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Individualization of Cycle Control

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

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Individualization of Cycle Control

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  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. 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 The first IVF Baby

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

  4. WHAT GOES AROUND COMES AROUND *American idiom Ovulation Stimulation

  5. Stimulated ovary

  6. Technology and product development timeline: gonadotrophins r-hFSH FbM Horse PMSG Pig FSH Pituitary FSH u-hMG u-FSH u-FSH r-hFSH (HP) 1930 1940 1950 1960 1980 1990 1995 2003 Consistency Quality Local reactions Potential side-effects Creutzfeldt–Jacobdisease Antibodies Local, systemicreactions Adapted from: Lunenfeld. Reprod Biomed Online 2002;4:11

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

  8. GnRHa Long Protocol vs No Suppressionmeta-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 Suppressionmeta-analysis GIFT cases Odds ratios for GIFT clinical pregnancy after GnRH-a versus clomiphene/FSH/hMG ovulation induction protocols

  10. 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 Results of first application of GnRH-agonists in the long protocol Porter et al., 1984

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

  12. 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 regulation of GnRH receptor affinity regulation of biologic activity activation of the GnRH receptor Structure of GnRH agonists

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

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

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

  16. Our contribution to 1. low dose short term agonist downregulation using decapeptyl 2. flexible low dose antagonist Aims: - to simplify treatment - to minimize drug usage Individualizing protocols

  17. Agonist Studies2000 - 2001

  18. Decapeptyl Down Regulation2000-2002

  19. Decapeptyl Down Regulation 2000-2003Laboratory Data

  20. Down Regulation

  21. 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. GnRH agonists

  22. 1 2 3 4 5 6 7 8 9 10 pyro (Glu) – His – Trp – Ser – Tyr – Gly – Leu – Arg – Pro – Gly – NH2 regulation of GnRH receptor affinity regulation of biologic activity activation of the GnRH receptor Structure of GnRH antagonists to achieve antagonistic properties of natural GnRH more modifications than only in position 6 and 10 are necessary

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

  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 Characteristics of GnRH antag R.E. Felberbaum and K. Diedrich, 1999.

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

  26. 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

  27. 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 Possibilities to individualize the multiple dose protocol

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

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

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

  31. LH and Cetrorelix 0.125mg/day • Range mIU/ml • Pre 1.2 - 7.8 • Day 1 post 0.9 - 4.9 • Day HCG 1.8 - 6

  32. Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006

  33. Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006(age <40)

  34. Cetrotide 0.125 mg vs 0.25 mg, 2004 – Sep 2006 (age ≥40)

  35. Antagonist vs Agonists

  36. 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: 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 Reduction of OHSS using Cetrotide®

  38. 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 The GnRH Antagonists

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

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

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

  42. Individualized stimulation

  43. Individualized Stimulation

  44. Individualizing Stimulation

  45. Individualized Stimulation

  46. Risk of OHSS Treatment options Cancel cycle Coasting No embryo transfer Convert to IVM Over responders

  47. For over responders For low responders Individualizing protocols

  48. 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 Over responders

  49. IVM stimulation

  50. 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

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