Role of sperm index in embryo quality what to do - 17th iranian congress


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17th International Congress of the Iranian Association for Fertility and Reproductive Medicine
Tehran– March 2011

Sandro C. Esteves, MD, PhD
Spermatozoa are highly specializedcells with the purpose of not onlydelivering competent paternal DNA to the oocyte but also to provide a robust epigenetic contribution to embryogenesis. The identification of sperm fertility markers and the ability to selecthealthy spermatozoa for ART have a dual objective of choosing the best treatment strategy and optimizing ART outcomes. Currently, sperm indexes determination in the clinical setting is generally based on cell morphology and DNA content. Both sperm morphology and DNA integrity results, obtained from raw semen samples, have been shown to be of prognostic value for unassisted and assisted conception and useful in the selection of the best assisted conception modality.
These assays, however,provide an assessment of the distribution of cells in a given ejaculatethat may not be representative of the sperm population used in the ART treatment cycle. In fact, severe teratozoospermia,using Kruger’s strict criteria on pre-ART semen analysis, does notcorrelate to fertilization and embryo formation (including blastocyst development) in ICSI cycles. Nonetheless, if a more holistic approach to sperm morphology is taken, two prognostic groups can still be identified in cases of severeteratozoospermia (<4% normal) because certain morphology patterns and sperm abnormalities are known to affect ICSI outcomes. The first group includes mostly genetically determined sperm pattern defects, such asglobozoospermia, short tail syndrome and small-headed spermatozoa (in most cases combined with very small acrosomes). All of these types represent untreatable conditions that have been associated with abnormal sperm function andpoor ART outcomes. The second group includes unspecifiedor non-genetically determined sperm defects or patternscaused by environmental factors, medication, infection and related infertility conditions, including varicocele. Treatment of these conditions has been shown to optimize sperm morphology indexes with a positive impact on ART outcomes. Although the technician microscopically selects morphologically normal individual sperm during ICSI, form normalcy does not necessarily imply normal DNA content. As such, sperm DNA testing has been advocated to be an independent and reliable marker of fertility potential since sperm chromatin andDNA integrity is essential to ensure that the fertilizing sperm cansupport normal embryonic development of the zygote.At present, conflicting reports exist on the role of sperm DNA fragmentation index for embryo development, and it is apparent that DNA fragmentation does not significantly impair zygote and cleaving embryo morphology because major activation of the embryonic genome only beginafter the 4-cell stage. These observations do no underscore the importance of finding ways to increase sperm DNA integrity, since it has been suggested that DNA fragmentation is associated with late paternal effects that may lead to early miscarriages or diseases in the offspring. The etiology of sperm DNA damage is multi-factorial and may be due to primary (ageing, cryptorchidism, genetic defects, idiopathic) and or secondary (drugs, environmental, tobacco smoking, genital tract inflammation, infection,testicular hyperthermia and varicoceles) factors. Specific or non-specific treatments, including antioxidant supplements, are generally associated with reduced levels of sperm DNA damage and/or improved fertility potential.
