Bakırköy Acıbadem Hospital
Infertility
Management in
Advanced Age
Prof Cihat Ünlü
Age Related
Predictive Factors in Infertility
Female Partner Age
Male Partner Age
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Loss of Ovarian Reserve
Oocyte Senescence
Increased sperm DNA Damage
Duration of Infertility
Increase in Other Gynecological
İnfertility Factors
– Tuboperitoneal Factors and PIDs
– Uterine Fibroids, etc.
Tatone C, Gynecol Endocrinol. 2008
Vagnini L et al. Reprod Biomed Online. 2007
Fecundability and Age of
Female Partner
Human Reprod 2004
The Influence of Female
Partner Age
Previous Pregnancy with ART
No Previous Pregnancy
Previous Pregnancy without ART
Fertil Steril 2003
Loss of Ovarian Reserve
• Change of Menstruel Cycles
• Endocrine and biochemical profile change
D3
• FSH
• E2
• Inhibin
• Decreased Success Rates Due to...
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•
•
•
•
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Decreased oocytes nb
Decreased fertilization rates
Decreased ET rates
Decreased cumulative PRs
Increased Abortion
Increased Aneuploidy
Clin Exp Obstet Gynecol. 2004, Minerva Ginecol. 2003
Basal FSH Levels
• 3401 IVF / ICSI patients, three cycle
FSH
group A, FSH <10 IU/ml;
group B, 10.1±15 IU/ml
group C,15.1±20 IU/ml
group D, FSH >20 IU/ml
PRs,
Live Births,
Hum Reprod 2004
Basal FSH and Age
group A, FSH <10 IU/ml;
group B, 10.1±15 IU/ml
group C,15.1±20 IU/ml
> 38 age
< 38 age
½
PRs,
Live Births,
> 38 age
2
Pregnancy Loss
Hum Reprod 2004
Prediction of Ovarian Response
in ART
Sensitivity Specifity
Age
Age
+
Basal FSH
% 73.58
% 82.80
% 55.56
% 77.27
Prognostic
Significance
OD (Range, %95 CI)
% 72.17
1.21
(1.05-1.39)
% 81.74
1.28
(Age; 1.09-1.51,
FSH; 1.42, 1.19-1.70)
Hum Reprod 2000
Prediction of Ovarian Reserve
•Basal FSH, < 12 mIU/ml
•Basal E2, < 75 pg/ml
•Basal İnhibin > 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
Duration of Infertility
Duration of Infertility as age related factor
Decreased Success
> 3 years!
Fertıl Sterıl 2003
Paternal and Maternal Age
Paternal age ≥40 accepted as a key risk factor
Fertil Steril 2003
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: < or =35 years,
Group II: 36-39 years,
Group III: > 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
DNA hasarlarının (DF) akridin orange ile gösterilmesi
DF -
DF +
<%56 DF+
60
50
40
30
20
10
0
A
C
p<0.05
Embriyo kalitesi
Ünlü C, Aydos K. 2006
DNA hasarı
Normal morfoloji
<%56
%60
>%56
%21
% Fertilizasyon
80
70
60
50
40
30
20
10
0
<%56
>%56
DNA hasarlı spermatozoa
Ünlü C, Aydos K. 2006
Practical Management of
Infertility in Advanced Age
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
Ethical and Medical Problems
in Advanced Aged Couples
1.
2.
3.
4.
5.
6.
7.
8.
What are the age limits for couples (Female and
Male Limits)?
Do insurance policies resisting for special age limits
in treatment of infertility against the human
reproduction rights?
Do couples have rights in selecting the treatment
method in advanced age?
No luxury for time loss according to wrong
treatment option.
Decreased Ovarian Response
Decreased ART success and increased drop outs.
Increased treatment anxiety (Doctor and Patient)
Should the optimum treatment numbers regaring the
methods be different in advanced age?
Infertility Treatment Choices
in Advanced Age
• Ovulation Induction
• Sperm Insemination Techniques
– IUI
– ICI
– FSP
• IVF / ICSI
• Advanced Treatment Options
Treatment Choices in OI
in 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
Efficacy of IUI in Advanced Age
4,199 cycles performed in 1,738 infertility patients
Age
Cycle
Patient
PRs
ITT
< 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
> 42
120
55
1
0.8
IUI with OI has virtually no place in their treatment.
