; IVM is ready as a treatment for PCOS patients
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IVM is ready as a treatment for PCOS patients


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									                     Current Criticism on IVM Treatment
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                             Dr. Milton Leong          MDCM DSc (McGill)
                                                        Director, IVF Center,
                                          Hong Kong Sanatorium & Hospital
                                         Specialist in Reproductive Medicine
                             Adjunct Professor, OBS-GYN, McGill University

                     Current Criticism of IVM
                     Lower fertilization rate
                     Lower pregnancy & implantation rates
The Women’s Clinic   Higher pregnancy loss

                     Inadequate neonatal and postnatal data
                     Possible genetic and epigenetic
                     Current Criticism of IVM

                     Inconsistent pregnancy rates
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                     Inconsistent clinical details regarding timing,
  婦產科中心                 endometrium, EC techniques
                     Inconsistent laboratory details regarding EC, culture
                        system and culture techniques
                     Inertia from IVF success vs “experimentation”
                        Current Status of IVM

                     Like IVF 25 years ago, IVM is a treatment
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                       tool waiting to be universally applicable.
  婦產科中心                At the moment, there is some sort of
                       alchemy bias.
                     There are also unresolved issues, like IVF
                       then, that needs to be clarified.
                        Current Status of IVM
                     • IVM is a CONCEPT
                     • IVM is a laboratory technique, not a stand
                       alone treatment modality
The Women’s Clinic   • IVM is a method of preparing oocytes so
                       IVF can be carried out
                     • IVF/M have its advantages over
                       conventional IVF in some patients
                     • IVM can enable IVF to be performed
                       when otherwise it is impossible
                        Current Status of IVM
                     Similar to IVF in 80’s, issues regarding
                     • Technical - timing of EC
                                   aspiration technique
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  婦產科中心                            drugs to use
                     • Laboratory - culture system
                     • Outcome - now there is IVF to compare
                     • Safety - baby registry
                                long term genetic changes
                                  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
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                       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).
                              Advantages of IVM
                     • No/minimal stimulation:
                        less OHSS
                        less long term effect
                        safety factor – cancer patients
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                     • Flexible start time, no preparation
                     • Cancer patients
                         no theoretical and actual risk (especially breast ca)
                         can treat anytime
                     Indications for IVFM treatment

                     • Polycystic ovaries (PCO) or polycystic ovary
                       syndrome (PCOS) (primary);
                     • Hyper responders for gonadotropin stimulation
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  婦產科中心                (alternative);
                     • Delayed responders for gonadotropin
                       stimulation (alternative);

                              PCOS and IVF
                     • Pregnancies were comparable to non-
                       PCOS patients
                     • Lowered fertilization rate
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                     • Increased miscarriage rate
                     • FSH requirement leads to under or over
                     • Higher cancellation rate
                     • Much higher chance of OHSS
                        PCOS, OHSS and IVF
                     • Risk up 5-30 fold (6-30%)
                     • Estradiol >3000pg/ml
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                     • # Follicles >20
                         OHSS in PCOS Undergoing IVF

                     • Preventive Measures:

                     •   Pre-treat with laparoscopic drilling
                     •   Use GnRH-ant then GnRH-a to trigger
The Women’s Clinic   •   Metformin (as short as 28 days)
                     •   No Transfer, Cryopreservation
                     •   Early Aspiration of Follicles - 2 operations

                     • Conversion to IVM
                     • IVM with and/or without stimulation
                     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%
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  婦產科中心              Pregnancy rate          same       41%
                     OHSS rate               < 1%

                     A. Fukuda et al, Fertility and Sterility 2008

                     IVM/IVF vs IVF for PCOS

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                                  Child TJ, et al,2002
                                 IVM-IVF in POS
                     210 cycles
                     1883 oocytes             56% maturation
                                              83% fertilization
The Women’s Clinic   Pregnancy rate    31% fresh
                                       32% frozen-thawed
                     50/56 pregnancies delivered
                     Miscarriage       11%

                     A. Fukuda et al, Fertility & Sterility 2008

                        McGill IVM results by age group
                     (own oocytes only – patients with PCOS)

                               Implantation       Clinical          Live birth
                       Age       rate per      pregnancy rate     rate per cycle
                     (years)     embryo       per cycle started      started
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                      <35         14.4%            34.8%             20.0%

                     35-37        5.4%             20.0%             20.0%

                     38-40        5.0%             20.0%             10.0%

                     Obstetric and perinatal
                      outcomes of the IVM
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                       Updated IVM success rates

                     • Clinical pregnancy rate 30-35% per ET;
                     • Implantation rate 9-15% per ET;
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  婦產科中心              • More than 1,000 healthy live births;

                       Pregnancy Outcome in IVM
                     • Malformation:
                       – Cha, Fertil. Steril. 2005        5,3% major
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  婦產科中心              • Later neuromotor development:
                       – Soderstrom-Anttila, Hum. Reprod. 2006

