Bourdon,  M.1,  Santulli,  P.  1,  Maignein,  C.1  ,  Gayet,  V.1,  Marcellin,  L.1,  Blanchet,  V.1,  Gonnot,    J.1,  De  Ziegler,  D.  1,  Chapron,  C.  1      

1  Université  Paris  Descartes,  Sorbonne  Paris  Cité,  Faculté  de  Médecine,  Assistance  Publique  –  Hôpitaux  de  Paris  (AP-­‐  HP),  Groupe  Hospitalier  Universitaire  (GHU)  Ouest,  Centre  Hospitalier  Universitaire  (CHU)  Cochin,  Department  of  Gynecology  Obstetrics  

II  and  ReproducMve  Medicine,  75679  Paris,  France    

GnRH  agonist  triggering  controls  painful  symptoms  scores  during  IVF/ICSI  cycle  

 

Mathilde  Bourdon  

Risk  of  pain  during  IVF  Cycles?    

Santulli  P.,  Bourdon  M.,  FS,    2016  

Ludwig  et  al,  2006,  Human  Reproduc?on    

A  link  between  pain  level  and  intensity  of  COS  response    

Mean  pain  score  2h  aTer  oocyte  retrieval  according  to  the  number  of  oocytes  retrieved  

Prospec?ve  cohort  study  (1058  OR)  

   

COS  

hCG  triggering    

OR   ET  

P4  

Fresh  ET    

IVF/ICSI  cycles:  type  of  triggering      

COS  

GnRHa  triggering      

OR  

P4   Menses    Deferred  ET    

P4  E2  

Frozen  ET  Cryopreserva?on  of  all  embryos  

Frozen  ET    

AnM-­‐inflammatory  effects    

GnRH  agonist  effects  

ü  Oocyte  donaOon.    

ü  IVF  with  embryo  transfer    

The First Copenhagen Interest Group meeting was held on 30November–1 December 2009 to evaluate the existing evidence onthe use of GnRHa to trigger final oocyte maturation. We herereport the discussions and expert opinions based on presentationssummarizing current literature and areas for future research.

MethodsPrior to The Copenhagen GnRHa triggering group meeting, specialists inreproductive medicine and scientists prepared presentations based ontheir own published research, ongoing research and published literatureon the subject of GnRHa triggering. At the meeting the presentations

were followed by group discussion to reach conclusions on the topicspresented. The contents of this report are based on the presentationsand the following discussions during the meeting. The discussionsrelated to each topic were supplemented with an electronic literaturesearch via PubMed for articles in the English language. However, a moredetailed description of the search strategy follows as a meta-analysis wasperformed regarding pregnancy rate and OHSS rate, including the RCTspublished so far.

Search strategy and eligibility criteriaTwo independent investigators (E.P. and J.G.V.) searched PubMed and theCochrane Library without language restriction through November 2010,

.............................................................................................................................................................................................

Table II OHSS incidence after GnRHa triggering of final oocyte maturation versus HCG triggering in published trials.

Studies Study design OHSS risk AGONIST triggering arm HCG triggering arm

Fresh IVF cycles with Embryotransfer (ET)

Fauser et al, (2002) RCT Normal 0% (0/32) 0% (0/15)

Humaidan et al. (2005) RCT Normal 0% (0/55) 0% (0/67)

Kolibianakis et al. (2005) RCT Normal 0% (0/52) 0% (0/54)

Pirard et al. (2006) RCT Normal 0% (0/06) 0% (0/06)

Humaidan et al. (2006) RCT Normal 0% (0/13) 0% (0/15)

Babayof et al. (2006) RCT High 0% (0/15) 31.0 % (4/13)

Engmann et al. (2008a, b) RCT High 0% (0/33) 31.0% (10/32)

Humaidan et al. (2010) RCT Normal/high 0% (0/152) 2.0% (3/150)

Papanikolaou et al. (2011) RCT Normal 0% (0/17) 0% (0/18)

Donor IVF cycles (no ET)

Acevedo et al. (2006) RCT Normal 0% (0/30) 17.0% (5/30)

Galindo et al. (2009) RCT Normal 0% (0/106) 8.5% (9/106)

Melo et al. (2009) RCT Very high 0% (0/50) 4.0% (2/50)

Sismanoglu et al. (2009) RCT Very high 0% (0/44) 6.8% (3/44)

Total embryo freezing (no ET)

Griesinger et al. (2007a, b) Observ Very high 0% (0/20) –

Manzanares et al. (2010) Observ Very high 0% (0/42) –

Figure 3 OHSS rate in fresh IVF cycles with embryo transfer.

