Infertility Management in Advanced Age

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Infertility Management in Advanced Age
Bakirköy Acibadem Hospital

• Prof Cihat Ünlü

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Age Related Predictive Factors in Infertility
Female Partner Age Male Partner Age

• Loss of Ovarian Reserve
• Oocyte Senescence
• Increased sperm DNA Damage
• Duration of Infertility
• Increase in Other Gynecological Infertility
  Factors
• Tuboperitoneal Factors and PIDs
• Uterine Fibroids, etc.

Tatone C, Gynecol Endocrinol. 2008 Vagnini L et
al. Reprod Biomed Online. 2007
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Fecundability and Age of Female Partner
Human Reprod 2004
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The Influence of Female Partner Age
Previous Pregnancy with ART No Previous Pregnancy
Previous Pregnancy without ART
Fertil Steril 2003
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Loss of Ovarian Reserve

• Change of Menstruel Cycles
• Endocrine and biochemical profile change
• D3
• FSH
• E2
• Inhibin
• Decreased Success Rates Due to...
• Decreased oocytes nb
• Decreased fertilization rates
• Decreased ET rates
• Decreased cumulative PRs
• Increased Abortion
• Increased Aneuploidy

Clin Exp Obstet Gynecol. 2004, Minerva Ginecol.
2003
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Basal FSH Levels

• 3401 IVF / ICSI patients, three cycle

group A, FSH lt10 IU/ml group B, 10.115 IU/ml
group C,15.120 IU/ml group D, FSH gt20 IU/ml
FSH
Hum Reprod 2004
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Basal FSH and Age
group A, FSH lt10 IU/ml group B, 10.115 IU/ml
group C,15.120 IU/ml

• gt 38 age
• lt 38 age

½
PRs, Live Births,
gt 38 age
2
Pregnancy Loss
Hum Reprod 2004
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Prediction of Ovarian Response in ART
Sensitivity Specifity Prognostic Significance OD (Range, 95 CI)
Age 73.58 55.56 72.17 1.21 (1.05-1.39)
Age Basal FSH 82.80 77.27 81.74 1.28 (Age 1.09-1.51, FSH 1.42, 1.19-1.70)
Hum Reprod 2000
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Prediction of Ovarian Reserve

• Basal FSH, lt 12 mIU/ml
• Basal E2, lt 75 pg/ml
• Basal Inhibin gt 45 pg/ml
• Decrease of Ovarian Volume
• Clomiphene Citrate Challenge Test,
• GAST
• Antral folllicle nb

Success in Prediction of Inducible Oocyte nb
Prediction of Oocyte Quality Solely by Age
Clin Exp Obstet Gynecol. 2004, Minerva Ginecol.
2003
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Duration of Infertility
Duration of Infertility as age related factor
Decreased Success
!
gt 3 years
Fertil Steril 2003
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Paternal and Maternal Age
Paternal age 40 accepted as a key risk factor
Fertil Steril 2003
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The influence of age on sperm DNA damage

• 508 men in an unselected group of couples
  attending infertility investigation and
  treatment.
• DNA fragmentation by (TUNEL) assay( at least 200
  spermatozoa) DNA fragmentation index (DFI).
• Group I lt or 35 years,
• Group II 36-39 years,
• Group III gt or 40 years.
• DFI was significantly lower in Group I than in
  Group II (P 0.034) or III (P 0.022).
• The regression analysis demonstrated a
  significant increase in sperm DFI with age (P
  0.02).
• TUNEL assay clearly demonstrates an increase in
  sperm DNA damage with age.

