IVF Treatments - An Overview : NEWLIFE INDIA


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IVF Treatments - An Overview : NEWLIFE INDIA

  1. 1. Genomics of oocyte and embryo-endometrium interaction at implantation ANDRES SALUMETS Competence Centre on Reproductive Medicine and Biology; Women’s Clinic and Institute of Bio- and Translational Medicine, University of Tartu, ESTONIA November / 2013 1
  2. 2. Andres Salumets – Short CV • 1993 - Graduated from University of Tartu as biochemist • 2003 - Doctoral degree from University of Helsinki Väestöliitto Helsingin Lapsettomuusklinikka, supervised by prof. T. Tuuri and prof. AM Suikkari • 2010 - ... Professor of reproductive medicine at Women’s Clinic and Institute of Bio- and Translational Medicine, University of Tartu • 2010 - ... Head of Competence Centre on Reproductive Medicine and Biology (CCRMB) • 2010 - ... President of Baltic Fertility Society • 2013 - ... Member of Executive Committee of ESHRE • Consultant to IVF clinics in Tartu, Tallinn, Tbilisi and Delhi 2
  4. 4. Karl Ernst von Baer (1792-1876) 1826 4
  5. 5. Humans are relatively infertile species o The chance for pregnancy per menstrual cycle is 1:3 o The cumulative pregnancy rate: 3 months - 60% 6 months - 75% 12 months - 85% 24 months - 95% Infertile couples o Average time to pregnancy 3-4 months o Infertility exists in 10% of couples o In vitro fertilization (IVF) is actively used in infertility treatment 5
  6. 6. The Nobel Prize in Physiology or Medicine 2010 Robert G. Edwards 6
  7. 7. Major shortcomings of IVF • IVF implantation and pregnancy results have remained almost unchanged for 30 years. Clinical pregnancy rate of ONLY 25-30%. • The selection of the best embryos is limited – no clear criteria to select the best embryos for transfer. Limited use of single embryo transfers. • Too many multiple pregnancies, 25-30%. • A few possibilities to help couples with recurrent IVF failure. • Limited possibilities to analyse and modulate the endometrial quality (receptivity). • Poor responders and limited amount of oocytes. How to coupe with the higher age of IVF patients? • IVF complications, like ovarian hyperstimulation syndrome. • Limited sources of donor oocytes and embryos. • Too expensive. 7
  8. 8. IVF is inefficient No. 1200 1000 120,0 100,0 100,0 80,0 60,0 60,0 700 200 40 30 % 80,0 40,0 15,0 20,0 3,0 2,5 0,0 Oocytes Zygotes Embryos with good quality Embryos Embryos replaced implanted Children CA 100 IVF CYCLES 8
  9. 9. Recent achievements • Human Genome Project – HGP, 2000 y – 46 chromosomes, XX and XY – ca 30 000 genes – 10 million single nucleotide polymorphisms (SNPs) – CNVs – DNA copy number variations (12% of our genome) – Gene and chromosomal mutations Female and male fertility and infertility phenotypes 9
  10. 10. Recent achievements – useful for IVF High-throughput OMICs analysing platforms for genetics, epigenetics, transcriptomics, proteomics and metabolomics METABOLOMICS PROTEOMICS TRANSCIPTOMICS Gene expression RNA splicing GENETICS Genes, gene variations DNA modifications 10
  11. 11. OMICS in reproductive medicine Polar body biopsy and genetic analysis – oocyte chromosomal aberrations. Preimplantation genetic diagnosis Gene variations related to the ovarian reserve and stimulation outcome Gene expression analysis of sperm cells Gene expression of cumulus cells and proteome analysis of follicular fluid samples Proteome and metabolome analysis of embryo’s culture media Biopsy and analysis of embryo cells for chromosomal aberrations and gene expression pattern 11
  12. 12. Menopausal age ... ... links to DNA repair and aging pathways • Genome-wide association study (GWAS) of women of European ancestry, with 38,968 women in the discovery stage, and 14,435 women in the replication stage • Gene donors from - EGCUT (Estonian Genome Center of University of Tartu) • In this large 2-stage GWAS analysis we confirmed 4 previously identified menopause loci and identified and replicated 13 novel loci associated with p<5e-08 age age at natural menopause OVARIAN AGING = SOMATIC AGING Stolk et al, Nature Genetics, 2012 12
