Management of Male Infertility - What the future holds
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Management of Male Infertility - What the future holds
- 1. Reproductive Andrology Surgery Workshop II Reproductive Medicine Unit - Jahra Hospital - Kuwait 2014 Management of Male Infertility What the future holds Sandro Esteves, MD., PhD. Medical & Scientific Director, ANDROFERT Campinas, Brazil
- 2. Learning objectives At the completion of this presentation, participants will have an overview of: • Sperm biomarkers as diagnostic and treatment tools • Prospects of male fertility preservation • Stem cells as new agents for the treatment of male infertility ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2014 December
- 4. Irvin S, et al 1996, Auger J et al, 1995, Irvine DS 1994, Jørgensen N et al 2001, Jørgensen N et al 2002, Swan SH 2003, Feki NC et al, 2009 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 5 2014 December
- 5. Male reproductive relatively simple anatomy hides an overwhelmingly complex system ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 6 2014 December
- 6. Spermatogenesis Process ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 7 2014 December
- 7. Genetic and epigenetic-regulated process ~2,000 genes, but only 30 in the Y chromosome Hamada et al 2012 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 8 2014 December
- 8. Extremely specialized cell type ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 9 2014 December
- 9. Unexplained infertility affects up to 40% of infertile men 1 in 100 men have no sperm in ejaculate (azoospermia) Up to 50% aspermatogenic (absolute sterility) ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 10 2014 December
- 10. Limitations of current management Conventional semen analysis Conventional surgeries Empirical medical treatments ART overuse ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 11 2014 December
- 11. Recent Advancements Sperm Function Testing Microsurgery Genetic diagnosis ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 12 2014 December YCMD molec ular diagno sis by PCR
- 13. The Era of Biomarkers Genomics Transcriptomics Proteomics Metabolomics ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 14 2014 December
- 14. Researchers first to determine entire genetic sequence of individual sperm We can look at a particular individual, make some calls about what they would likely contribute genetically to an embryo and perhaps even diagnose or detect potential problems, and identify healthy sperm for use in IVF ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 15 2014 December
- 15. DNA Micro-array Technology Normalcy of Sperm Chromatin Content • Glass or silicon slides where thousands of features are arrayed • Gene expression is measured hybridization process • Microarrays are read using laser-based fluorescence scanners • Determine which genes are active and at what levels • Compare with controls, etc. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 16 2014 December
- 16. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 17 2014 December
- 17. Potential Clinical Applications of Sperm Molecular Genetic Fingerprinting • Infertility diagnosis • Assessment of treatment outcome (medical, surgical) • ART outcome (IUI, IVF, ICSI) • Sperm selection techniques ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 18 2014 December
- 18. ANDROFERT androfert.com.br Seminal Fluid Molecular Genetic ANDROFERT Fingerprinting ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 19 2014 December
- 19. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 20 2014 December
- 20. Proteins are also critical to understanding disease ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 21 2014 December
- 21. Proteomics ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 22 2014 December Mass Spectroscopy Raman Spectroscopy Nuclear Magnetic Resonance
- 22. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 23 2014 December
- 23. Sperm & Seminal Plasma Proteomic Profiles ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 24 2014 December
- 24. Sperm Proteomics
- 25. Change in proteomic profiling in seminal ANDROFERT androfert.com.br plasma of adult men before and after ANDROFERT varicocelectomy ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 26 2014 December Camargo M et al. Hum. Reprod. 2013;28:33-46
- 27. Sperm, spermatids Embryos Oocytes Ovarian tissue ?Male germ cells ?Testicular tissue ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 28 2014 December
- 28. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 29 2014 December
- 29. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 30 2014 December