Vagnini L et al. Reprod Biomed Online. 2007
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DNA hasarlarinin (DF) akridin orange ile
gösterilmesi
DF
DF -
lt56 DF
plt0.05
Embriyo kalitesi
Ünlü C, Aydos K. 2006
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DNA hasari Normal morfoloji
lt56 60
gt56 21
Fertilizasyon
DNA hasarli spermatozoa
Ünlü C, Aydos K. 2006
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Practical Management of Infertility in Advanced
Age
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Aims of Management in Infertility

1. Detection of Infertility Factors
2. Consideration of the Advantages / Disadvantages
   of the treatment choices
3. The Counseling of Infertile Couple
4. Planning the Treatment
5. Performing Treatment choices with optimum time
   intervals

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Ethical and Medical Problems in Advanced Aged
Couples

1. What are the age limits for couples (Female and
   Male Limits)?
2. Do insurance policies resisting for special age
   limits in treatment of infertility against the
   human reproduction rights?
3. Do couples have rights in selecting the treatment
   method in advanced age?
4. No luxury for time loss according to wrong
   treatment option.
5. Decreased Ovarian Response
6. Decreased ART success and increased drop outs.
7. Increased treatment anxiety (Doctor and Patient)
8. Should the optimum treatment numbers regaring the
   methods be different in advanced age?

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Infertility Treatment Choicesin Advanced Age

• Ovulation Induction
• Sperm Insemination Techniques
• IUI
• ICI
• FSP
• IVF / ICSI
• Advanced Treatment Options

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Treatment Choices in OIin Advanced Age

• Short GnRH analog protocols
• Flare-up Protocols
• Mikrodose GnRH protocols
• GnRH antagonist protocols
• Minimal stimülation protocols
• GnRH Analog Cessations

• Addition of Cortisol
• Addition of CC
• Addition of Aromatase inh.
• Addition of low dose aspirine
• Addition of Growth hormone
• Natural cycle

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Efficacy of IUI in Advanced Age
4,199 cycles performed in 1,738 infertility
patients
Age Cycle Patient PRs ITT
lt 35 2351 983 11.5 10.1
35-37 947 422 9.2 8.2
38-40 614 265 7.3 6.5
41-42 166 81 4.3 3.6
gt 42 120 55 1 0.8

• IUI with OI has virtually no place in their
  treatment.

Dovey S Fertil Steril 2008
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IVF/ ICSI and Advanced Age
Normo-responders

• Cumulative PRs Rate of Abortion
• IVF-ET gt 38 16
  21 lt 38 28 13
• ICSI
• gt 38 9 26 lt 38
  27 14

Poor-responders
PRs 34 yas 19.5 35- lt
39 7.2 40 yas 1.5
Clin Exp Obstet Gynecol. 2004, Reprod Biomed
Online. 2003
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Indications of IVF

• Tubal Infertility
• Tuboperitoneal Factor
• Endometriosis
• Unexplained Infertility
• Male Factor
• Immunological Infertility     
• Recurrent IUI Failure
• Preimplantation Genetic Diagnose(PGD)

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Tubal Infertility
IVF / ET cost effective 4 cycles PR 70

• Mild
• Moderate

Proximal Tubal Obst.
Distal Tubal Obst
Age gt 35 Poor Ovarian Reserve Infertilite
duration gt 3 years Additional Factor Insurance
?? Hydrosalpinx
Reconstructive Surgery
Reconstructive Surgery
6-12 months Observation
6-12 months Observation
4-6 cycles OI IUI
4-6 cycles OI IUI
IVF / ET
Curr Opin Obstet Gynecol, 2004
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Unexplained Infertility???

• Fecundity rate 1.3 !
• Spontaneus Pregnancy ?????
• Spontaneus Pregnancy
• (Timed Intercourse)
• 3 years 30-60
• 5 years 50-80

Randolph 2000, Godon Sperof 2002, Guzick et al
1998
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Unexplained Infertility

