Management of Male Infertility What the future holds

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Sandro Esteves, MD., PhD. Medical & Scientific Director, ANDROFERT Campinas, Brazil Management of Male Infertility What the future holds Reproductive Andrology Surgery Workshop II Reproductive Medicine Unit - Jahra Hospital - Kuwait 2014

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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

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Infertility Figures Infertile couples worldwide (50-80 million people) 10-15% male factor infertility Up to 50% seek assistance for fertility issues 1 in 8 men

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Irvin S, et al 1996, Auger J et al, 1995, Irvine DS 1994, Jorgensen N et al 2001, Jorgensen N et al 2002, Swan SH 2003, Feki NC et al, 2009

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Male reproductive relatively simple anatomy hides an overwhelmingly complex system

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Spermatogenesis Process

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Genetic and epigenetic- regulated process ~2,000 genes, but only 30 in the Y chromosome Hamada et al 2012

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Extremely specialized cell type

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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)

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Limitations of current management Conventional semen analysis Conventional surgeries Empirical medical treatments ART overuse

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Recent Advancements Sperm Function Testing Microsurgery Genetic diagnosis YCMD molecular diagnosis by PCR

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Prospects in DIAGNOSIS

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Genomics Transcriptomics Proteomics Metabolomics The Era of Biomarkers

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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

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DNA Micro-array Technology 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.

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Potential Clinical Applications of Sperm Molecular Genetic Fingerprinting Infertility diagnosis Assessment of treatment outcome (medical, surgical) ART outcome (IUI, IVF, ICSI) Sperm selection techniques

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Seminal Fluid Molecular Genetic Fingerprinting

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Proteins are also critical to understanding disease

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Sperm & Seminal Plasma Proteomic Profiles

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Sperm Proteomics

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Camargo M et al. Hum. Reprod. 2013;28:33-46 Change in proteomic profiling in seminal plasma of adult men before and after varicocelectomy

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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

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Nonobstructive azoospermia irreversible condition Esteves et al. Clinics 2011; 66: 691-700

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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

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Morphometric Evaluation of Seminiferous Tubules Verza Jr S, Esteves SC. Fertil Steril 2012; 98: S242 N=54; Tubule Diameter: KW-H (1;54) = 25.2; P<0.001

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Novel methods for identification of sperm production sites in men with nonobstructive azoospermia Najari et al, J Urol 2012; Smith et al J Urol 2012; Ramasamy et al., J Pathol Inform 2012

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No residual sperm production in up to 50% of men with NOA

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In mice, transplanted stem cell-derived male gametes resulted in proper spermatogenesis

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In mice, derived gametes generate viable offspring Aponte et al, Clinics 2013

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Biotechnological advancements in the treatment of aspermatogenic men

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Conclusions Novel genomic and 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

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Why we should do all that … Courtesy of E.N. & T.A.S. with permission

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Thank YoU ???? OBRIGADO