                       ))) Minor developmental delay at first year
                       ))) No Difference in the second year
                      Outcome of IVM, IVF, ICSI and
                           normal pregnancies

                     • obstetrical and perinatal outcome of 432
                       babies (55 IVM, 217 IVF, 160 ICSI)
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                       compared with 1,296 age-matched
                       spontaneous pregnancies (controls)
                       delivered at a single hospital (MUHC)

                                                   Buckett et al.
                                          Obstet Gynecol 2007; 110:885-91
                                              Perinatal outcome
                                                  IVM      IVF       ICSI    Controls    p-value

                     Twin pregnancy rate          12.0%    16.0%     14.0%      1.3% p<0.001

                     Triplet pregnancy rate        4.0%    2.0%       3.0%      0        p<0.001

The Women’s Clinic   Mean birthweight (g)          2,812   2,826     2,801     3,289     p<0.001
                     Mean gestational age (wks)      37      37        36           39   p<0.001

                     Mean Apgar scores at 1 min       8          8      8            8     n/s

                     Mean Apgar scores at 5 min       9          9      9            9     n/s

                     Mean cord pH                  7.29     7.30      7.30      7.29       n/s
                     Congenital abnormalities following
                                IVM (n=55)
                     Major malformations                2
                     • ompalocele                       1
                     • small ventricuoloseptal defect   1
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                     Minor malformations                3
                     • patent ductus arteriosus         1
                     • congenital hip dislocation       2
                       Relative risk for any congenital
                     abnormality compared with controls

                                    RR        95% CI

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  婦產科中心              IVM            1.19    0.35 – 3.25

                     IVF            1.01    0.52 – 1.90

                     ICSI           1.41    0.72 – 2.68
                     Pregnancy Outcome in IVM
                     • Mikkelsen et al. (2005) ----- 47 IVM
                        –   2 twins
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                        –   1 NT           Normal karyotype
                        –   2 preterm deliveries
                        –   1 stillbirth (42 weeks)
                        –   1 chromozomal abnormality
                      Worldwide IVM babies born (2007)
                     Korea                  455
                     Taiwan                  20
                     Colombia                 7
                     Canada                 131
                     Finland                 52
                     Turkey                   8
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                     China                   58
                     Japan                   51
                     Vietnam                 42
                     Hong Kong               18
                     Denmark                 34
                     Italy                   56
                     UK                       8
                     Total                  930
                             Drawbacks in IVM
                     –   Lower development competence
                     –   Lower blastocysts formation
                     –   Lower implantation rate
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  婦產科中心              –   Lower pregnancy rate
                     –   Higher miscarriage rate

                         But, where is the beef?

                     Development Competence of Oocytes

                     1. Nuclear maturation – progression to
                        Meta phase II stage.
                     2. Cytoplasmic maturation – coordinated
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                        arrangement of proteins, organelles.

                     Gosden R et al, Bioessays 1997
                     Nogueira D et al, Fertil Steril 2007

                      Development Competence of Oocytes
                     1. IVM results in asynchronous nuclear vs.
                        cytoplasmic maturation
                     2. IVM (mouse oocytes) showed different
                        spindle morphology when assessed with
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                        immuncytologic staining.

                     Combelles CM et al, Human Reprod 2002
                     Sanfins A et al, Biol Reprod 2003

                     Results of the spindle and chromosome analysis in both experimental groups.

                                                     No.(%) of oocytes with        No. (%) of oocytes with

                     Oocyte Group                    Spindle configuration              Chromosome
                                                     Normal      Abnormal            Normal      Abnormal

                     Oocytes matured in vitro       27(56.3)     21(43.7)a        32(66.7)      16(33.3)a
                      (n = 48)
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  婦產科中心              Oocytes matured in vivo        19(86.4)     3 (13.6)         20(90.9)      2(9.1)
                      (n = 22)
                     aP<.05   vs. oocytes matured In vivo.

                     Li. Spindle and chromosome configurations of human oocytes. Fertil Steril 2008

                                     Does size matter

                     – In vivo matured oocytes > immature.
                     – Maturation rate (IVM) related to diameter
                       of oocytes.
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  婦產科中心              – Zona thickness, total oocytes + zona
                       diameter has no correlation.

                     Cavilla JL et al, Human Reprod 2008

                                     Outcome of IVM
                     – In mouse, in vitro vs. in vivo maturation.
                     – In vitro:     a) established optimized culture fluid
                                     b) no amino acid culture fluid
                     – Comparing life span, and variety of physiological and
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                       psychological tests.
  婦產科中心              – No difference between in vitro or in vivo life span or
                     – In culture fluid a) reduction in cardiac output and
                       pulse rate.