• lt 35 age
• lt 2 years
• Prior Pregnancy

Observation 6-12 ay

• gt 35- 39 age
• lt 2 years

CC / HMG IUI 4 cycles

• gt 35- 39 age
• gt 3 years

IVF / ET 6 cycles

• gt 40 age
• gt 3 years
• Prior Treatment

Guzick 1998, Soules, 2000
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Influence of Age in Endometriosis
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Stage of Endometriosis
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Management in Endometriosis
Am J Obstet Gynecol 2003
Fertil Steril 2002
Moderate / Severe (Stage III / IV)
Mild / Moderate (Stage I / II)
Normal tubo-ovarian restoration
Suboptimal resection
Age gt38 Duration of Infertility gt 8
years Additional Factor Poor Ovarian
Reserve Diagnose gt 5 years
Age lt 38 Duration of Infertility lt 8 years Normal
Ovarian Reserve Diagnose gt 5 years
6 Months Expectant ( 50)
Impossible Tubo-ovarian Restoration
4-6 cycles OI IUI
IVF / ET
IVF / ET
IVF / ET
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Male Infertility
TMS gt 5 x mil
TMS 1.5 - 5 x mil
TMS lt 1.5 x mil
Normal Morphology
5-14
lt 4
gt 14
Male Age lt 40 ? Female Age lt 35 Infertility
duration lt 2 years No Additional Factor
Male Age gt 40 ? Female Age gt 35 Infertility
duration gt 3 years Additional Factor
ICSI 4-6 x
IUI 3-4 x
IVF4-6 x
Oehninger, Ombelet Reprod Bio Med 2003
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Male Infertility
Intratesticular obst.
Epididymal obst.
Congenital
Aquired
TESE
PESA
MESA
Microsurgery
TURED
Additional Factor Epididymal obst. Female Age gt
35 Duration of Infertility gt 15
years Difficulties in surgery
Inflamation
Vas deferens obs.
Ejaculatuar canal obs.
MIBPPC, Fertil Steril 2002
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Further Treatment Options

• Preimplantation Genetic Diagnose
• Assisted Embryo Hatching
• Enriched Culture Media
• Co-Culture Methods (ECC, etc)
• Blastocyst Transfer
• Cytoplasmic Transfer
• Nuclear Transfer
• Oocyte Donation
• Oocyte Sharing
• Sperm Donation

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Preimplantation Genetic Diagnose

• Maternal Age (gt 35)
• Recurrent IVF Failure (gt3)
• Recurrent Pregnancy Loss
• Unexplained Infertility 
• Severe Male Infertility
• Y Chromosome Deletions
• Translocation Carriers
• Abnormal Embryo Morphology

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Advanced Age and PGD ?
Maternal Age Trizomi 21 Trizomi 18 Trizomi 13
15 - 19 11250 117000 133000
20 - 24 11400 114000 125000
25 - 29 11100 111000 120000
30 - 34 1700 17100 114000
35 - 39 1200 12400 14800
40 - 44 160 1700 11600

• Mendelien Disease Screening
• Increase implantation rates 15.6
  26.6
• Increase pregnancy rates
• Decrease abortion rates 14 4.3

J Ass Reprod Genet 1998 Human Reprod 1999
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Preimplantation Genetic Diagnose

• Mono Genetic Disease
• X linked
• Frajil X 
• Duchenne/Becker muscular distrophy
• Hemofili
• Otosomal dominant
• Myotonic distrophy
• Huntington disease
• Charcot-Marie-Tooth
• Otosomal Resessive
• Cystic Fibrosis
• Talasemi
• Spinal muscular atrophy

• Aneuploidy
• Chromosomal abnormality
• Chromosomal 13, 14, 15, 16, 17, 18, 21, 22, X and
  Y
• Down sendrom
• Turner sendrom
• Kleinfelter sendrom
• Structural Abnormality
• Translocation
• Invertion
• Deletion
• Duplication
• Y Chromosome deletions
• Uniparental Disomi (UDP)
• Genomic Imprinting

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Oocyte Donations
Indications

• 35.
• Premature ovarian failure,
• Gonadal disgenesis (Turner send., etc),
• Bilateral Ooforectomy,
• Iatrogenic Ovarian Failure (Chemotherapy or
  Radiotherapy)
• IVF failures with risk of genetic disorders