Taken in conjunction, it is apparent that there is no unique sperm factor able to predict embryo development, but several candidate biomarkers are involved in this complex process.As a result, a wide variety of techniques have been proposed, including externalization of phosphotidylserine (magnetic-activated cell sorting),cell

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  • Role of sperm index in embryo quality what to do - 17th iranian congress

    1. 1. Sandro Esteves, MD, PhD Director, ANDROFERT Center for Male Reproduction and Infertility Campinas, BRAZIL Esteves, 17 th International Congress of the Iranian Association for Fertility and Reproductive Medicine Tehran– March 2011
    2. 2. Objectives Esteves
    3. 3. Esteves Sperm function The paternal contribution
    4. 4. Oocyte Activating Factor Sofikitis et al ., 1996 Esteves Oocyte activating factor
    5. 5. Centrosome Bornens et al ., 1990 Esteves Microtubule organizing center Formation of an efficient mitotic spindle for syngamy and cleavage
    6. 6. Sperm contribution to the Embryo Summary Esteves
    7. 7. 1) Morphology 2) DNA integrity Esteves <ul><li>Sperm Fertility Markers </li></ul><ul><ul><li>Beyond the routine semen analysis </li></ul></ul>
    8. 8. Strict Sperm Morphology and Embryo Quality French DM et al. Severe teratozoospermia and ICSI outcomes. Fertil Steril 93:1097, 2010 P>0.05 Esteves 0% 1% 2% 3% 4% 5-7% >7% N transfers 138 167 137 129 113 236 154 Maternal age (yrs.) 32.3 32.7 32.4 32.5 32.0 32.3 32.8 N oocytes injected (mean) 10.2 11.0 11.0 10.6 10.1 10.3 9.3 FR (%) 75 75 77 77 74 76 77 ET (n) 2.3 2.4 2.4 2.5 2.3 2.3 2.4 Blastulation (%) 50 43 44 47 41 42 45 % Top quality blastocysts 37 29 26 31 27 28 29 LBR (%) 56 54 47 44 52 49 52
    9. 9. Kruger Sperm Morphology and Embryo Quality Esteves
    10. 10. Case 1
    11. 11. Case 2
    12. 12. Menkveld R et al . Significance of sperm morphology. AJA (2011); 13:59-68 Tesarik J et al. Paternal effect on embryo development. Hum Reprod (2004); 19: 611-15 Sperm Defects and Embryo Quality Esteves Mid-piece defect Acrossomeless Double tail Tapered Cytoplasmic droplet Genetically determined Stress-induced (Elevated OS)
    13. 13. Sperm DNA Integrity Testing Esteves
    14. 14. Sperm DNA Integrity Testing & ART OR 0.07 (0.01-0.48) Esteves Adapted from Bungum et al., Hum Reprod 2007 Adapted from Bungum et al., Hum Reprod 2007 * <.05 *
    15. 15. Sperm DFI and Embryo Quality Esteves Reference Assay N ART Findings Larson KL et al (2000) SCSA 24 IVF; ICSI No impact (D3) Gandini et al (2004) SCSA 34 IVF; ICSI No impact (D3) Payne JF et al (2006) SCSA 100 IVF; ICSI No impact (D3) Sun JG et al (1997) TUNEL 236 IVF ↓ Cleavage (D3) Morris ID et al (2002) Comet 60 ICSI ↓ Cleavage; Morphology (D3) Virro MR et al (2004) SCSA 249 IVF; ICSI ↓ Blastulation rate Nasr-Esfahani et al. (2005) Comet, CMA 3 28 ICSI ↓ Blastocyst development
    16. 16. Sperm DFI, Pregnancy Loss & Baby Health Esteves
    17. 17. Zeta method Modified HOST IMSI PICSI Sperm head birefringence Laser-assisted sperm selection Esteves Magnetic- activated cell sorting Improving Sperm Health What to do ?
    18. 18. <ul><li>Pregnancy rate </li></ul><ul><ul><li>66% vs 30% (n=50) Bartoov et al. 2003 </li></ul></ul><ul><ul><li>48% vs 20% (n=80) Bartoov et al. 2006 </li></ul></ul><ul><ul><li>39% vs 26% (P=.004; RCT; N=416); Antinori et al., 2008 </li></ul></ul>Esteves <ul><li>Embryo Quality </li></ul><ul><li>No difference! </li></ul><ul><ul><li>Mauri et al. (N=30), 2010 </li></ul></ul>400X 8,450X Parameters (%) ICSI IMSI Fertilization rate 70.9 70.4 Early embryo cleavage rate 66.9 60.4 Cleavage rate 99.2 99.1 Proportion of top quality embryos 57.8 52.2
    19. 19. Watanabe S et al., J Mamm Ova Res 2008; 25:259-65 Tanaka A et al, ASRM 2009 (P-272) Esteves
    20. 20. Hyaluronic Acid Sperm Selection-ICSI and Embryo Quality <ul><li>HA binding-sperm: </li></ul><ul><ul><li>Mature sperm able to bind HA receptors </li></ul></ul><ul><ul><li>Low DNA fragmentation </li></ul></ul><ul><ul><li>Decreased chromosomal aneuploidy </li></ul></ul><ul><ul><li>Decreased protamine deficiency </li></ul></ul>Esteves Reference Design Sample Size Embryo Quality Findings Parmegiani et al. (2010) RCT 306 35.8% vs 24.1% (P=.046) No impact FR, IR, CPR Nasr-Esfahani et al. (2008) RCT 100 96.4% vs 97.6% (NS) ↑ FR No impact TQE, IR, CPR
    21. 21. Life-style modifications Antioxidant Treatment Varicocele Repair Leukocyte Reduction Esteves Improving Sperm Health What to do ?
