Planning of GnRH antagonist cycles Christophe Blockeel

UZ Brussel Evolution of the number of ovum pick ups over the years Blockeel - Planning GnRH antagonists 22-4-2017

Oocyte retrievals May 2011 Blockeel - Planning GnRH antagonists 22-4-2017

Oocyte retrievals June 2011 Blockeel - Planning GnRH antagonists 22-4-2017

1. OCP PRETREATMENT

Oral Contraceptive Pill Pretreatment Potentially relevant RCTs identified and screened for retrieval (n=34) RCTs excluded (n=27) RCTs retrieved for more detailed evaluation (n=7) RCTs excluded (n=3) RCTs with usable information, by outcome (n=4) Cedrin-Durnerin et al, 2006 Huirne et al, 2006 Kolibianakis et al, 2006 Rombauts et al, 2006 Until 3/2007 Inclusion: true RCTs Griesinger et al. Fertil Steril. 2008;90:1055. Blockeel - Planning GnRH antagonists 22-4-2017

Effect of OCP Pretreatment P Value Gonadotropin consumption +542 IU 95% CI, +127 to +956 <0.01 Stimulation duration +1.41 days 95% CI, +1.13 to +1.68 Number of COCs +1.63 95% CI, –0.34 to +3.61 0.11 OR for ongoing PR per randomized patient 0.74 95% CI, 0.53 to 1.03 0.08 Rate difference for ongoing PR –5% 95% CI, –10.0 to +0.4 0.07 . Griesinger et al. Fertil Steril. 2008;90:1055. Blockeel - Planning GnRH antagonists 22-4-2017

Ongoing pregnancy per randomized patient Griesinger et al., 2010 Fertil Steril Ongoing pregnancy per randomized patient Duration of stimulation Gonadotropin consumption Number of COCs

2. Early vs Late hCG

When is the correct moment to induce final oocyte maturation ? At least 3 follicles of ≥ 17 mm present in ultrasound Borm and Mannaerts HR 2000, The Middle East orgalutran study group HR 2001, Fluker FS 2001, Kolibianakis FS 2002, 2003 At least 3 follicles of ≥ 18 mm present in ultrasound Garcia - Velasco HR 2001 Leading follicle attained 18-20 mm and estradiol levels were indicating satisfactory follicular development Olivennes HR 1998 At least ≥ 1 follicle of ≥ 18 mm and 3 follicles of ≥ 15 mm de Jong FS 2001 At least 1 follicle of ≥ 20 mm and an estradiol level 1200 pg/ml Albano HR 2000 At least 1 follicle of ≥ 20 mm or an estradiol level 1200 pg/ml Felberbaum HR 2000 Blockeel - Planning GnRH antagonists 22-4-2017

Effect of Delaying hCG by 2 Days Early hCG Late hCG P Value Duration of recFSH stimulation (d) 9.6 ± 0.2 11.3 ± 0.2 0.001 COCs 11.2 ± 0.5 12.4 ± 0.5 0.07 2PN oocytes 6.4 ± 0.1 7.2 ± 0.3 NS Embryos transferred 2.0 ± 0.1 Mean quality score of transferred embryos 1.6 ± 0.4 Ongoing PR 35.6 25.0 0.03 Kolibianakis et al. Hum Reprod. 2005;20:2453. Blockeel - Planning GnRH antagonists 22-4-2017

Advancement or delay with 1 day Tremellen et al., Hum Reprod, 2010 Blockeel - Planning GnRH antagonists 22-4-2017

3. GnRH antagonists

Introduction Laboratory assessment prior to start of stimulation Inefficient luteolysis - elevated progesterone Blockeel - Planning GnRH antagonists 22-4-2017

Elevated progesterone before start Kolibianakis, Hum Reprod, 2004 Blockeel - Planning GnRH antagonists 22-4-2017

Elevated progesterone before start Normal-P High-P P Ongoing pregnancy rate Per started cycle % (n) 31.8 (124/390) 5.0 (1/20) 0.011 Per oocyte retrieval % (n) 33.8 (124/367) 6.3 (1/16) 0.026 Per embryo transfer % (n) 36.9 (124/336) 0.014 Ongoing implantation rate % (n) 21.1 (151/714) 3.6 (1/28 ) 0.028 Kolibianakis, Hum Reprod, 2004 Blockeel - Planning GnRH antagonists 22-4-2017

