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Individualization of Cycle Control Dr. Milton Leong MDCM DSc (McGill) Director, IVF Center, HKSH Specialist in Reproductive Medicine Adjunct Professor, OBS-GYN, McGill University The first IVF Baby Drs. Steptoe and Edwards decided to abandon the use of fertility medications and try aspirating a single egg in a natural menstrual cycle. On their second attempt, Louise Brown was conceived Preparation for Ovum Collection • • • • • Natural Cycles Minimal stimulation (clomiphene/FSH) IVM FSH stimulation with agonists FSH stimulation with antagonists Ovulation Stimulation WHAT GOES AROUND COMES AROUND *American idiom Stimulated ovary Technology and product development timeline: gonadotrophins Horse PMSG Pig FSH Pituitary FSH u-hMG 1930 1940 1950 1960 u-FSH 1980 FbM 1995 2003 Quality Potential side-effects Creutzfeldt– Jacob disease 1990 r-hFSH r-hFSH Consistency Local reactions Antibodies u-FSH (HP) Local, systemic reactions Adapted from: Lunenfeld. Reprod Biomed Online 2002;4:11 Premature LH surge • Poor quality • No fertilization or very poor pregnancy rate • Cancel egg retrieval 5-20% 5-20% All cycles treated in early 1980’s GnRHa Long Protocol vs No Suppression meta-analysis IVF cases Odds ratios for IVF clinical pregnancy after GnRH-a versus clomiphene/FSH/hMG ovulation induction protocols GnRHa Long Protocol vs No Suppression meta-analysis GIFT cases Odds ratios for GIFT clinical pregnancy after GnRH-a versus clomiphene/FSH/hMG ovulation induction protocols Results of first application of GnRH-agonists in the long protocol • 11 patients eligible for IVF • GnRH agonists s.c. (busereline) started at day of menstruation of one day before • Ovarian stimulation started with HMG or purified FSH when all ovarian follicles and the endometrial lining has disappeared on ultrasound (average 15 days) • One ongoing pregnancy achieved Porter et al., 1984 OVARIAN STIMULATION • • • • • • FSH with agonist down regulation FSH with antagonists Low dose clomid/FSH stimulation Delayed stimulation IVM Natural cycles Structure of GnRH agonists Modifications of natural GnRH to have GnRH agonistic properties 1 2 3 4 5 6 7 8 9 10 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 activation of the GnRH receptor regulation of GnRH receptor affinity regulation of biologic activity Action of GnRH agonists Down regulation GnRH LH + FSH GnRH - receptor post-receptor-cascade Flare up effect Pituitary suppression GnRH - agonist Schematic representation of different protocols using GnRH agonists in combination with gonadotrophins for ovarian stimulation in IVF The long luteal protocol ovulation induction gonadotropin administration in an individualized dosage oocyte pick up embryo transfer start of GnRH agonist 22nd day of previous cycle 1st day of gonadotropins 14 days luteal phase support Individualizing protocols • Our contribution to 1. low dose short term agonist down regulation using decapeptyl 2. flexible low dose antagonist • Aims: - to simplify treatment - to minimize drug usage Agonist Studies 2000 - 2001 Deca Long Luc Long Bus <40 <40 <40 Number of OPU 69 76 61 Number of Eggs Retrieved 881 885 726 Number of MTII 647, 73% 642, 73% 552, 76% Number of MTI 136, 15% 44, 5% 101, 14% 74% 76% 71% 3.1 3.2 2.8 Pregnancy Rate per