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Infertility Management in Advanced Age

Bakırköy Acıbadem Hospital. Infertility Management in Advanced Age. Prof Cihat Ünlü. Age Related Predictive Factors in Infertility. Female Partner Age Male Partner Age. Loss of Ovarian Reserve O ocyte S enescence Increased sperm DNA Damage Duration of Infertility

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Infertility Management in Advanced Age

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  1. Bakırköy Acıbadem Hospital Infertility Management in Advanced Age Prof Cihat Ünlü

  2. Age Related Predictive Factors in Infertility Female Partner Age Male Partner Age • Loss of Ovarian Reserve • Oocyte Senescence • Increased sperm DNA Damage • Duration of Infertility • Increase in Other Gynecological İnfertility Factors • Tuboperitoneal Factors and PIDs • Uterine Fibroids, etc. Tatone C, Gynecol Endocrinol. 2008 Vagnini L et al. Reprod Biomed Online. 2007

  3. Fecundability and Age of Female Partner Human Reprod 2004

  4. The Influence of Female Partner Age Previous Pregnancy with ART No Previous Pregnancy Previous Pregnancy without ART Fertil Steril 2003

  5. Loss of Ovarian Reserve • Change of Menstruel Cycles • Endocrine and biochemical profile change D3 • FSH • E2 • Inhibin • Decreased Success Rates Due to... • Decreased oocytes nb • Decreased fertilization rates • Decreased ET rates • Decreased cumulative PRs • Increased Abortion • Increased Aneuploidy Clin Exp Obstet Gynecol. 2004, Minerva Ginecol. 2003

  6. PRs, Live Births, Basal FSH Levels • 3401 IVF / ICSI patients, three cycle group A, FSH <10 IU/ml; group B, 10.1±15 IU/ml group C,15.1±20 IU/ml group D, FSH >20 IU/ml FSH Hum Reprod 2004

  7. Basal FSH and Age group A, FSH <10 IU/ml; group B, 10.1±15 IU/ml group C,15.1±20 IU/ml > 38 age < 38 age ½ > 38 age PRs, Live Births, 2 Pregnancy Loss Hum Reprod 2004

  8. Prediction of Ovarian Response in ART Hum Reprod 2000

  9. Prediction of Ovarian Reserve • Basal FSH, < 12 mIU/ml • Basal E2, < 75 pg/ml • Basal İnhibin > 45 pg/ml • Decrease of Ovarian Volume • Clomiphene Citrate Challenge Test, • GAST • Antral folllicle nb Success in Prediction of Inducible Oocyte nb Prediction of Oocyte Quality Solely by Age Clin Exp Obstet Gynecol. 2004, Minerva Ginecol. 2003

  10. Duration of Infertility Duration of Infertility as age related factor Decreased Success ! > 3 years Fertıl Sterıl 2003

  11. Paternal and Maternal Age Paternal age ≥40 accepted as a key risk factor Fertil Steril 2003

  12. The influence of age on sperm DNA damage 508 men in an unselected group of couples attending infertilityinvestigation and treatment. • DNA fragmentation by (TUNEL) assay;( at least 200 spermatozoa) [DNA fragmentation index (DFI)]. Group I: < or =35 years, Group II: 36-39 years, Group III: > or =40 years. DFI was significantly lower in Group I than in Group II (P = 0.034) or III (P = 0.022). The regression analysis demonstrated a significant increase in sperm DFI with age (P = 0.02). TUNEL assay clearly demonstrates an increase in sperm DNA damage with age. Vagnini L et al. Reprod Biomed Online. 2007

  13. DNA hasarlarının (DF) akridin orange ile gösterilmesi DF + DF - <%56 DF+ p<0.05 Embriyo kalitesi Ünlü C, Aydos K. 2006

  14. % Fertilizasyon DNA hasarlı spermatozoa Ünlü C, Aydos K. 2006

  15. Practical Management of Infertility in Advanced Age

  16. Aims of Management in Infertility • Detection of Infertility Factors • Consideration of the Advantages / Disadvantages of the treatment choices • The Counseling of Infertile Couple • Planning the Treatment • Performing Treatment choices with optimum time intervals

  17. Ethical and Medical Problems in Advanced Aged Couples • What are the age limits for couples (Female and Male Limits)? • Do insurance policies resisting for special age limits in treatment of infertility against the human reproduction rights? • Do couples have rights in selecting the treatment method in advanced age? • No luxury for time loss according to wrong treatment option. • Decreased Ovarian Response • Decreased ART success and increased drop outs. • Increased treatment anxiety (Doctor and Patient) • Should the optimum treatment numbers regaring the methods be different in advanced age?

