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Reproductive Medicine : an update

Limits and Interfaces in Science Humboldt­Kolleg Sao Paulo, Brasil 28.-30. November 2009. Reproductive Medicine : an update. T. Cordes and K. Diedrich Dept. of Obstetrics & Gynecology University of Schleswig-Holstein, Campus Lübeck, Germany. City of Lübeck. City of Lübeck.

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Reproductive Medicine : an update

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  1. Limits and Interfaces in Science Humboldt­Kolleg Sao Paulo, Brasil 28.-30. November 2009 ReproductiveMedicine:an update T. Cordes and K. Diedrich Dept. of Obstetrics & Gynecology University of Schleswig-Holstein, Campus Lübeck, Germany

  2. City of Lübeck

  3. City of Lübeck ... around christmas time

  4. 1960 - ovarian stimulation with clomifene and gonadotrophins - radioimmunoassay 1970 - secretion, synthesis, mechanism of GnRH a. gonadotrophins - in vitro fertilisation 1980 - cryopreservation 1990 - recombinant gonadotrophins - preimplantation genetic diagnosis - intracytoplasmatic sperm injection (ICSI) - GnRH-antagonists and gonadotrophins 2000 - in vitro maturation of oocytes - embryonic stemcells - SET (single embryo transfer) - vitrification Milestones in reproductive medicine

  5. Once upon a time… Birth after reimplantation of a human embryo Steptoe P.C. / Edwards R.G. Lancet 2 (1978): 366 07/78 Louise Brown was born

  6. Number of infertile couples in Germany: approx. 15 - 20% of all couples(1.2 – 1.6 Millions)

  7. Probability of successfull infertility treatmentafter: Dor et al., 1996

  8. Children born after ART until 2006

  9. Ovarian stimulation: GnRH-antagonists and long acting FSH Elective single embryotransfer (eSET) Blastocyst transfer Preimplantation genetic diagnosis and screening In-vitro-maturation Cryopreservation and vitrification New Developments in Reproductive Medicine

  10. 1970 Clomifen hMG 1980 GnRH-agonist / hMG 1990 recFSH GnRH-antagonist / hMG or recFSH 2000 long acting FSH History of ovarian stimulation

  11. endogeneous LH surge (progesterone): 22% (Stanger et al. 1985) Efficiancy of ovarian stimulation with hMG oocyte quality embryo quality pregnancy rate incidence after down regulation: <2%

  12. GnRH-agonist and antagonist protocol LHRH-agonist: daily injection/ depot/ nasal spray OPU 8 d -14 HCG 6 4 Ampoules HMG ET 2 Menses 0 17 16 -16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 day of cycle Cetrorelix 8 d 6 HCG 6 OPU ET 4 Ampoules Gonadotropins 2 Menses 0 17 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 day of cycle „long protocol“ „Lübeck protocol“

  13. Gonadotrophins & GnRH-antagonist

  14. Does the probability of live birth after ovarian stimulation and IVF depend on the type of GnRH-analogue used? A systematic review and meta-analysis G Griesinger, J Collins, B Tarlatzis, P Devroey, K Diedrich, EM Kolibianakis

  15. LIVE BIRTH Odds ratio:0.859 p=0.085 Rate difference 2.7%

  16. Hospital admission due to OHSS RR : 0.47 ~ 2 times less risk to be admitted due to OHSS with GnRH antagonists

  17. Advantages of GnRH-antagonists • fits into the normal cycle • („the patients like it“) • less side effects in comparison to the long protocol: • Ø cysts • Øhormonal withdrawl • less OHSS • simple • no significant difference in the probability of live birth between GnRH-agonists and antagonists

  18. long acting FSH follicle aspirationafter 36h FSH-CTP 10000 IE hCG 1 2 3 4 5 6 7 8 9 10 11 12 13 14 …. GnRH-Antagonist LF 10 mm LF 17mm LF 14 mm

  19. Ovarian stimulation: GnRH-antagonists and long acting FSH Elective single embryotransfer (eSET) Blastocyst transfer Preimplantation genetic diagnosis and screening In-vitro-maturation Cryopreservation and vitrification New Developments in Reproductive Medicine

  20. Children after ART: 1997-2002 DIR 2001

  21. pregnancy related diseases prematurity increase of neonatal morbidity and mortality costs Problems of multiple pregnancies

  22. To avoid multiple pregnancies Improve the pregnancy and life birth rate Solution:Transfer of one selected embryo Aims

  23. Embryo selection > 30% < 5% Implantation

  24. eSET = 40.3% pregnancy rate 1% gemini eDET = 44% pregnancy rate 32% gemini Pregnancy rate after elective single embryo transfer (eSET) and elective double embryo transfer (eDET) Gerris, 2005 ESHRE

