New Techniques For TESE Success: Genetic Tests

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New Techniques For TESE Success Genetic Tests

• Prof. Dr. Bülent Alici
• I.Ü. Cerrahpasa Tip Fakültesi
• Üroloji AD, Androloji BD

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Treatment Options
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Why do we evaluate men in the era of ICSI?

1. To distinguish treatable causes
2. Decision of necessity for artificial
   insemination techniques
3. To diagnose genetic risks if AI is needed
4. To diagnose the life treatening conditions seen
   with infertility

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Genetic Risks in Male Infertility

• 10-15 of men with azoospermia and 5 of men
  with oligozoospermia have chromozomal
  abnormalities
• AUA, EAU Guidelines
• After sperm retrieval/ICSI
• Chromozomal abnormalities 3x
• Malformations 2x

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ICSI Genetic Risks

• Malformation
• IVF 1.4
• ICSI 2.35
• Malformation ICSI/IVF risk ? 1.27
• Dietrich et al. 2004

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Aging Fathers Genetic Risks for the Children

• Structural chromosomal anomalies
• Autosomal dominant transferrable diseases
• (Polycystic renal degeneration, tubular
  sclerosis)
• Age of the partner decisive for the indication
  of a pre-implantation diagnosis

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Why Do We Need Genetic Investigation?

• To yield a diagnosis and etiology
• For genetic counselling
• Prevent unnecessary medical or surgical treatment

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Sperm of Infertile Men

• Aneuploidy
• Genetic abnormalities
• DNA damage

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Chromozomal Abnormalities

• Numerical (trisomy e.t.c.)
• Structural (inversions or translocations)

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• 11 publications, n 9766 infertile men
• Chromozomal abnormalities 5.8
• Sex chromo. abnorm 4.2
• Autosomal abnorm 1.5
• Johnson MD Fertil
  Steril. 1998397-411
• New born male infants (n 94.465)
• Chromozomal abnormalities 0.38
• Sex chromo. abnorm 0.14 Autosomal
  abnorm 0.25
• Van Assche EV Hum Reprod. 1996
  Suppl 41-24

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Klinefelters Syndrome

• Chromosome disorder
• a. Classic form 47 XXY (90) results from
  meiotic nondisjunction
• b. Mosaic form 46 XY/47 XXY (10)
• Karyotopic varieties XXYY, XXXY e.t.c.
• Very common 1/500 male births

I.Ü. CTF Üroloji AD Arsivi
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Genetic Counseling

• AZFa, b ve c deletions on long arm of Y
  chromosome may have a prognostic value

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Y Microdeletions

• Specific microdeletion frequency
• AZFa 5
• AZFb 35
• AZFc 60
• Krauzs C, Int J Androl, 2003

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Y Microdeletions

• Patients with AZF microdeletion
• Azoospermia 66
• Severe Oligozoospermia 28
• Oligozoospermia 6
• Y microdeletion in azoospermia 7 (2-53)
• Koh E et al, Reprod.Med. 2005

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Y Microdeletion and Histopathology

• AZFa
• Sertoli Cell Only
• AZFb
• Maturation arrest
• AZFc
• Different histopathological changes
• Koh E et al, Reprod.Med. 2005

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Y Microdeletion and Histopathology
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Chance of Sperm Retrieval

• AZFc
• Partial AZFc
• Partial AZFa and AZFb
• AZFa
• AZFb
• AZFbc
• AZFabc

50-70 chance
No chance of sperm retrieval
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Sperm Retrieval Rate According to Histopathology

• Hypospermatogenesis 90
• Maturation Arrest 60-70
• SCO (Germinal Aplasia) 30
• Over-all Success 50-60

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Translocations in Men

• Neonatal population 0.2
• Infertile couples 0.6
• Severe infertility 2-3.2
• Recurrent miscarriages 9.2
• Stern C, Hum Reprod 1999142097101
• Meschede D, Hum Reprod 19981357682

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Translocations and Fertility

• Preimplantation genetic diagnosis (PGD) has been
  offered to carriers of translocations
• By selecting only normal and balanced embryos
  after PGD higher chance of conceiving
  reduced probability of abortions
• Patients with 65 or less chromosomally abnormal
  sperm have a good chance at conceiving
• Escudero T et al Fertility Sterility 2003
  79 1526-33
• Munne S et al, Fertil Steril 200073120918

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What Genetic Testing Should be Offered?

• For patients with NOA or counts lt 5-10 mil/ml
• Karyotyping Chromozomal deletions, duplications
  or translocations
• Y Chromosome analysis gene microdeletions
• For patients with vasal agenesis
• CFTR testing to CF mutations
• ? For patients with repeated pregnancy loss
• FISH of sperm

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Genetic Work-up in Azoospermia
Parameter Clinic Comment
CFTR-Gene (Cystic Fibrosis Transm Regulator) CBAVD (Azoospermia) Patient/Partner
Klinefelter (47xxy) Most Common Sex Chromozome abnormality TESE/ICSI Preimplantation diagnosis
Y microdeletion 10-15 of Testicular azoospermia or severe Oligozoospermia Before TESE/ICSI
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