Administration of a GnRH antagonist before start in case of elevated progesterone Blockeel - Planning GnRH antagonists 22-4-2017

Poor ovarian response, n = 2 Normal P Group Embryo transfer, n = 400 No transfer: No mature oocytes at retrieval, n = 3 No fertilization, n = 10 Poor embryo quality, n = 17 No transferable embryo after diagnosis (PGD patients), n = 16 OHSS, n = 6 Oocyte pick-up, n = 452 Poor ovarian response, n = 2 Normal P Group n = 454 Embryo transfer, n = 24 Poor embryo quality, n = 1 No transferable embryo after diagnosis (PGD patient), n = 1 Oocyte pick-up, n = 26 Poor ovarian response, n = 4 High P Group n = 30 484 patients assessed for eligibility Blockeel et al., Curr Pharmac Biotech, 2011

GnRH antagonist before start Blockeel et al., Curr Pharmac Biotech, 2011. Blockeel - Planning GnRH antagonists 22-4-2017

GnRH antagonist before start (2) Blockeel et al., Curr Pharmac Biotech, 2010. Blockeel - Planning GnRH antagonists 22-4-2017

GnRH antagonist before start Blockeel et al., Curr Pharmac Biotech, 2011. Blockeel - Planning GnRH antagonists 22-4-2017

Administration of a GnRH antagonist before start in case of normal progesterone Blockeel - Planning GnRH antagonists 22-4-2017

Treatment of Subjects Group A GnRH antagonist 150-225 IU recFSH Cycle day 2 5 6 9 OPU ET Group B 150-225 IU recFSH 10.000IU hCG GnRH antagonist GnRH antagonist Blockeel - Planning GnRH antagonists 22-4-2017

Patients assessed for eligibility (n=70) Enrollment Did not meet inclusion criteria (n=1) Randomly assigned to a treatment arm (n=69) Allocation Assigned to control group (n= 36) Assigned to pretreatment group (n= 33) Insufficient ovarian response (n=1) Premature Pg rise (n=1) (Did not undergo oocyte retrieval) Oocyte retrieval (n= 36) Oocyte retrieval (n= 31) Received no embryo transfer (n=1) (Had no embryos available) Received no embryo transfer (n=2) (Had no embryos available) Follow-up Embryo transfer (n= 35) Embryo transfer (n= 29) Lost to follow-up (n=0) Lost to follow-up (n=0) Analysis Assessed for pregnancy outcome (n=35) Assessed for pregnancy outcome (n=29)

Results Control group Pretreatment group P - value Starting dose of rFSH (IU) 177.7 ± 32.3 166.9 ± 22.9 0.125 Days of rFSH stimulation 8.8 ± 1.7 8.8 ± 1.4 1.000 Number of COCs* 9.9 ± 4.9 13.6 ± 7.3 0.016 Ongoing pregnancy rate per started cycle % (n) 33.3% (12/36) 42.4% (14/33) 0.596 Blockeel et al., Fertil Steril, 2011 Blockeel - Planning GnRH antagonists 22-4-2017

Protocol for oocyte donors 150-225 IU recFSH GnRH antagonist GnRH antagonist Cycle day 2 5 6 9 OPU GnRH agonist trigger Recruitment of oocytes No OHSS Blockeel - Planning GnRH antagonists 22-4-2017

4. ESTRADIOL

Luteal estradiol pretreatment Fanchin et al. Hum Reprod. 2003;12:2698. Blockeel - Planning GnRH antagonists 22-4-2017

Luteal estradiol pretreatment Suppression of FSH Coordination of antral follicle growth (homogeneity - synchronisation) More physiological than GnRH agonist or OCP Fanchin et al. Hum Reprod. 2003;12:2698. Blockeel - Planning GnRH antagonists 22-4-2017

Planning purposes RCT oestradiol valerate - GnRH antagonist (n: 426) GnRH agonist long day 1 (n: 412) Oestradiol valerate 4 mg from J25 until wanted day of start of stimulation i.e. Thursday to Sunday A Guivarc’h - Levêque et al GOF 2010 Blockeel - Planning GnRH antagonists 22-4-2017

