Docstoc

ART FOR PCOS-DIFFICULTIES AND SOLUTIONS

Document Sample
ART FOR PCOS-DIFFICULTIES AND SOLUTIONS Powered By Docstoc
					ART FOR PCOS-DIFFICULTIES
     AND SOLUTIONS
            Dr. Bulent Urman
     American Hospital, ISTANBUL
       Assisted Reproduction Unit
   Koç University, Faculty of Medicine
        Department of OB/GYN
  Consensus on infertility treatment
          related to PCOS
        R
        E
        S                 FIRST LINE
        I
        S             CLOMIPHENE CITRATE
        T
        A
        N                                                   F
        C                                                   A
        E
                                                            I
                         SECOND LINE                        L
        R            LOD/GONADOTROPINS                      U
        E                                                   R
        S
        I
                                                            E
        S
        T
        A
        N
        C                   THIRD LINE
        E
                               IVF

The Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group March
           2–3, 2007, Thessaloniki, Greece. Human Reproduction 2008
Does Ovulation = Live Birth ?
        Ovulation
                                ?Poor Oocyte Quality



        Fertilization
                                              ?Endometrial
                                               Abnormality

        Implantation
                                         ?Effects
                                   Hyperinsulinemia

         Fetal Viability

                                 ? Effects gestational
                                       diabetes and
        Healthy Liveborn               hypertension


                           Legro et al Hum Reprod 2004
   Surgical induction of ovulation
                        Wedge                  LOD
                    resection by LT
Publications                18                 11

Patients                  1766                 729

Ovulation                  74.6                84.2
Pregnancy                  58.8                55.7
Adhesions             Moderate to        Minimal to mild
                        severe
               From Urman and Yakin JRM 2006
Challenges of treating infertility with
    IVF in the PCOS/PCO patient
• Propensity for an exaggerated ovarian
  response
• Difficulties in titrating gonadotropin dose
• Increased risk of cycle cancellation
• Increased incidence of early and late OHSS
• Increased risk of spontaneous pregnancy loss
    Optimal ovarian stimulation for IVF
•   Avoid understimulation
•   Avoid overstimulation
•   Minimize cycle cancellation
•   Minimize if not avoid altogether OHSS
FSH
Normal responder

       OVER STIMULATION

   OPTIMAL STIMULATION

      UNDER STIMULATION
Hyper responder


         OVER STIMULATION
     OPTIMAL STIMULATION
        UNDER STIMULATION
PCOS AND OHSS
Artini et al. Human fertility 2009;12:40
       VEGF induced permeability
                                 hCG




Nature Rev Cancer;2005:437:497
          VEGF induced permeability




Nature Rev Cancer;2005:437:497
     Insulin resistance and OHSS
• Insulin is a stimulator of VEGF secretion in
  vascular endothelial cells.
     Doronzo et al. Eur. J. Clin. Invest. 34(10); 664 - 673
• Effect of metformin on OHSS seems to be
  mediated by declined insulin levels
          Metformin and OHSS
• Two meta-analyses found that metformin co-
  administration in PCOS women undergoing IVF
  decreased the incidence of OHSS
• The beneficial effect was observed in all RCTs
  regardless of duration and dosage of metformin
• Number of oocytes collected and peak E2 levels
  were unaffected by metformin
           Costello et al. 2006 Hum. Rep. 21(6);1387 – 1399
           Moll et al. 2007 Hum. Reprod. Update 13(6); 527 - 537
       VEGF induced permeability
                                 hCG
                                       Cabergoline inhibits phosphorylation
                                       of VEGR2
                                       Gomez et al Endocrinology 2006;147:5400




Nature Rev Cancer;2005:437:497
        PreIVF considerations
• Weight loss in overweight women
• Metformin
• LOD
Impact of weight on IVF outcome




       From Bellver et al. Fertil Steril 2010
Metformin co-treatment
 Metformin prior to and during IVF
                          Metformin              Placebo   P value
Number of patients            52                    49
CPR>12 weeks                38.5%                 16.3%    P=0.02
Live birth rate             32.7%                 12.2%    P=0.027
Severe OHSS                  3.8%                 20.4%    P=0.023
Side effects                45.1%                 8.2%     P=0.001


All patients treated with luteal long protocol
Metformin started on the first day of down regulation
Dose 2 x 850 mg/day

From Tang et al. Hum Reprod 2006
Metformin co-treatment




  From Moll et al. Hum Reprod Update 2007
Laparoscopic ovarian drilling as an
         adjunct to IVF
• May decrease the frequency and severity of
  OHSS in women with a previous episode of
  OHSS
• May facilitate ovarian stimulation in the
  brittle PCOS patient (Ferraretti, Fertil Steril 2001)
Ovarian stimulation for IVF in the
          PCOS patient
• Type of gonadotropin?
• How to suppress LH surge and premature
  luteinization (agonist vs antagonist)?
• How to trigger final oocyte maturation?
• Coasting
Urinary vs recFSH in women with
    PCOS undergoing IVF-RCT
Agonist vs antagonist




 From Kurzawa et al. J Assist Reprod Genet 2008
Agonist vs antagonist-RCT




    From Lainas et al. Hum Reprod 2010
GnRH triggering of final oocyte
         maturation
     GnRHa triggering of final oocyte
   maturation in patients at risk for OHSS
Author/year Study Type   No of cycles   GnRHa used Pregnancy    OHSS