  25. Prison sentence up to three years or financial penalty for § 1, Abs. 1, Nr. 3 „a person transfering more than 3 embryos to the womb in the course of one treatment cycle“ § 1, Abs. 1, Nr. 5 „a person fertilizing more oocytes than he or she intends to tranfer in the course of one treatment cycle“

  26. Germany vs. Sweden Andersen et al., 2008

  27. Germany vs. Sweden:Multiple pregnancies after ART DIR 2004; Andersen et al., 2008

  28. Ovarian stimulation: GnRH-antagonists and long acting FSH Elective single embryotransfer (eSET) Blastocyst transfer Preimplantation genetic diagnosis and screening In-vitro-maturation Cryopreservation and vitrification New Developments in Reproductive Medicine

  29. Blastocyst

  30. Blastocyst culture Cochrane , 2007

  31. Preimplantation Genetic Diagnosis Indication: High risk of genetic diseases. Preimplantation Genetic Screening (PGS) Aneuploidie-Screening improves the pregnancy rate and abortion rate especially in older women (??)

  32. PGS: a metaanalysis Mastenbroek et al. 2008, Hum. Reprod. 23

  33. Präimplantationsscreening ASRM Committee Report, 2008 A careful review of the published studies of this technique led the ASRM Practice Committee to conclude thatthe available evidence does not support the use of PGS to improve live-birth ratesin patients with advanced maternal age, previous implantation failure, recurrent pregnancy loss, or to reduce miscarriage rate in patients with recurrent pregnancy loss related to aneuploidy at this time.

  34. Ovarian stimulation: GnRH-antagonists and long acting FSH Elective single embryotransfer (eSET) Blastocyst transfer Preimplantation genetic diagnosis and screening In-vitro-maturation Cryopreservation and vitrification New Developments in Reproductive Medicine

  35. The Lancet 1965 „Oocytes from antral follicles can finalize their meiotic maturation in vitro in 24 – 48 hours“ R.G. Edwards et al. First oocyte maturation in vitro Edwards RG et al. 1965

  36. Early oocyte retrieval from antral follicles before selection and atresia . . . Physiological basics of IVM day 3 day 8 - 12 d>10mm

  37. Development of IVM 1983Veeck First birth after IVM 1991Cha IVM on immature oocyte extracted by using ovarian biopsy during a cesarean section resulted in healthy twins 2000Cha birth of 20 healthy children after IVM 2003Mikkelsen birth of 33 healthy children after IVM today >300 children after IVM

  38. PCOS high responder with a risk for OHSS normo-cyclic patients cryopreservation of oocytes (oncology) low responder implantation failure Therapeutic indications for IVM Mikkelsen et al. 2003, Smitz 2005, von Otte 2005

  39. Estradot 100 Crinone 8% primordial follicle ≥ 12mm and E ≥7mm10.000 IE hCG 36h later aspiration of small antral follicles 4 daysof low dose hMG(„priming“ with 75IE hMG/day) ♂Male: sperms Fertilizationvia ICSI Treatment protocol first Examination: basicultrasound and hormone level Exam. 2,3, … ultrasound and hormone level Embryotransfer2-3 days after ovum aspiration Tag 1 2 3 4 5 6 7 8 9 10 …. IVMoocyte maturation (24 h) embryo culture(2- 3 days) Menses

  40. number of patients 140 Metaphase II 57% 2 pronuclei after in vitro maturation and ICSI 47% pregnancies 30 In vitro maturation of oocytes v. Otte 2007

  41. Ovarian stimulation: GnRH-antagonists and long acting FSH Elective single embryotransfer (eSET) Blastocyst transfer Preimplantation genetic diagnosis and screening In-vitro-maturation Cryopreservation and vitrification New Developments in Reproductive Medicine

  42. slow cooling vitrification Methods of cryopreservation

  43. Vitrification vs slow cooling V I T R I F I C A T I O N 37°C Slow freezing (equilibrated) H2O total dehydratation H2O Room temperature -5 0.3 – 0.5°C/min > 25000°C/min -35 Temp Degrees C weak dehydratation Weak dehydratation -80 -196 Storage Storage Storage 30 Temps (min) 10 20

  44. Vitrification (Rall and Fahy 1985) Slow cooling (Whittingham et al., Science 1972, Willmut et al., Life Science 1972) 2 sec. - 0.3°C/min - 50.000°C/min

  45. In contrast to slow-rate freezing protocols, during vitrification the entire solution remains unchanged and the water does not precipitate, so no ice crystals are formed.

  46. Clin. pregnancies / ETafter cryo transfer(1996-2004) German IVF Index 2004

  47. Lübeck Results (till 01/2007) survival rate pregnancy rate n=155 n=752

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