                     Eppig JJ et al, Human Reprod 2009

                                     Outcome of IVM
                     21 children IVM vs. non IVM, age 2-5
                     PE – neurological examination and developmental (Bayley

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                     Normal Karyotype, Normal PE
                     Mean Mental Developmental Index Score 92.7% vs. 97.2%,
                     Mean Psychomotor Development Index Scores 96.7% vs.
                     Conclusion: No developmental delay in infancy and early

                     Shu-chi M et al, Early Hum Dev 2006

                                     Outcome in IVM
                     46 children assessed at 6, 12, 24 months
                     Muenchener Funktionelle Entwicklungs Diagnostik and
                       Bayley Scales
                     6 mths                Normal
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                     12 mths               19% IVM expressed minor
                                           developmental problem
                                           1/43 had optic glioma
                     24 mths               Normal development

                     Suikkari M et al, Human Repro 2006

                                      Outcome of IVM
                                    IVM vs. IVF vs. ICSI
                       N = 1581                             IVM   IVF     ICSI
                       Biochemical loss                     17.5% 17%     18%    ND
                       Clinical miscarriage                 25.3% 15.7% 12.6% SD
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                       Ectopic preg.                        1%    2.3%    1.8%   ND
                       Late foetal loss                     1%    2.7%    2.9%   ND

                       PCOS                                 24.5% 22.2%          ND

                     Buckett WM et al, Fertil Steril 2008

                                      IVM outcome

                     High miscarriage rate may be due to
                     other causes (endometrium?) because
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                     cytogenetic and DNA fragmentation
  婦產科中心              analysis of the aborted embryos were
                     not different from routine IVF.

                     Benkhalifa Meta, Reprod Biomed Online 2009

                                    Genetics in IVM
                     Methylation of the KCNQ1OT1 gene in vitro
                      matured oocytes methylate DNA the same as
                      GV and mature genes.

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                     At 28 hours of culture, however, GV and MI
                       oocytes from natural cycles significantly
                       methylate more than those from stimulated
                     ?Hyperstimulation recruits too young follicles

                     Khoueiry R, J Med Genet 2008

                                     Genetics in IVM
                     No difference in meiotic spindle organization,
                     chromosome alignment and aneuploidy
                     (mouse oocytes)
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                     Xu L et al, Syst Biol Reprod Med. 2008

                     Effect of IVM on Genes
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                                    Genes and IVM
                     Rhesus Monkey oocytes
                     IVM vs. VVM
                     Only 56 mRNA’s differentially expressed. These are
                       related to cell homeostasis, cell-cell interactions,
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                       cell adhesion, mRNA stability and translation.

                     Over expression of maternal genes.
                     IVM oocytes can be very close to VVM oocytes but
                       interruption of normal oocyte-somatic cell
                       interaction may disturb full developmental

                     Lee YS et al, Physiol Genomics 2008
                                     Genes and IVM
                     IVM, then examine GV, MI, MII oocytes, using
                     H19. Differentially methylated region
                     GV       Unmethylated
                     MI       Arrested – altered methylation pattern
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                     MII      15/20 normal unmethylated pattern
                                     5/20 methylated pattern
                     Risk of epigenetic changes so safety of IVM should
                     be assessed.

                     Borghol N et al, Genomics 2006

                                       Genes in IVM
                     Although in vivo maturated an in vitro
                     maturated oocytes has very similar gene
                     expression, the major difference is in
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                     persistence of immature genes.
                     IVM oocytes differs in gene expression
                     related to cytoplasmic function and cellular
                     storage and homeostasis.

                     Well D et al, Am J Obstet Gynecol. 2008

                                      IVM successes
                     – PCOS patients
                     – Natural cycle IVF/M
                     – Birth after vitrification
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                     – Repeated successful pregnancies in same
                     – Birth after preservation of oocytes for
                       cancer patients

                     McGill Reproductive Centre

                     • IVM is efficient infertility treatment,
                       especially for patients with PCO/PCOS;
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                     • IVM provides an alternative for some
                       patients during ovarian stimulation

                     • IVM simplifies treatment, reduces costs and eliminates
                     • IVM successful in women with high AFC
The Women’s Clinic   • hCG increases final number of MII oocytes and rate of
  婦產科中心                maturation
                     • IVM may be helpful in women with repeated poor
                       embryo quality in previous IVF cycles for no obvious
                       reason, or repeated poor responders to ovarian
                     • IVM produces CPR/C of 35%, and up to 48% in selected
                       cases, in women up to 35 .
                     • obstetric and perinatal outcomes of IVM pregnancies
                       comparable with IVF and ICSI
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  婦產科中心              • IVM may be useful for oocyte donation or PGD
                     • IVM may offer a chance for fertility preservation to
                       young women with cancer and undergoing cytotoxic
                     • IVM may not replace standard IVF but appears to play
                       increasingly important role in ART
                            Current Status of IVM
                             An established treatment for PCO/PCOS
                               In experienced hands closing on IVF
                              Needs registry outcome and follow up
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  婦產科中心                     Some animal data regarding genetic changes
                                    May be epigenetic changes

                     All can be solved by proper practice and follow up and large
                                   data collection as in REGISTRY

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