  18. Infertility Treatment Choicesin Advanced Age • Ovulation Induction • Sperm Insemination Techniques • IUI • ICI • FSP • IVF / ICSI • Advanced Treatment Options

  19. Short GnRH analog protocols Flare-up Protocols Mikrodose GnRH protocols GnRH antagonist protocols Minimal stimülation protocols GnRH Analog Cessations Addition of Cortisol Addition of CC Addition of Aromatase inh. Addition of low dose aspirine Addition of Growth hormone Natural cycle Treatment Choices in OIin Advanced Age

  20. Efficacy of IUI in Advanced Age 4,199 cycles performed in 1,738 infertility patients IUI with OI has virtually no place in their treatment. Dovey S Fertil Steril 2008

  21. IVF/ ICSI and Advanced Age Normo-responders Cumulative PRs Rate of Abortion • IVF-ET > 38 16% 21% < 38 28% 13% • ICSI > 38 9% 26% < 38 27% 14% Poor-responders PRs ≤ 34 yaş 19.5% ≥ 35- < 39 7.2% ≥ 40 yaş 1.5% Clin Exp Obstet Gynecol. 2004, Reprod Biomed Online. 2003

  22. Indications of IVF • Tubal Infertility • Tuboperitoneal Factor • Endometriosis • Unexplained Infertility • Male Factor • Immunological Infertility      • Recurrent IUI Failure • Preimplantation Genetic Diagnose(PGD)

  23. Mild Moderate Tubal Infertility IVF / ET cost effective 4 cycles PR% 70 Proximal Tubal Obst. Distal Tubal Obst Age > 35 Poor Ovarian Reserve Infertilite duration > 3 years Additional Factor Insurance ?? Hydrosalpinx + Reconstructive Surgery Reconstructive Surgery 6-12 months Observation 6-12 months Observation 4-6 cycles OI + IUI 4-6 cycles OI + IUI IVF / ET Curr Opin Obstet Gynecol, 2004

  24. Unexplained Infertility??? • Fecundity rate % 1.3 ! • Spontaneus Pregnancy ????? • Spontaneus Pregnancy • (Timed İntercourse) • 3 years 30-60% • 5 years 50-80% Randolph2000, Godon & Sperof2002, Guzick et al 1998

  25. Unexplained Infertility • < 35 age • < 2 years • Prior Pregnancy Observation 6-12 ay • > 35- 39 age • < 2years CC / HMG + IUI 4 cycles • > 35- 39 age • > 3years IVF / ET 6 cycles • > 40 age • > 3 years • Prior Treatment Guzick 1998, Soules,2000

  26. Influence of Age in Endometriosis

  27. Stage of Endometriosis

  28. Management in Endometriosis Am J Obstet Gynecol 2003 Fertil Steril 2002 Moderate / Severe (Stage III / IV) Mild / Moderate (Stage I / II) Normal tubo-ovarian restoration Suboptimal resection Age >38 Duration of Infertility > 8 years Additional Factor Poor Ovarian Reserve Diagnose > 5 years Age < 38 Duration of Infertility < 8 years Normal Ovarian Reserve Diagnose > 5 years 6 Months Expectant (% 50) Impossible Tubo-ovarian Restoration 4-6 cycles OI + IUI IVF / ET IVF / ET IVF / ET

  29. Male Infertility TMS > 5 x mil TMS 1.5 - 5 x mil TMS < 1.5 x mil 5-14 Normal Morphology < 4 > 14 Male Age < 40 ? Female Age < 35 Infertility duration < 2 years No Additional Factor Male Age > 40 ? Female Age > 35 Infertility duration > 3 years Additional Factor ICSI 4-6 x İUİ 3-4 x IVF4-6 x Oehninger, Ombelet Reprod Bio Med 2003

  30. Male Infertility Epididymal obst. Intratesticular obst. Aquired Congenital Microsurgery MESA PESA TESE TURED Additional Factor + Epididymal obst. Female Age > 35 Duration of Infertility > 15 years Difficulties in surgery Inflamation Vas deferens obs. Ejaculatuar canal obs. MIBPPC, Fertil Steril 2002

  31. Further Treatment Options • Preimplantation Genetic Diagnose • Assisted Embryo Hatching • Enriched Culture Media • Co-Culture Methods (ECC, etc) • Blastocyst Transfer • Cytoplasmic Transfer • Nuclear Transfer • Oocyte Donation • Oocyte Sharing • Sperm Donation

  32. Preimplantation Genetic Diagnose • Maternal Age (> 35) • Recurrent IVF Failure (>3) • Recurrent Pregnancy Loss • Unexplained Infertility • Severe Male Infertility • Y Chromosome Deletions • Translocation Carriers • Abnormal Embryo Morphology

