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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
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ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
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3.
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
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5. Male reproductive relatively simple
anatomy hides an overwhelmingly
complex system
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6. Spermatogenesis Process
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7. Genetic and
epigenetic-regulated
process
~2,000 genes, but only
30 in the Y
chromosome
Hamada et al 2012
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8. Extremely specialized cell type
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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)
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10. Limitations of current management
Conventional
semen analysis
Conventional
surgeries
Empirical
medical
treatments
ART overuse
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11. Recent Advancements
Sperm Function
Testing
Microsurgery
Genetic
diagnosis
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YCMD
molec
ular
diagno
sis by
PCR
12.
13. The Era of Biomarkers
Genomics
Transcriptomics
Proteomics
Metabolomics
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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
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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.
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16. ANDROFERT
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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
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18. ANDROFERT
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Seminal Fluid Molecular Genetic
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Fingerprinting
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19. ANDROFERT
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20. Proteins are also critical to
understanding disease
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21. Proteomics
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Mass Spectroscopy
Raman Spectroscopy
Nuclear Magnetic
Resonance
22. ANDROFERT
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23. Sperm & Seminal Plasma Proteomic
Profiles
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25. Change in proteomic profiling in seminal
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plasma of adult men before and after
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varicocelectomy
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Camargo M et al. Hum. Reprod. 2013;28:33-46
26.
27. Sperm,
spermatids
Embryos
Oocytes
Ovarian tissue
?Male germ cells
?Testicular
tissue
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28. ANDROFERT
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29. ANDROFERT
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30. ANDROFERT
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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
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32.
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
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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
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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
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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
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37. No residual sperm production in
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up to 50% of men with NOA
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38. In mice, transplanted stem cell-derived
male gametes resulted in
proper spermatogenesis
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39. In mice, derived gametes generate
viable offspring
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Aponte et al, Clinics 2013
40. Biotechnological advancements in the
treatment of aspermatogenic men
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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
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• Novel genomic and
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42. Why we should do all that …
Courtesy of E.N. & T.A.S. with permission
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Editor's Notes
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.