ET 51% 49% 44% Implantation Rate 20% 22% 18% Average Age 34.4 33.2 34.9 Fertilization Rate Mean # of Embryos Transferred per ET Decapeptyl Down Regulation 2000-2002 Total ≥ 40 < 40 # of patients 90 76 (32.9) 14(40.8) # of pregnancy 42 40 2 Pregnancy % 46.7 52.6 14 # of twins+ 10 10 0 # of babies 43 42 1 16% 50% Miscarriage rate Decapeptyl Down Regulation 2000-2003 Laboratory Data # of eggs 831 MTII 539 (67%) MTI 139 (16.7%) # of eggs ICSI 551 # of fertilized 427 Fert. % 76.4 # of E.T. 244 Mean transferred 2.7 # of preg. (F.H.) 46 Implantation rate 21% Down Regulation GnRH agonists Undesirable effects: • Over-suppression: – LH becomes so low that it affects the production of estrogen, and possibly progesterone in the luteal phase – Leads to poor response, poor pregnancy outcome due to early abortion. Also it is: • Too long and too much drug use, cost, cancelled cycles and it is unnatural. Structure of GnRH antagonists to achieve antagonistic properties of natural GnRH more modifications than only in position 6 and 10 are necessary 1 2 3 4 5 6 7 8 9 10 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 activation of the GnRH receptor regulation of GnRH receptor affinity regulation of biologic activity Action of GnRH antagonists GnRH LH + FSH GnRH - receptor post-receptor-cascade pituitary suppression GnRH - antagonist Characteristics of GnRH antag Ganirelix Cetrorelix • Fully effective • Fully effective within 4 hours, with within 8 hours, with a half-life of about a half-life of about 13 hours 36 hours R.E. Felberbaum and K. Diedrich, 1999. The Cetrotide® 0.25 mg multiple dose protocol ovulation induction gonadotropin administration in an individualized dosage oocyte pick up embryo transfer 1st day of menstruation 1st day of gonadotropins luteal phase support Cetrotide® 0.25 mg administration daily s.c. starting on day 6 of stimulation Possibilities to individualize the multiple dose protocol • To avoid a premature LH rise the administration of cetrotide® 0.25 mg on day 6 of stimulation should be the standard procedure • Using the standard procedure, a mean of 6.3 injections are necessary • This is in accordance with the package size of 7 ampoules cetrotide® 0.25 mg per patient Possibilities to individualize the multiple dose protocol • Individualized administration of Cetrotide® 0.25 mg can be done – According to follicle size: only if leading follicle is 14 mm • Thereby, the multiple dose protocol can also be adapted to patients with a lower response Cetrorelix 0.125mg Flexible Dose Trial Selection Criteria: 1. 2. 3. Previous over-suppression with agonist Previous poor response Previous LH surge if no agonist BMI Distribution 10 9 8 7 6 5 4 3 2 1 0 <20 20 21 22 Mean = 21.8 (range 19-30) >25 # Days Cetrorelix Used 10 9 8 7 6 5 4 3 2 1 0 1 2 3 Mean = 2.2 days (range 1-3) 4 LH and Cetrorelix 0.125mg/day 9 7.8 8 7 6 6 4.9 5 Low Average 4 High 3 2 2.4 1.2 1 2.1 2.5 1.8 0.9 0 Pre-C ET Day 1 Post Day HCG • • • • Range Pre Day 1 post Day HCG mIU/ml 1.2 - 7.8 0.9 - 4.9 1.8 - 6 Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006 0.125 mg/day 0.25 mg/day P Cycles 121 331 Average age 37.1±4.0 37.5±4.2 NS Days of stimulation 9.3±1.7 9.4±1.8 NS Total dose of FSH used (amp) 31.4±14.4 36.0±14.5 0.004 E2 on HCG day (pg/ml) 1943±941.8 2028.0±1376.0 NS LH on