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using the search algorithm ‘GnRH agonist OR Leuprorelin OR TriptorelinOR Buserelin OR nafarelin AND ovulation triggering OR ovulation induc-tion OR oocyte maturation’. In addition the references of all eligible trialswere reviewed and cross-searches in PubMed were performed, using thenames of the investigators who were lead authors in at least one eligibletrial.

All randomized, prospective or retrospective controlled trials that allo-cated patients undergoing IVF/ICSI cycles to receive either a GnRHa orhCG for final oocyte maturation were considered eligible for the narrativereview. Only RCTs were eligible regarding the meta-analysis.

Data extraction and analysisTwo independent investigators (D.B. and J.C.C.F.) were involved in thedata extraction. The following data were extracted from each arm ofthe eligible trials: authors’ names, journal and year of publication,country of origin, enrolment year, protocol used, type of gonadotrophinused for ovarian stimulation, ovulation triggering medication, incidenceof OHSS, ongoing pregnancy rate and delivery rate.

The primary outcome was delivery rate or ongoing pregnancy rateabove 12 weeks of gestation. Secondary outcome was OHSS rate.

Meta-analyses included only RCTs. Two-by-two tables were con-structed, calculating the risk difference for each primary study to estimaterelative risks among GnRHa triggering and HCG triggering groups. In orderto test the homogeneity of the estimates of risk differences among eligiblestudies, we used the x2 test with a level of significance of 0.1, and wefurther quantified the degree of heterogeneity by using the I2 test. Dataacross studies were synthesized, using the fixed effects (Mantel–Haenszel)model whenever no statistical heterogeneity was observed, or using therandom effects model (DerSimonian and Laird).

A prespecified subgroup analysis was performed according to the typeof LPS adopted within eligible trials (Table I; Fig. 2a and b) as a modifiedluteal support was involved in the studies published after 2006 in order toreverse the previously reported low reproductive outcome. Data wereanalysed using RevMan 5 software. All P-values were two-tailed with alevel of significance ,0.05.

Results

Eligible trials characteristicsA total of 1725 reports were retrieved through searches in PubMed(1393 hits) and Cochrane Central trials Registry (332 hits). Finally

through careful scrutiny of the results obtained and the referencesof all eligible trials, 30 trials were considered eligible.

Among 30 eligible trials, 9 RCTs involving a GnRH-Antagonist pro-tocol were available including 745 patients, 375 allocated to GnRHatriggering and 370 allocated to hCG triggering. The GnRHa regimentused to induce final oocyte maturation differed among them; fourtrials using buserelin (0.2–0.5 mg), three triptorelin 0.2 mg, one trialwith Leuprorelin 1.0 mg and one trial using either Leuprorelin 0.5 ortriptorelin 0.2 mg. LPS also differed among eligible randomized trials;three of them used conventional LPS (Fauser et al., 2002; Kolibianakiset al., 2005; Humaidan et al., 2005) whereas six used modified LPS(Babayof et al., 2006; Humaidan et al., 2006; Pirard et al., 2006;Engmann et al., 2008a, b; Humaidan et al., 2010; Papanikolaouet al., 2011).

Follicular fluid

Follicular fluid composition after GnRHatriggeringFollowing the reports from the first RCTs on GnRHa versus hCG trig-gering (Humaidan et al., 2005; Kolibianakis et al., 2005), the questionwas asked whether the poor reproductive outcome seen in thesetrials could be related to the surge of gonadotrophins elicited by abolus of GnRHa, leading to an insufficient follicular maturation andthus oocytes with a reduced developmental competence. Speakingagainst this theory, however, was the fact that significantly more MIIoocytes (16%) were retrieved after GnRHa triggering (Humaidanet al., 2005).

In a study comparing hormonal characteristics of follicular fluid (FF)after GnRHa and hCG triggering, respectively, a total of 138 FF from69 patients were examined (Andersen et al., 2006). Significantly higherlevels of FSH and LH, a 25% lower level of P4 and a total absence ofhCG was seen in FF after GnRHa triggering, confirming previous find-ings (Yding Andersen et al., 1993). In the hCG triggering group thetotal lower level of gonadotrophins (LH and FSH) was compensatedfor by hCG levels more than one order of magnitude higher thanLH and FSH in the GnRHa group. No differences were seen regardinginhibin-A and inhibin-B between groups (Andersen et al., 2006). Theauthors concluded that GnRHa triggering secures a proper preovula-tory maturation leading to the release of non-compromised mature

Figure 4 OHSS rate in oocyte donation IVF cycles.