    22. 22. Esteves
    23. 23. Microsurgical varicocele repair prior to ICSI (N=80) ICSI in the presence of varicocele (N=162) Clinical Outcome of Intracytoplasmic Sperm Injection in Infertile Men With Treated and Untreated Clinical Varicocele SC Esteves, FV Oliveira, RP Bertolla ANDROFERT, Center for Male Reproduction, Campinas, BRAZIL and Division of Urology, São Paulo Federal University, São Paulo, BRAZIL. The Journal of Urology Vol. 184,1442-6, October 2010 Esteves P<0.01
    24. 24. Esteves SC, Oliveira FV, Bertolla RP. Clinical Outcome of ICSI in Infertile Men with Treated and Untreated Clinical Varicocele. J Urol 2010;184:1442-1446 Esteves *P<0.05 Miscarriage (%) Odds ratio 1.87 0.43 95% CI 1.08 - 3.25 0.22 – 0.84 P-value 0.03 0.01
    25. 25. Pasqualotto et al., Fertil Steril 2000
    26. 26. Antioxidant Treatment Cochrane Review 2011 Outcome N studies N participants Effect size (OR; 95% CI) Live birth 3 214 4.85 [1.92, 12.24] Pregnancy rate 15 964 4.18 [2.65, 6.59] DNA fragmentation 1 64 -13.80 [-17.50, -10.10] Miscarriage, sperm count, sperm motility 6-16 242-700 No effect Adverse effects 6 426 No effect Showell MG, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD007411. DOI: 10.1002/14651858.CD007411.pub2.
    27. 27. <ul><li>Which patients? </li></ul><ul><ul><li>How? </li></ul></ul><ul><ul><li>Vitamic C 500mg </li></ul></ul><ul><ul><li>Vitamin E 400 UI </li></ul></ul><ul><ul><li>Folic acid 2 mg </li></ul></ul><ul><ul><li>Zinc 25 mg </li></ul></ul><ul><ul><li>Selenium 26 mcg </li></ul></ul><ul><li>How long? </li></ul>Esteves Misell LM et al., J Urol 2006; 175: 242.
    28. 28. Henkel R et al, AJA 2007; Alvarez et al. Fertil Steril 2002 Endtz Test
    29. 30. Caffeine Smoking Alcohol Psychological Stress Obesity
    30. 31. Klonoff-Cohen H. Human Reproduction Update, Vol.11, No.2 pp. 180–204, 2005
    31. 32. Esteves <ul><li>Current Perspectives </li></ul><ul><ul><li>What is coming soon? </li></ul></ul><ul><ul><li>Genomics </li></ul></ul><ul><ul><li>Transcriptomics </li></ul></ul><ul><ul><li>Proteomics </li></ul></ul><ul><ul><li>Metabolomics </li></ul></ul>‘ Omics Revolution
    32. 33. Esteves Varicocele Infection Lifestyle habits ICSI w/ejaculated and testicular sperm ICSI w/ejaculated sperm
    33. 34. Key Messages Esteves