HCG day (IU/L) 3.5±3.9 2.1±1.9 0.001 Oocytes collected 1160 (9.6) 3198 (9.7) NS MTII 902 (77.75%) 2503 (78.26) NS Fertilized oocytes (fertilization rate) 770 (85.4%) 2085 (83.3%) NS Embryos transferred 2.8±0.8 2.9±0.8 NS Pregnancy rate/ET 50/121 (41.3%) 106/331 (32.0%) NS (P=0.066) Implantation rate 17.3% 13.4% NS (P=0.081) Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006 (age <40) 0.125 mg/day 0.25 mg/day P Cycles 86 215 Average age 35.1±3.1 35.2±2.9 NS Days of stimulation 9.4±1.7 9.3±1.8 NS Total dose of FSH used (amp) 29.6±11.9 33.2±11.6 0.016 E2 on HCG day (pg/ml) 2081.5±977.6 2040.6±1300.2 NS LH on HCG day (IU/L) 3.7±4.4 2.1±1.8 0.002 Oocytes collected 941 (10.9) 2240 (10.4) NS MTII 732 (77.78%) 1742 (77.76) NS Fertilized oocytes (fertilization rate) 623 (85.1%) 1448 (83.1%) NS Embryos transferred 2.8±0.6 2.8±0.7 NS Pregnancy rate/ET 43/86 (50.0%) 84/215 (39.1%) NS (P=0.083) Implantation rate 21.8% 17.4% NS (P=0.144) Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006 (age ≥40) 0.125 mg/day 0.25 mg/day P Cycles 35 116 Average age 41.6±1.7 42.0±2.3 NS Days of stimulation 9.1±1.8 9.4±1.9 NS Total dose of FSH used (amp) 36.0±18.6 41.1±17.7 NS E2 on HCG day (pg/ml) 1602.2±756.1 2003.9±1517.8 NS LH on HCG day (IU/L) 3.0±2.4 2.2±2.1 NS Oocytes collected 219 (6.26) 958 (8.25) NS MTII 170 (77.6%) 761 (79.4%) NS Fertilized oocytes (fertilization rate) 147 (86.5%) 637 (83.7%) NS Embryos transferred 2.9±1.1 3.0±1.0 NS Pregnancy rate/ET 7/35 (20.0%) 22/116 (19.0%) NS Implantation rate 6.9% 6.6% NS Antagonist vs Agonists Cet Agonist <40 ≥40 <40 ≥40 Number of OPU 371 184 171 23 Number of Eggs Retrieved 3994 1388 2126 199 Number of MTII 2984(75%) 1055(76%) 1575(74%) 152(76%) Number of MTI 526 (13%) 160 (12%) 205 (10%) 25 (13%) Number of ICSI’d 3269 1131 1729 173 Number of 2PN 2472 870 1303 126 Fertilization Rate 76% 77% 75% 73% Total # of Embryos Transferred 1039 521 532 62 Mean # of Embryos Transferred per ET 2.8 2.8 3.1 2.7 Number of Pregnancy 145 25 82 5 Pregnancy Rate per ET 39% 14% 48% 22% Implantation Rate 17% 5% 20% 10% Average Age 35.1 41.8 33.7 41.5 Comparison: Mode of Actions Antagonists •Immediate onset of actions (shortens treatment durations) •Prevents hormonal withdrawal symptoms Agonists •long pre-treatment •Hormonal (estrogen) withdrawal symptoms through desensitization of pituitary •Recovery of the •No recovery time of the pituitary gonadotrophin pituitary secretion, after stopping the treatment takes about 2 weeks. Reduction of OHSS using Cetrotide® • Multiple dose protocol – rate of OHSS: 6.5% vs. 1.1% (agonist vs. antagonist protocol) – RR 6.2, 95% CI: 1.4 - 27.1, p = 0.03 • Single dose protocol – rate of OHSS: 11.1% vs. 3.5% (agonist vs. antagonist protocol) 95% CI: - 18.4 to 3.2 – patients requiring hospitalisation: 5.6% vs. 1.8% – (agonist vs. antagonist protocol) 95% CI: - 11.7 to 4.1 • With both Cetrotide® protocols a clear reduction of OHSS was achieved The GnRH Antagonists • • • • • • Conclusions: Why treat 100% of patients when we are trying to prevent 5-10% LH surge Avoid over-suppression and poor response Effective in preventing LH surge Reduction of hyper-stimulation Lower costs Ovum Preparation for IVF • • • • • • FSH/GnRH Down Regulation FSH/GnRH Antagonists Clomid, Clomid/FSH Minimal Stimulation IVM Natural Cycles