514 Humaidan et al.

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Humaidan  P  et  al.  HRU.  2011  

AnM-­‐angiogenic  effects    

Khan  et  al,  HR,  2010      

Prevent  OHSS  risk     Immunohistolocalisa?on  of  macrophage  marker    

Immunohistolocalisa?on  of  a  vascular  marker    

Does  the  mode  of  triggering  might  partake  in  the  development  of  pain  during  ART  procedures?    

 

?

GnRHa  triggerring    

hCG  triggerring    

   …is  to  evaluate  the  impact  of  the  mode  of  triggering  (GnRHa  versus  hCG  triggering)  on  pain  symptoms  

progression  during  IVF/ICSI  cycle  

The  purpose  of  the  present  study…  

?

GnRHa  triggerring    

hCG  triggerring    

non  pregnant  

01/2014     06/2014  RetrospecMve  cohort  study    

“GnRHa  triggering”  group  N=57  

“hCG  triggering”  group  N=70  

127  cycles  were  analyzed  from  paMents  undergoing  IVF/ICSI    

methods  

01/2014     06/2014  observaMonal  cohort  study    

ü  Baseline  characterisMcs  

ü  IVF  characterisMcs    

“GnRHa  triggering”  group  N=57  

“hCG  triggering”  group  N=70  

ü  Painful  symptoms  using  VAS    

 

methods  

prospec?vely  collected  

T1:  SynchronisaMon  

evaluaMon      

T2: Three  weeks  post  

retrieval    

Pain  evaluaOon    

Painful  symptoms  using  VAS    

Dysmenorrhea  

LU  symptoms  

Non  cyclic  pelvic  pain    GI  symptoms  

Dyspareunia  

Total  VAS  Score  /50      

Trends  for  VAS  change:  (VAS  T2)-­‐(VAS  T1)                                negaMve  trend              posiMve  trend    Decreasing  pain                                                        Increasing  pain    

hCG  triggering  n=70     GnRHa  triggering  n=57     P  value  Age  at  IVF  (years)   34.79±4.44   34.91±7.46   0.915  t  Body  Mass  Index  (kg/m2)   24.02±4.42   23.04±4.04   0.197  t  GesOty     0.61±0.95   0.74±1.13   0.508  t  Parity     0.23±0.54   0.23±0.50   0.996  t  Smoking   12(17.14)   4(7.02)   0.087  k  University  educaOon     46(65.71)   37(64.91)   0.920  k      Ethnicity             0.842  k            -­‐Caucasian   43(61.43)   37(64.91)            -­‐Mediterranean   9(12.86)   7(12.28)            -­‐African   13(18.57)   11(19.30)            -­‐Others     5(7.14)   2(3.51)      Causes  of  inferOlity                      -­‐OvulaBon  disorder   4(5.71)   2(3.51)   0.628  k            -­‐Male  factor   19(27.14)   18(31.58)            -­‐Tubal  factor   9(12.86)   3(5.26)            -­‐Endometriosis   20(28.57)   19(33.33)            -­‐Idiopathic   3(4.29)   5(8.77)            -­‐Diminished  ovarian  reserve   3(4.29)   1(1.75)            -­‐More  than  one  eBology   12(17.14)   9(15.79)      Endometriosis   32(45.71)   28(49.12)   0.854  k      Previous  surgery  for  endometriosis   13(22.86)   11(19.30)   0.960  k      Type  of  inferOlity             0.521  k            -­‐  Primary   48(68.57)   36(63.16)            -­‐  Secondary   22(31.43)   21(36.84)      Number  of  previous  IVF  cycle   1.61±0.91   2.24±1.25   0.002  t  

Baseline  characterisOcs  

hCG  triggering  n=70     GnRHa  triggering  n=57     P  value  Ovarian reserve         - Day 3 FSH (UI/L)   7.59±3.04   6.78±2.00   0.092 t   - Day 3 LH (UI/L)   4.89±2.02   5.27±2.46   0.367 t   - Day 3 Estradiol (pg/mL)   54.30±39.82   46.43±39.93   0.211 t   - AFC   13.64±8.14   16.79±8.50   0.041 t   - AMH (ng/mL)   3.11±2.17   4.62±2.68   0.001 t  Protocol of stimulation       <0.001 k   - GnRH antagonist   52(74.29)   57(100.00)     - Long protocol   8(11.43)   0(0.00)     - Short protocol   10(14.29)   0(0.00)    Ovarian hyper stimulation syndrome   0(0.00)   0(0.00)   --  Total dose of injected gonadotropin (IU)  