  33. Advanced Age and PGD ? • Mendelien Disease Screening • Increase implantation rates %15.6 % 26.6 • Increase pregnancy rates • Decrease abortion rates % 14 % 4.3 J Ass Reprod Genet 1998 Human Reprod 1999

  34. Aneuploidy Chromosomal abnormality Chromosomal 13, 14, 15, 16, 17, 18, 21, 22, X and Y Down sendrom Turner sendrom Kleinfelter sendrom Structural Abnormality Translocation Invertion Deletion Duplication Y Chromosome deletions Uniparental Disomi (UDP) Genomic Imprinting Mono Genetic Disease X linked Frajil — X  Duchenne/Becker muscular distrophy Hemofili Otosomal dominant Myotonic distrophy Huntington disease Charcot-Marie-Tooth Otosomal Resessive Cystic Fibrosis Talasemi Spinal muscular atrophy Preimplantation Genetic Diagnose

  35. Oocyte Donations Indıcations: 35. • Premature ovarian failure, • Gonadal disgenesis (Turner send., etc), • Bilateral Ooforectomy, • Iatrogenic Ovarian Failure (Chemotherapy or Radiotherapy) • IVF failures withrisk of genetic disorders RCOG Guideline, 2001

  36. Oocyte Donation Success Human Reprod 1999

  37. Oocyte Donation Success Recipient Age and Clinical PRs, Live Births Oocyte Donation and Embryo Quality Fertil Steril 2001

  38. Oocyte Donation Success Endometrial Thickness and Clinical PRs, Live Births Endometrial Pattern and Clinical PRs, Live Births Fertil Steril 2001

  39. Co-culture One factor that may contribute to thepoor successrates inART is the current in-vitro culture conditions !!!! • Only 20-50% of preembryos tothe blastocyst stage. Aim is to transfer Co-culture with somatic cells Growth factor media Activation of Maternally derived genetic information

  40. Co-culture • Co-culture celllines used in human IVF express a number of growthfactors. • Growthrates and morphology have been significantlyimproved for preembryos maintained in co-culture systems. • Preembryo development on somatic cell lines mayenhance implantation and pregnancy rates in human IVF. • It appears that the autocrine and paracrine interactions between the preembryo and its culture environment takes place. Wiemer KE et al. Hum Reprod 1993, Barmat LI et al. Fertil Steril 1997, Magli MC et al. Int J Fertil 1995, Morgan K et al. Hum Reprod 1995,

  41. Mechanism of the Effects of Co-culture • Detoxify the culture medium. • Produce embryotrophic factors. • GM-CSF, • IL-1, • LIF. Jacobs AL, Endocrinology 1993, De Los Santos MJ et al. BiolReprod 1996, Spandorfer SD et al. Am J Reprod Immunol 1998, Spandorfer SD, ASRM AnnualMeeting, 1999, Spandorfer SD, et al. Am J Reprod Immunol 2000,

  42. Coculture Results • Improvement in preembryo grade, • Increase in theaverage number of blastomeres, • Decrease in theaverage percentage of fragments per preembryo • Improvement in implantation and pregnancy rates Jayot S et al. Fertil Steril 1995. Nieto FS et al. J Assist Reprod Genet 1996, Barmat et al. J Ass Reprod Genet, 1999 Barmat et al. Fertil Steril 1998, Spandorfer et al. J Ass Reprod Genet, 2002

  43. Co-culture • Bovine reproductive tract cells, • African green monkey kidney cells (Vero), • Human oviduct cells, • Humangranulosa cells lines, • Human Tubal Epithelialcelllines, • HumanEndometrialcelllines. Menezo Y. et al Biol Reprod 1990, Bongso A et al. Fertil Steril 1992, Wiemer KE et al. Hum Reprod 1993, Sakkas D et al. FertilSteril 1994, Quinn P et al. J Assist Reprod Genet 1996, Barmat et al. J Ass Reprod Genet, 1999 Barmat et al. Fertil Steril 1998, Spandorfer et al. J Ass Reprod Genet, 2002

  44. Somatic Cell Coculture • Xenologous • Heterologous • Autologous Risk of diseasetransmission to the exposed preembryos ! Autologous human endometrial cells coculture Jayot S et al. Fertil Steril 1995 Nieto FS et al. J Assist Reprod Genet 1996,

  45. Endometrial Cell Coculture Results

  46. Time of Endometrial Biopsy (<5 versus >5 days from LH surge)

  47. Endometrial Cell Coculture

  48. Endometrial Cell Coculture Autologous endometrial coculture in patients with IVF failure: outcome of the first 1,030 cases. • Significant improvement in embryo quality with ECC. • Patients with a poor prognosis secondary to prior IVF failures can have a good outcome when utilizing AECC • Improved implantation and pregnancy rates with AECC. J Reprod Med. 2004

  49. Thank You

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