Bankowski     Retro       97            1 mg LA      CPR 11.3   None
2004          comparative
Erden 2005    Retro      97             0.2 mg TR    CPR 41.0   NR
              Cohort
Shapiro       Retro      30             4-8 mg LA    CPR 31.0   None severe
2005          Cohort
Bar Hava      Observat   67             0.2 mg TR    CPR 30.0   1/67
2005
Koresi 2006   Retro       25            0.1-0.2 TR   CPR 28.0   NR
              comparative
GnRHa triggering of oocyte
    maturation-RCT




     From Engman et al. Fertil Steril 2008
GnRHa triggering of oocyte
    maturation-RCT




    From Engman et al. Fertil Steril 2008
  Main characteristics, luteal phase support and reproductive outcome of published
  RCT on GnRHa triggering of final oocyte maturation
Reference       Ovulation   n    LPS                Clinical     Ongoing        Delivery    P-
                trigger                             Pregnancy%   pregnancy %    rate %      value
                                                    (n)          (n)            (n)
Humaidan        GnRHa       55   P 90 mg (8%) vag   6 (3/55)     6 (3/55)       6 (3/55)    0.002
et al. (2005)                    + 4 mg oral E2
                hCG         67   P 90 mg (8%) vag   36 (24/67)   36 (24/67)     36
                                 + 4 mg oral E2                                 (24/67)
Kolibianakis    GnRHa       50   P 600 mg vag + 4   *            5.6 (1/18)     *           0.005
et al. (2005)                    mg oral E2
                                                                 2.9 (1/34)

                hCG         54   P 600 mg vag + 4   *            41.7 (10/24)   *
                                 mg oral E2
                                                                 16.7 (5/30)

Humaidan        GnRHa       13   1500 IU hCG OPU    46 (6/13)    38 (5/13)      38 (5/13)   0.43
et al. (2006)                    day + P 90 mg
                                 (8%) vag + 4 mg
                                 oral E2
                hCG         15   P 90 mg (8%) vag   53 (8/15)    53 (8/15)      53 (8/15)
                                 + 4 mg oral E2
Pirard et al.   GnRHa       6    GnRHa nasal 100    33 (2/6)     *              *           0.51
(2006)                           µg IN 3xd
                hCG         6    P 600 mg vag       17 (1/6)     *              *

                                                                     Humaidan et al. Hum Reprod 2009
 Main characteristics, luteal phase support and reproductive outcome of published RCT on
 GnRHa triggering of final oocyte maturation (intention to treat)


Reference       Ovulation   n    LPS                Clinical      Ongoing        Delivery    P-
                trigger                             Pregnancy %   pregnancy %    rate %      value
                                                    (n)           (n)            (n)

Babayof et      GnRHa       15   P 50 i.m. 100 mg   20 (3/15)     6.6 (1/15)     6.6         0.46
al. (2006)                       ± 4 mg oral E2                                  (1/15)
                hCG         13   P 50 i.m. 100 mg   31 (4/13)     15 (2/13)      15 (2/13)
                                 ± 4 mg oral E2
Engmann et      GnRHa       33   P 50 i.m. 75 mg    52 (17/33)    48 (16/33)     *           0.90
al. (2008)                       + E2 patches 3–4
                                 x 0.1 mg/2d ± 4
                                 mg oral E2

                hCG         32   50 mg P i.m.       47 (15/32)    44 (14/32)     *

Humaidan        GnRHa       15   1500 IU hCG OPU    33 (50/152)   26 (40/152)    24          0.16
et al. (2009)               2    day + P 90 mg                                   (36/152)
                                 (8%) vag + 4 mg
                                 oral E2

                hCG         15   P 90 mg (8%) vag   37 (55/150)   33 (49/150)    31
                            0    + 4 mg oral E2                                  (47/150)


                                                                     Humaidan et al. Hum Reprod 2009
     GnRHa triggering of oocyte
      maturation-hints and tips
• Lower implantation rates reported in some
  studies may be attributed to the luteolytic
  effect of the GnRHa
• Titration of the luteal phase support is
  important
Optimal cycle management in the
          PCOS patient
• Careful titration of the gonadotropin dose
• Measures to prevent OHSS
  – Coasting
  – GnRHa for triggering final oocyte maturation
  – Single Blast transfer vs Cryopreservation of all
    embryos
  – Cabergoline
Outcome of IVF in PCOS
Outcome of IVF in women with
      PCOS vs controls
                      PCOS                TUBAL/OTHER




      From Urman et al. RBM Online 2004
Outcome of IVF in women with
      PCOS vs controls




            From Urman et al. RBM Online 2004
     Cumulative PR in PCOS vs controls




From Pirinen et al. Gynecol Endocrinol 2010
From Heijnen Hum Reprod Update 2006
IVM
Clinical outcome of IVM in PCOS or PCO




   From Suikkari, Curr Opin Obstet Gynecol 2008
           IVM vs IVF in PCOS
• Randomized trials do not exist
• Comparative studies, noncomparative case
  series and randomized trials comparing
  different protocols of IVM show:
  – Favorable maturation, fertilization, pregnancy
    and live birth rates with IVM compared to IVF
  – The rate of congenital anomalies appear to be
    similar
  – Urgent randomized trials are needed
                Conclusions
• PCOS patient is the most difficult to treat
  with IVF
• Cycle cancellation rates and risk of OHSS are
  higher
• Fine tailoring of ovarian stimulation is
  necessary to avoid complications
• Treating physicians should be aware of the
  difficulties and remedies/solutions

				
DOCUMENT INFO
Shared By:
Categories:
Tags:
Stats:
views:16
posted:9/25/2011
language:English
pages:45