Luteal estradiol pretreatment RCT by Guivarc’h-Levêque et al (2010) Long GnRH agonist protocol (n=412) versus GnRH antagonist protocol with estradiol pretreatment (n=426) Lower proportion of OR during weekend days > programming feasible PR equivalent with long agonist protocol (Guivarc’h-Levêque et al, GOF, 2010)

Programming of egg retrievals days A Guivarc’h - Levêque et al GOF 2010 Blockeel - Planning GnRH antagonists 22-4-2017

Results Results Antagonist Long Agonist P Age (years) 32.5 33.1 Cycles (n) 426 412 OPU rate (%) 88% Eggs inseminate (mean) 6.8 7.6 < 0.01 Pregnancy rate 29% 28% NS A Guivarc’h - Levêque et al GOF 2010 Blockeel - Planning GnRH antagonists 22-4-2017

Control Group A Pretreatment Group B GnRH antagonist 150 IU recFSH No treatment 2 7 10.000IU hCG ET OPU Pretreatment Group B Estradiol valerate 4mg GnRH antagonist Figure 1 150 IU recFSH 6 – 7 – 8 – 9 – 10 days 25 7 OPU ET 10.000IU hCG 34

If day 25 is…. Monday 6 days Progynova 4 mg Tuesday 10 days Progynova 4 mg Wednesday 9 days Progynova 4 mg Thursday 8 days Progynova 4 mg Friday 7 days Progynova 4 mg Saturday 6 days Progynova 4 mg Sunday 6 days Progynova 4 mg Blockeel - Planning GnRH antagonists 22-4-2017

%OR during weekend days Results Primary endpoint: proportion of patients undergoing an oocyte retrieval during weekend days Monday Tuesday Wednesday Thursday Friday Saturday Sunday Total %OR during weekend days Control 5 8 2 10 6 3 39 8/39 (20.5%) Progynova 7 11 4 1 37 1/37 (2.70%) P=0.029

Study design Prospective randomized trial Primary outcome: number of egg retrievals during weekend days Inclusion criteria: Female age  36 years FSH < 12 IU/l BMI 18-29 kg/m2 Regular cycle (25-35 days) No major uterine or ovarian abnormalities 1st or 2nd IVF cycle Written informed consent Exclusion criteria: Oocyte donation Medical contra indication for pregnancy or IVF treatment Endometriosis ≥ grade 3 PCOS Endocrine or metabolic abnormalities Blockeel - Planning GnRH antagonists 22-4-2017

Pretreatment group (n=37) Results (2) Stimulation characteristics and embryological data Control group (n=39) Pretreatment group (n=37) P-value * Days of rFSH stimulation 8.6 ±1.5 9.6 ± 1.4 0.004 Total dose of rFSH consumption, IU 1295.0 ± 254.2 1485.1 ± 248.7 0.002 Number of COCs 12.2 ± 8.7 12.2 ± 6.2 1.00 Number of MII oocytes 9.9 ± 7.8 10.0 ± 4.7 0.947 Number of 2-PN oocytes 7.6 ± 6.5 8.4 ± 3.7 0.625 * P-value for Student’s t test; P-values less than 0.5 are bold

Results (3) Ongoing pregnancy rates Control group Pretreatment group P-value * Ongoing pregnancy rate Per started cycle, n (% ) 16/42 (38.1%) 16/44 (36.4%)° 0.868 Per pickup, n (%) 16/39 (41.0%) 16/37 (43.2%)° 0.845 Per embryo transfer, n (%) 16/37 (43.2%) 16/35 (45.7%)° 0.833 * P-value for Fisher’s exact of Chi-squared test ° pregnancy outcome still awaited for 3 patients in the pretreatment group

Conclusion Estradiol valerate pretreatment allows scheduling of GnRH antagonist cycles, with a significantly lower proportion of patients undergoing OR during weekend days without deleterious effects on the number of oocytes retrieved and the ongoing pregnancy rates

Conclusion: planning is possible! Today’s protocol… Corifollitropin alfa: 1 injection GnRH antagonist GnRH antagonist Cycle day 2 5 6 9 OPU ET 10.000IU hCG Blockeel - Planning GnRH antagonists 22-4-2017

Conclusion: planning is possible! Or… Estradiol valerate 4mg GnRH antagonist Corifollitropin alfa: 1 injection 6 – 7 – 8 – 9 – 10 days 25 7 OPU ET 10.000IU hCG Blockeel - Planning GnRH antagonists 22-4-2017