- 30. ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 31 2014 December
- 31. Spermatogonial stem cell preservation and transplantation • Boys facing gonadotropic treatment • Klinefelter syndrome patients Cryopreservation before SSC loss • Extraction: testicular biopsy • Freezing : slow-freezing and storage of testicular tissue or cell suspension in LN • Cryoprotectant: DMSO • Grafting: ectopic or homotopic (mouse) • When to graft: unknown • Fertilizing capacity in humans: unknown ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 32 2014 December
- 33. Nonobstructive azoospermia irreversible condition Congenital Testicular dysgenesis/cryptorchidism Genetic abnormalities (Klinefelter syndrome, Yq microdeletions, etc.) Acquired Testicular torsion; Trauma Post-inflammatory (eg. Mumps orchitis) Exogenous factors (eg. Cytotoxic drugs, irradiation) Testicular cancer Systemic diseases (eg. Liver cirrhosis, renal failure) Idiopathic (Unknown etiology) Esteves et al. Clinics 2011; 66: 691-700 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 34 2014 December
- 34. Current method for identification of sperm production sites in nonobstructive azoospermia Esteves et al Int Braz J Urol 2013; 37: 570-83; Deruyver et al Andrology 2014; 2: 20-4 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 35 2014 December
- 35. Morphometric Evaluation of Seminiferous Tubules Median 25%-75% 5%-95% Raw Data yes No Presence of Sperm 420 400 380 360 340 320 300 280 260 240 220 200 180 160 Max. Tubule Diameter Verza Jr S, Esteves SC. Fertil Steril 2012; 98: S242 N=54; Tubule Diameter: KW-H (1;54) = 25.2; P<0.001 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 36 2014 December
- 36. Novel methods for identification of sperm production sites in men with nonobstructive azoospermia Multi-photon microscopy (ex vivo; human model) Confocal fluorescence microscopy (in vivo; murine model) Full-field optical coherence tomography (ex vivo; rat model) Najari et al, J Urol 2012; Smith et al J Urol 2012; Ramasamy et al., J Pathol Inform 2012 ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 37 2014 December
- 37. No residual sperm production in ANDROFERT androfert.com.br up to 50% of men with NOA ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 38 2014 December
- 38. In mice, transplanted stem cell-derived male gametes resulted in proper spermatogenesis ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 39 2014 December
- 39. In mice, derived gametes generate viable offspring ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 40 2014 December Aponte et al, Clinics 2013
- 40. Biotechnological advancements in the treatment of aspermatogenic men ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 41 2014 December
- 41. Conclusions proteomic biomarkers could add to work-up and clinical treatment strategies • Advances in immature germ cells cryopreservation/transplantation will expand fertility options for oncological boys • Biotechnological approaches for generating male gametes last frontier to be accomplished ANDROFERT androfert.com.br • Novel genomic and ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 42 2014 December
- 42. Why we should do all that … Courtesy of E.N. & T.A.S. with permission ANDROFERT androfert.com.br ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 43 2014 December
Notas do Editor
- 50-80 million people worldwide
- It has been estimated that 2,000 genes are essential for spermatogenesis, from which only 30 genes are present in Y chromosome and most of the remaining genes are on the autosomal chromosomes.
- The researchers also identified 25 to 36 new single nucleotide mutations in each sperm cell that were not present in the subject's diploid genome. Such random mutations are another way to generate genetic variation, but if they occur at particular points in the genome they can have deleterious effects.
- Various conditions that include genetic and congenital abnormalities, post-infectious, exposure to gonadotoxins, medications, varicocele, trauma, endocrine disorders, and idiopathic may cause NOA
- Stem cell-derived male gametes. Several growth factors and cytokines are used for in vitro differentiation of pluripotent cells into male gametes/SSC-like cells. The transplantation of stem cell-derived SSC-like cells in sterile mice results in proper spermatogenesis. Pluripotent stem cells open new perspectives in the treatment of patients with azoospermia. Although the use of ESCs is connected with many ethical concerns, there are no ethical issues regarding the use of iPSCs. Moreover, ESCs are genetically unrelated to the patients, while it may be possible to get offspring with their own genetics by using iPSCs in derivation of functional male gametes.