RCOG Guideline, 2001
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Oocyte Donation Success
Human Reprod 1999
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Oocyte Donation Success
Recipient Age and Clinical PRs, Live Births
Oocyte Donation and Embryo Quality
Fertil Steril 2001
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Oocyte Donation Success
Endometrial Thickness and Clinical PRs, Live
Births
Endometrial Pattern and Clinical PRs, Live Births
Fertil Steril 2001
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Co-culture

• One factor that may contribute to the poor
  success rates in ART is the current in-vitro
  culture conditions !!!!

• Only 20-50 of preembryos to the blastocyst
  stage.
• Aim is to transfer

Activation of Maternally derived genetic
information
Co-culture with somatic cells Growth factor media
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Co-culture

• Co-culture cell lines used in human IVF express a
  number of growth factors.
• Growth rates and morphology have been
  significantly improved for preembryos maintained
  in co-culture systems.
• Preembryo development on somatic cell lines may
  enhance implantation and pregnancy rates in human
  IVF.
• It appears that the autocrine and paracrine
  interactions between the preembryo and its
  culture environment takes place.

Wiemer KE et al. Hum Reprod 1993, Barmat LI et
al. Fertil Steril 1997, Magli MC et al. Int J
Fertil 1995, Morgan K et al. Hum Reprod 1995,
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Mechanism of the Effects of Co-culture

• Detoxify the culture medium.
• Produce embryotrophic factors.
• GM-CSF,
• IL-1,
• LIF.

Jacobs AL, Endocrinology 1993, De Los Santos MJ
et al. Biol Reprod 1996, Spandorfer SD et al. Am
J Reprod Immunol 1998, Spandorfer SD, ASRM Annual
Meeting, 1999, Spandorfer SD, et al. Am J Reprod
Immunol 2000,
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Coculture Results

• Improvement in preembryo grade,
• Increase in the average number of blastomeres,
• Decrease in the average percentage of fragments
  per preembryo
• Improvement in implantation and pregnancy rates

Jayot S et al. Fertil Steril 1995. Nieto FS et
al. J Assist Reprod Genet 1996, Barmat et al. J
Ass Reprod Genet, 1999 Barmat et al. Fertil
Steril 1998, Spandorfer et al. J Ass Reprod
Genet, 2002
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Co-culture

• Bovine reproductive tract cells,
• African green monkey kidney cells (Vero),
• Human oviduct cells,
• Human granulosa cells lines,
• Human Tubal Epithelial cell lines,
• Human Endometrial cell lines.

Menezo Y. et al Biol Reprod 1990, Bongso A et al.
Fertil Steril 1992, Wiemer KE et al. Hum Reprod
1993, Sakkas D et al. Fertil Steril 1994, Quinn P
et al. J Assist Reprod Genet 1996, Barmat et al.
J Ass Reprod Genet, 1999 Barmat et al. Fertil
Steril 1998, Spandorfer et al. J Ass Reprod
Genet, 2002
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Somatic Cell Coculture

• Xenologous
• Heterologous
• Autologous

Risk of disease transmission to the exposed
preembryos ! Autologous human endometrial
cells coculture
Jayot S et al. Fertil Steril 1995 Nieto FS et
al. J Assist Reprod Genet 1996,
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Endometrial Cell Coculture Results
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Time of Endometrial Biopsy (lt5 versus gt5 days
from LH surge)
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Endometrial Cell Coculture
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Endometrial Cell Coculture

• Autologous endometrial coculture in patients with
  
• IVF failure outcome of the first 1,030 cases.
• Significant improvement in embryo quality with
  ECC.
• Patients with a poor prognosis secondary to prior
  IVF failures can have a good outcome when
  utilizing AECC
• Improved implantation and pregnancy rates with
  AECC.

J Reprod Med. 2004
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Thank You