Management of Male Infertility - What the future holds
-
Upload
sandro-esteves -
Category
Health & Medicine
-
view
1.630 -
download
2
Transcript of Management of Male Infertility - What the future holds
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
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
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 2
2014 December
ANDROFERT
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
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 5
2014 December
ANDROFERT
Male reproductive relatively simple anatomy hides an overwhelmingly
complex system
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 6
2014 December
ANDROFERT
Spermatogenesis Process
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 7
2014 December
ANDROFERT
Genetic andepigenetic-regulated process
~2,000 genes, but only
30 in the Y
chromosomeHamada et al 2012
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 8
2014 December
ANDROFERT
Extremely specialized cell type
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 9
2014 December
ANDROFERT
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)
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 10
2014 December
ANDROFERT
Limitations of current management
Conventional semen analysis
Conventional surgeries
Empirical medical treatments
ART overuse
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 11
2014 December
ANDROFERT
Recent Advancements
Sperm Function Testing
MicrosurgeryGenetic diagnosis
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 12
2014 December
ANDROFERT
YCMD molecular
diagnosis by PCR
Genomics
Transcriptomics
Proteomics
Metabolomics
The Era of Biomarkers
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 14
2014 December
ANDROFERT
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
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 15
2014 December
ANDROFERT
Normalcy of Sperm Chromatin Content
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.
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 16
2014 December
ANDROFERT
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 17
2014 December
ANDROFERT
Potential Clinical Applications of Sperm Molecular Genetic
Fingerprinting
• Infertility diagnosis
• Assessment of treatment outcome (medical, surgical)
• ART outcome (IUI, IVF, ICSI)
• Sperm selection techniques
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 18
2014 December
ANDROFERT
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 19
2014 December
ANDROFERT
Seminal Fluid Molecular Genetic Fingerprinting
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 20
2014 December
ANDROFERT
Proteins are also critical to understanding disease
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 21
2014 December
ANDROFERT
Proteomics
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 22
2014 December
ANDROFERT
Mass Spectroscopy
Raman Spectroscopy
Nuclear Magnetic
Resonance
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 23
2014 December
ANDROFERT
Sperm & Seminal Plasma Proteomic Profiles
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 24
2014 December
ANDROFERT
Sp
erm
P
rote
om
ics
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 26
2014 December
ANDROFERTCamargo M et al. Hum. Reprod. 2013;28:33-46
Change in proteomic profiling in seminal plasma of adult men before and after
varicocelectomy
Sperm,
spermatids
Embryos
Oocytes
Ovarian tissue
?Male germ cells
?Testicular
tissue
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 28
2014 December
ANDROFERT
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 29
2014 December
ANDROFERT
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 30
2014 December
ANDROFERT
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 31
2014 December
ANDROFERT
Spermatogonial stem cell preservation and transplantation
• Boys facing gonadotropic treatment
• Klinefelter syndrome patientsCryopreservation 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
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 32
2014 December
ANDROFERT
Nonobstructive azoospermia irreversible condition
Testicular torsion; Trauma
Post-inflammatory (eg. Mumps orchitis)
Exogenous factors (eg. Cytotoxic drugs, irradiation)
Testicular cancer
Systemic diseases (eg. Liver cirrhosis, renal failure)
Congenital
Testicular dysgenesis/cryptorchidism
Genetic abnormalities (Klinefelter syndrome, Yq microdeletions, etc.)
Acquired
Idiopathic (Unknown etiology)
Esteves et al. Clinics 2011; 66: 691-700
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 34
2014 December
ANDROFERT
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
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 35
2014 December
ANDROFERT
Morphometric Evaluation of Seminiferous Tubules
Median 25%-75% 5%-95% Raw Data
yes No
Presence of Sperm
160
180
200
220
240
260
280
300
320
340
360
380
400
420
Max.
Tubule
Dia
mete
r
Verza Jr S, Esteves SC. Fertil Steril 2012; 98: S242
N=54; Tubule Diameter: KW-H (1;54) = 25.2; P<0.001
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 36
2014 December
ANDROFERT
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
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 37
2014 December
ANDROFERT
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 38
2014 December
ANDROFERT
No residual sperm production in up to 50% of men with NOA
In mice, transplanted stem cell-derived male gametes resulted in
proper spermatogenesis
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 39
2014 December
ANDROFERT
In mice, derived gametes generate viable offspring
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 40
2014 December
ANDROFERTAponte et al, Clinics 2013
Biotechnological advancements in the treatment of aspermatogenic men
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 41
2014 December
ANDROFERT
Conclusions
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 42
2014 December
ANDROFERT
• 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
Why we should do all that …
Courtesy of E.N. & T.A.S. with permission
ANDROFERTandrofert.com.br
ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION
S ESTEVES, 43
2014 December
ANDROFERT