Presentation is loading. Please wait.

Presentation is loading. Please wait.

Individualization of Cycle Control Dr. Milton Leong MDCM DSc (McGill) Director, IVF Center, HKSH Specialist in Reproductive Medicine Adjunct Professor,

Similar presentations


Presentation on theme: "Individualization of Cycle Control Dr. Milton Leong MDCM DSc (McGill) Director, IVF Center, HKSH Specialist in Reproductive Medicine Adjunct Professor,"— Presentation transcript:

1 Individualization of Cycle Control Dr. Milton Leong MDCM DSc (McGill) Director, IVF Center, HKSH Specialist in Reproductive Medicine Adjunct Professor, OBS-GYN, McGill University

2 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

3 Preparation for Ovum Collection Natural Cycles Minimal stimulation (clomiphene/FSH) IVM FSH stimulation with agonists FSH stimulation with antagonists

4 Ovulation Stimulation WHAT GOES AROUND COMES AROUND *American idiom

5 Stimulated ovary

6 Adapted from: Lunenfeld. Reprod Biomed Online 2002;4: Horse PMSG Pig FSH Pituitary FSH u-hMG u-FSH u-FSH r-hFSH (HP) r-hFSH FbM Local reactions Potential side-effects Consistency Quality AntibodiesLocal, systemic reactions Creutzfeldt– Jacob disease Technology and product development timeline: gonadotrophins

7 5-20% All cycles treated in early 1980’s Premature LH surge Poor quality No fertilization or very poor pregnancy rate Cancel egg retrieval 5-20%

8 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

9 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

10 Porter et al., 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 Results of first application of GnRH-agonists in the long protocol

11 OVARIAN STIMULATION FSH with agonist down regulation FSH with antagonists Low dose clomid/FSH stimulation Delayed stimulation IVM Natural cycles

12 Modifications of natural GnRH to have GnRH agonistic properties pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH 2 activation of the GnRH receptor regulation of GnRH receptor affinity regulation of biologic activity Structure of GnRH agonists

13 LH + FSH post-receptor-cascade GnRH - receptor GnRH GnRH - agonist Down regulation Action of GnRH agonists Pituitary suppression Flare up effect

14 Schematic representation of different protocols using GnRH agonists in combination with gonadotrophins for ovarian stimulation in IVF

15 22 nd day of previous cycle 14 days 1 st day of gonado- tropins gonadotropin administration in an individualized dosage ovulation induction oocyte pick up embryo transfer luteal phase support start of GnRH agonist The long luteal protocol

16 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

17 DecaLong LucLong Bus <40 Number of OPU Number of Eggs Retrieved Number of MTII647, 73%642, 73%552, 76% Number of MTI136, 15%44, 5%101, 14% Fertilization Rate74%76%71% Mean # of Embryos Transferred per ET Pregnancy Rate per ET51%49%44% Implantation Rate20%22%18% Average Age Agonist Studies

18 Total< 40≥ 40 # of patients9076 (32.9)14(40.8) # of pregnancy42402 Pregnancy % # of twins+10 0 # of babies43421 Miscarriage rate16%50% Decapeptyl Down Regulation

19 # of eggs831MTII 539 (67%) MTI 139 (16.7%) # of eggs ICSI551 # of fertilized427Fert. % 76.4 # of E.T.244Mean transferred 2.7 # of preg. (F.H.)46Implantation rate 21% Decapeptyl Down Regulation Laboratory Data

20 Down Regulation

21 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.

22 to achieve antagonistic properties of natural GnRH more modifications than only in position 6 and 10 are necessary pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH 2 activation of the GnRH receptor regulation of GnRH receptor affinity regulation of biologic activity Structure of GnRH antagonists

23 LH + FSH post-receptor-cascade GnRH - receptor GnRH GnRH - antagonist pituitary suppression Action of GnRH antagonists

24 Ganirelix Fully effective within 4 hours, with a half-life of about 13 hours Cetrorelix Fully effective within 8 hours, with a half-life of about 36 hours R.E. Felberbaum and K. Diedrich, Characteristics of GnRH antag

25 1 st day of gonado- tropins gonadotropin administration in an individualized dosage ovulation induction oocyte pick up embryo transfer luteal phase support 1 st day of menstruation Cetrotide ® 0.25 mg administration daily s.c. starting on day 6 of stimulation The Cetrotide® 0.25 mg multiple dose protocol

26 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

27 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

28 Cetrorelix 0.125mg Flexible Dose Trial Selection Criteria: 1. Previous over-suppression with agonist 2. Previous poor response 3. Previous LH surge if no agonist

29 Mean = 21.8 (range 19-30) BMI Distribution

30 Mean = 2.2 days (range 1-3) # Days Cetrorelix Used

31 Range mIU/ml Pre Day 1 post Day HCG LH and Cetrorelix 0.125mg/day

32 0.125 mg/day0.25 mg/dayP Cycles Average age37.1± ±4.2NS Days of stimulation9.3±1.79.4±1.8NS Total dose of FSH used (amp) 31.4± ± E2 on HCG day (pg/ml)1943± ±1376.0NS LH on HCG day (IU/L)3.5±3.92.1± Oocytes collected1160 (9.6)3198 (9.7)NS MTII902 (77.75%)2503 (78.26)NS Fertilized oocytes (fertilization rate) 770 (85.4%)2085 (83.3%)NS Embryos transferred2.8±0.82.9±0.8NS Pregnancy rate/ET50/121 (41.3%)106/331 (32.0%)NS (P=0.066) Implantation rate17.3%13.4%NS (P=0.081) Cetrotide mg vs 0.25 mg, 2004 – Sep 2006

