOS 300 ųg Buserelin vs 10000 unit HCG Maturation rate same (±50%) Fertilization rate same 85% Pregnancy rate same 41% OHSS rate < 1% A. Fukuda et al, Fertility and Sterility 2008

Pregnancy Outcome in IVM Malformation: Cha, Fertil. Steril. 2005 5,3% major malformation rate Later neuromotor development: Soderstrom-Anttila, Hum. Reprod. 2006 ))) Minor developmental delay at first year ))) No Difference in the second year

Known live deliveries from IVM/IVF Korea 455 Taiwan 20 Colombia 7 Canada 131 Finland 52 Turkey 8 China 58 Japan 51 Vietnam 42 Hong Kong 18 Denmark 34 Italy 56 UK Total 930

McGill IVM results by age group (own oocytes only – patients with PCO or PCOS) (years) Implantation rate per embryo Clinical pregnancy rate per cycle started Live birth rate per cycle started <35 14.4% 34.8% 20.0% 35-37 5.4% 38-40 5.0% 10.0%

Results of IVM from Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan* Cycles 68 Age 31.3 ± 4.1 No. of oocytes collected 1,528 (21.9 ± 9.4) % of oocyte maturation 72.5% % of fertilization 75.8% % of cleavage 89.4% Mean of embryos transferred 3.8 ± 0.9 No. of clinical pregnancies (%) 23 (33.8) % of implantation 11.3% % of OHSS <1% * Data from Dr. Lin & Dr. Hwang (2003)

IVM/IVF in PCOS Conclusions: PCOS is associated with OHSS OHSS = 80% post EC hospital admissions IVM/IVF is an established clinical technique IVM/IVF can reduce incidence of OHSS IVM/IVF can now be the treatment of choice for PCOS in IVF