2672.14±923.18   2350.00±759.49   0.036 t  

Duration of stimulation (days)   9.84±1.38   9.96±1.66   0.651 t  Peak serum Estradiol levels (pg/ml) a   2091.30±1406.11   2778.18±1608.16   0.040 t  Number of oocytes retrieved   8.23±4.32   13.82±8.77   <0.001 t  Number of 2PN embryos obtained   2.03±1.24   3.30±2.27   <0.001 t  

Baseline  characterisOcs  

Pain  evoluOon  between    final  and  synchronizaOon  evaluaOons  

hCG  triggering  n=70  

GnRHa  triggering  n=57  

P  value  

Trend  for  VAS  change    

           

     -­‐Total  VAS  score   6.50±6.57   3.77±7.73   0.009  m  

     -­‐Dysmenorrhea   3.84±3.44   2.35±3.43   0.020  m  

     -­‐Dyspareunia   0.56±2.53   -­‐0.14±2.03   0.230  m  

     -­‐Non  cyclic  pelvic  pain  

1.43±2.85   1.18±2.51   0.875  m  

   -­‐GI  symptoms   0.49±2.14   0.37±2.74   0.617  m  

   -­‐LUT  symptoms     0.19±1.05   0.02±1.45   0.787  m  

ProporMon  of  women  with   an   increasing  pain  

58(82.86)   36(63.15)   0.012    k  

   Univariate  logisOc  regression  analysis  

MulOple  logisOc  regression  analysis  *  

Parameters   Odds  raMo  

95%  CI   p   Odds  raMo  

95%  CI   p  

Age  at  IVF  (years)   1.02   0.95-­‐1.10   0.610              Body  Mass  Index  (kg/m2)   1.03   0.93-­‐1.13   0.587              Endometriosis  status             0.811              No  Endometriosis     1                      Endometriosis   1.10   0.49-­‐-­‐2.44                  Number  of  previous  IVF   0.83   0.59-­‐1.18   0.302              Type  of  protocol             0.600              GnRH  antagonist   1                      Long  protocol   2.66   0.31-­‐22.52   0.370              Short  protocol   1.52   0.31-­‐7.57   0.610              Total  dose  of  injected  gonadotropin  (IU)   1.00   1.00-­‐1.01   0.572              Type  of  triggering:             0.013           0.006  hCG  triggering     1           1          GnRH-­‐a  triggering     0.35   0.16-­‐0.81       0.31   0.13-­‐0.71      Number  of  oocytes  retrieved   0.95   0.90-­‐1.00   0.061              

Independent  predictors  for  increasing  pain    during  IVF/ICSI  procedure    

•  ReverMng   to   a   GnRHa   triggering   aTer   COS   limits   the   progression   of   pain   symptoms  during  ART,  as  compared  to  an    hCG  triggering.    

     •  Randomized  clinical  trials  are  needed:      

-­‐  To  confirm  the  advantage  of  this  strategy      -­‐  To  determine  if  it  could  be  beneficial  to  painful  women  like  endometriosis  inferOle  women.    

   

Conclusion  

Gynecology Surgical unit: C Chapron, B Borghese, P Santulli,

H Foulot, MC Lafay-Pillet, A Bourret, G Pierre, M Even, MC Lamau, L Marcellin, P Marzouk, Medical unit: A Gompel, G Plu-Bureau, L Maitrot

Reproductive Endocrinology unit: D de Ziegler, P Santulli, V Gayet, C Maignien, FX Aubriot

Intestinal surgery B Dousset, S Gaujoux, M Leconte

Radiology AE Millischer, L Maitrot

Laboratory: Genetic D Vaiman, F Mondon, S Barbaux

Laboratory: Imunulogy

F Batteux, S Chouzenoux C Nicco, C Chéreau, B Weill

Laboratory: Reproductive biology

JP Wolf, V Lange, K Pocate, JM Kuntzman, C Chalas

Statistical unit

F Goffinet, PY Ancel, C Prunet

D. de Ziegler, Professor and Head, Reproductive Endocrinology and Infertility unit, A. Gompel, Professor and Head, Medical Gynecological unit,

C. Chapron, Professor and Chair, Gynecology Obstetrics II and Reproductive Medicine