33 0.125 mg/day0.25 mg/dayP Cycles86215 Average age35.1± ±2.9NS Days of stimulation9.4±1.79.3±1.8NS Total dose of FSH used (amp) 29.6± ± E2 on HCG day (pg/ml)2081.5± ±1300.2NS LH on HCG day (IU/L)3.7±4.42.1± Oocytes collected941 (10.9)2240 (10.4)NS MTII732 (77.78%)1742 (77.76)NS Fertilized oocytes (fertilization rate) 623 (85.1%)1448 (83.1%)NS Embryos transferred2.8±0.62.8±0.7NS Pregnancy rate/ET43/86 (50.0%)84/215 (39.1%)NS (P=0.083) Implantation rate21.8%17.4%NS (P=0.144) Cetrotide mg vs 0.25 mg, 2004 – Sep 2006 (age <40)

34 0.125 mg/day0.25 mg/dayP Cycles35116 Average age41.6± ±2.3NS Days of stimulation9.1±1.89.4±1.9NS Total dose of FSH used (amp) 36.0± ±17.7NS E2 on HCG day (pg/ml)1602.2± ±1517.8NS LH on HCG day (IU/L)3.0±2.42.2±2.1NS Oocytes collected219 (6.26)958 (8.25)NS MTII170 (77.6%)761 (79.4%)NS Fertilized oocytes (fertilization rate) 147 (86.5%)637 (83.7%)NS Embryos transferred2.9±1.13.0±1.0NS Pregnancy rate/ET7/35 (20.0%)22/116 (19.0%)NS Implantation rate6.9%6.6%NS Cetrotide mg vs 0.25 mg, 2004 – Sep 2006 (age ≥40)

35 Antagonist vs Agonists CetAgonist <40≥40<40≥40 Number of OPU Number of Eggs Retrieved Number of MTII2984(75%)1055(76%)1575(74%)152(76%) Number of MTI526 (13%)160 (12%)205 (10%)25 (13%) Number of ICSI’d Number of 2PN Fertilization Rate76%77%75%73% Total # of Embryos Transferred Mean # of Embryos Transferred per ET Number of Pregnancy Pregnancy Rate per ET39%14%48%22% Implantation Rate17%5%20%10% Average Age

36 AntagonistsAgonists Immediate onset of actions (shortens treatment durations) Prevents hormonal withdrawal symptoms No recovery time of the pituitary long pre-treatment Hormonal (estrogen) withdrawal symptoms through desensitization of pituitary Recovery of the pituitary gonadotrophin secretion, after stopping the treatment takes about 2 weeks. Comparison: Mode of Actions

37 Multiple dose protocol –rate of OHSS: 6.5% vs. 1.1% (agonist vs. antagonist protocol) –RR 6.2, 95% CI: , p = 0.03 Single dose protocol –rate of OHSS: 11.1% vs. 3.5% (agonist vs. antagonist protocol) 95% CI: to 3.2 –patients requiring hospitalisation: 5.6% vs. 1.8% –(agonist vs. antagonist protocol) 95% CI: to 4.1 With both Cetrotide® protocols a clear reduction of OHSS was achieved Reduction of OHSS using Cetrotide®

38 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

39 Ovum Preparation for IVF FSH/GnRH Down Regulation FSH/GnRH Antagonists Clomid, Clomid/FSH Minimal Stimulation IVM Natural Cycles

40 Problems with Ovarian Stimulation Drug Costs Side effects: immediate and delayed Future long term risks Not “User Friendly”

41 Problems with Ovarian Stimulation Waste of Human Resources Excess eggs ? how to deal with Excess embryos - even worse Multiple pregnancies and their associated complications

42 Individualized stimulation

43 Individualized Stimulation

44 Individualizing Stimulation

45 Individualized Stimulation

46 Over responders Risk of OHSS Treatment options a)Cancel cycle b)Coasting c)No embryo transfer d)Convert to IVM

47 Individualizing protocols For over responders For low responders

48 Over responders Prolonged Coasting Aim: To prevent hyperstimulation Practice: Coast till E2 ≤ 3000 pg/mL Sher, 1995Start when 30% follices > 15 mm Nilsson, 1999When 3 follicles > 17mm

49 IVM stimulation

50 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)

51 Poor responders High dose Microdose flare Low dose clomid/FSH stimulation Delayed stimulation IVM

52 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

53 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

54 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

55 Poor responders High dose Microdose flare Low dose clomid/FSH stimulation Delayed stimulation IVM

56 Minimal stimulation

57 Poor responders High dose Microdose flare Low dose clomid/FSH stimulation Delayed stimulation IVM

58 Delayed Stimulation

59 Poor responders High dose Microdose flare Low dose clomid/FSH stimulation Delayed stimulation IVM

60 IVM stimulation

61 IVM results 2004 Aug to 2007 Jun <38≥38 Patients (n) Average age Total eggs420 (12.7 )160 (10.0) MTII stage314 (74.8%)123( 76.9%) Fertilization rate254 (80.9%)107 (87.0%) Pregnancy rate33.3%37.5% Embryos transferred 8434 Implantation rate 14.3%14.3%17.6%

62 Modern Trend in ART Minimize multiple pregnancies Minimize number of embryos transfer Minimize patients’ load and stress Physiological Psychological Financial

63 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

64 Answer We should look at the clinical aim of “Preparing Eggs for the treatment of IVF” rather than Ovarian Stimulation

65 Preparation for Ovum Collection Natural Cycles Minimal stimulation (clomiphene/FSH) IVM FSH stimulation with agonists FSH stimulation with antagonists

66 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.

67 Stimulated ovary

68


Download ppt "Individualization of Cycle Control Dr. Milton Leong MDCM DSc (McGill) Director, IVF Center, HKSH Specialist in Reproductive Medicine Adjunct Professor,"

Similar presentations


Ads by Google