Problems with Ovarian Stimulation • • • • Drug Costs Side effects: immediate and delayed Future long term risks Not “User Friendly” Problems with Ovarian Stimulation • Waste of Human Resources • Excess eggs ? how to deal with • Excess embryos - even worse • Multiple pregnancies and their associated complications Individualized stimulation Individualized Stimulation Individualizing Stimulation Individualized Stimulation Over responders • • Risk of OHSS Treatment options a) b) c) d) Cancel cycle Coasting No embryo transfer Convert to IVM Individualizing protocols • For over responders • For low responders Over responders Prolonged Coasting • • • • Aim: To prevent hyperstimulation Practice: Coast till E2 ≤ 3000 pg/mL Sher, 1995 Start when 30% follices > 15 mm Nilsson, 1999 When 3 follicles > 17mm IVM stimulation Poor responders • • • • Age (average age of ML patient 38.7 yrs) Decrease ovarian reserve (↑D2 FSH) Decrease preantral follicles Previous ovarian surgery (Laparoscopic ovarian cystectomy) Poor responders • • • • • High dose Microdose flare Low dose clomid/FSH stimulation Delayed stimulation IVM Microdose Flare Regimen (1) • • • • Oral Contraceptive 20 mcg leuprolide cs bd x 2 d uFSH for ovarian stimulation Results: ↑oocytes Less ampoules FSH Source: Scott et al, 1994 Microdose Flare Regimen (2) • • • • • Oral Contraceptive 40 mcg leuprolide sc bd 4 IU/d growth hormone IM Followed by uFSH 2 days later Results: ↓Cancellation rate ↑E2 levels, number of oocytes Source: Schoolcraft et al, 1997 Microdose Flare Regimen (3) • • • • Oral Contraceptive 40 mcg leuprolide sc bd uFSH starting 2 days later Results ↓Cancellation rate ↑E2 levels, number of oocytes Source: Surrey et al, 1998 Poor responders • • • • • High dose Microdose flare Low dose clomid/FSH stimulation Delayed stimulation IVM Minimal stimulation Poor responders • • • • • High dose Microdose flare Low dose clomid/FSH stimulation Delayed stimulation IVM Delayed Stimulation Poor responders • • • • • High dose Microdose flare Low dose clomid/FSH stimulation Delayed stimulation IVM IVM stimulation IVM results 2004 Aug to 2007 Jun <38 ≥38 Patients (n) 33 16 Average age 32.6 40.0 Total eggs 420 (12.7 ) 160 (10.0) MTII stage 314 (74.8%) 123( 76.9%) Fertilization rate 254 (80.9%) 107 (87.0%) Pregnancy rate 33.3% 37.5% 84 34 14.3% 17.6% Embryos transferred Implantation rate Modern Trend in ART • Minimize multiple pregnancies • Minimize number of embryos transfer • Minimize patients’ load and stress • Physiological • Psychological • Financial Question • Is it time to revisit the aim and clinical practice of so called Controlled Ovarian Hyperstimulation. Should we be heading towards a modified direction Answer • We should look at the clinical aim of “Preparing Eggs for the treatment of IVF” rather than Ovarian Stimulation Preparation for Ovum Collection • • • • • Natural Cycles Minimal stimulation (clomiphene/FSH) IVM FSH stimulation with agonists FSH stimulation with antagonists Conclusions: 1. It is possible to choose stimulation procotol according to: age Ovarian status Previous history 2. We should aim for minimal stress (in all senses) for the patients provided similar result can be obtained. 3. Individualization of stimulation should be considered for every case. Stimulated ovary Stimulated ovary