  13. 13. Genes and ovarian stimulation in IVF CUMULATED GENETIC VARIATIONS >> IMPAIRED IVF STIMULATION OUTCOME >> EARLY MENOPAUSE • Predicting fertility potential, infertility treatment outcome and the duration of the reproductive period • Fertility prediction testing (ultrasound, hormones and genetic predisposition) – FERTILITY PRESERVATION AND OOCYTE FREEZING 13 13
  14. 14. Oocytes in ovaries ... IVF and fertility & menopause Oocyte stem cells in ovaries – renewal of oocytes? Genetic variations leading to more oocytes in IVF. Genetic testing of IVF patients and personalised stimulation protocols Genetic variations DISCOVERED leading to earlier menopause and accelerated follicular death (earlier age-related infertility) GENE TESTING and IMPROVED IVF OUTCOME Better drugs for IVF hormonal stimulation (more oocytes from poor responders) Drugs postponing the menopause and prolonging the reproductive lifespan Oocyte freezing and biobanking 14
  15. 15. Chromosomal aberrations Stage of conception and pregnancy 0 (weeks) 6-8 20 40 Sperm cells - 1-2% Oocytes - ca 20% (POSITIVE RELATIONSHIP WITH WOMAN’S AGE!) Preimplantation stage embryos - 20-50% Spontaneous abortions (6-20) - 35% DOWN SYNDROME TRISOMY 21 Stillbirths (20-40) - 4% Live births - 0,3% Woman’s age ↑ More chromosomal aberrations in oocytes ↑ Fewer embryo implantations and pregnancies ↓ More spontaneous abortions ↑ 15
  16. 16. Genomic analysis in IVF • Polar body and embryo diagnostics FISH – limited number of chromosomes • Array and sequencing based technologies - Analysis of all chromosomes and gene transcripts from single cell! • 90% of the embryos are chromosomally abnormal (polar body vs embryo diagnostics) 16
  17. 17. EMBRYO SELECTION and -OMICS Genomics Chromosomes SNPs and mutations Transcriptomics Single mRNAs mRNA arrays Proteomics Immuno-techniques Microscopics Oocytes Embryos Mass spectrometry, MS Metabolomics HPLC MS and spectroscopy 17
  18. 18. Ultra-sensitive sensors for embryo selection SENSOR OVERVIEW Sensor overview HLA-G and HCG HLA-G “sandwich” TIRF measurement Image 18
  19. 19. The window of implantation (WOI) ES MS LS WOI  20.-24. cycle day  6-8 days after ovulation  48 hours PINOPODES ES, no TR 1 pinopodes Altmäe et al, Reprod Sci, 2011 MS, fully developed pinopodes LS, no pinopodes Inf, few pinopodes 19
  20. 20. Fertile women vs women with unexplained infertility Abnormalities in gene expression pathways GENE EXPRESSION HISTOLOGY Altmäe et al., MHR, 2010 20 20
  21. 21. ENDOMETRIAL RECEPTIVITY MARKERS  We identified a number of genes in the embryo-endometrial interactions that are known to be involved in the implantation process, like LEP, LEPR, VCAN, TGFB1, laminins, collagens and fibulins  In addition, several new molecules involved in the interactions were identified, like APP, BMP2, DSC2, PDGFRA, ADAMST1 and others 21 Altmäe et al., 2012, Mol Endocrinology
  22. 22. Individualised day for embryo transfer DAYS D1 D2 D3 D4 D5 Women 1 Women 2 Women 3 Endometrial biopsy and gene expression analysis Women 1 Women 2 Women 3 Array analysis Selection of the BEST day for (frozen) embryo transfer! 22
  23. 23. FUTURE VIEW WITHOUT LIMITATIONS In vitro produced oocyte! Granulosa cells Genetic analysis of oocytes, polar bodies and granulosa cells Oocytes Sertoli cells Oocyte freezing and banking IVF DIFFERENTIATION OF: • Embryonal stem cells • Induced pluripotent stem cells, iPS cells Endometrial cell transplantation and improved implantation Spermatogonia and sperm cells 23 In vitro produced sperms!
  24. 24. Thank you for the attention Andres.Salumets@ccrmb.ee