Dovey S Fertil Steril 2008
IVF/ ICSI and Advanced Age
Normo-responders
Cumulative PRs
•
•
IVF-ET
> 38
< 38
ICSI
> 38
< 38
Rate of Abortion
16%
28%
21%
13%
9%
27%
26%
14%
Poor-responders
≤ 34 yaş
≥ 35- < 39
≥ 40 yaş
PRs
19.5%
7.2%
1.5%
Clin Exp Obstet Gynecol. 2004, Reprod Biomed Online. 2003
Indications of IVF
• Tubal Infertility
• Tuboperitoneal Factor
• Endometriosis
• Unexplained Infertility
• Male Factor
• Immunological Infertility
• Recurrent IUI Failure
• Preimplantation Genetic Diagnose(PGD)
Tubal Infertility
IVF / ET cost effective
Distal
Tubal Obst
4 cycles PR % 70
Mild
Moderate
Proximal
Tubal Obst.
Age > 35
Poor Ovarian Reserve
Reconstructive
Surgery
Infertilite duration > 3
years
Reconstructive
Surgery
Additional Factor
6-12 months
Observation
4-6 cycles
OI + IUI
Insurance ??
Hydrosalpinx +
IVF / ET
6-12 months
Observation
4-6 cycles
OI + IUI
Curr Opin Obstet Gynecol, 2004
Unexplained Infertility???
Spontaneus
Pregnancy
25
20
PRs / cycle
•Fecundity rate % 1.3 !
•Spontaneus Pregnancy
?????
15
10
5
+
HM
G
IV
F
IU
I
G
HM
IU
I
+
CC
IU
I
CC
tre
at
m
en
t
0
No
(Timed İntercourse)
3 years
30-60%
5 years
50-80%
Randolph 2000, Godon & Sperof 2002, Guzick et al 1998
Unexplained Infertility
•< 35 age
•< 2 years
Observation 6-12 ay
•Prior Pregnancy
•> 35- 39 age
•< 2 years
CC / HMG + IUI 4 cycles
•> 35- 39 age
•> 3 years
•> 40 age
IVF / ET 6 cycles
•> 3 years
•Prior Treatment
Guzick 1998, Soules, 2000
Influence of Age in Endometriosis
Stage of Endometriosis
Management in Endometriosis
Am J Obstet Gynecol 2003
Fertil Steril 2002
Moderate / Severe (Stage
III / IV)
Mild / Moderate (Stage I / II)
Normal tuboovarian
restoration
Age < 38
Duration of Infertility < 8
years
Normal Ovarian Reserve
Diagnose > 5 years
6 Months Expectant
(% 50)
Age >38
Duration of
Infertility > 8 years
Additional Factor
Poor Ovarian
Reserve
Diagnose > 5 years
Impossible
Tubo-ovarian
Restoration
4-6 cycles OI + IUI
IVF / ET
Suboptimal
resection
IVF / ET
IVF / ET
Male Infertility
TMS > 5 x mil
TMS 1.5 - 5 x mil
5-14
TMS < 1.5 x mil
Normal Morphology
<4
> 14
Male Age < 40 ?
Female Age < 35
Infertility duration < 2 years
No Additional Factor
Male Age > 40 ?
Female Age > 35
Infertility duration > 3 years
Additional Factor
İUİ 3-4 x
IVF4-6 x
Oehninger, Ombelet Reprod Bio Med 2003
ICSI 4-6 x
Male Infertility
Epididymal obst.
Intratesticular obst.
Aquired
Congenital
Microsurgery
MESA
TESE
Additional Factor
+ Epididymal obst.
Female Age > 35
Duration of Infertility > 15 years
Difficulties in surgery
Vas deferens obs.
PESA
TURED
Inflamation
Ejaculatuar canal obs.
MIBPPC, Fertil Steril 2002
Further Treatment Options
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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
Preimplantation Genetic
Diagnose
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Maternal Age (> 35)
Recurrent IVF Failure (>3)
Recurrent Pregnancy Loss
Unexplained Infertility
Severe Male Infertility
Y Chromosome Deletions
Translocation Carriers
Abnormal Embryo Morphology
Advanced Age and PGD ?
Maternal Age
Trizomi 21
Trizomi 18
Trizomi 13
15 - 19
1:1250
1:17000
1:33000
20 - 24
1:1400
1:14000
1:25000
25 - 29
1:1100
1:11000
1:20000
30 - 34
1:700
1:7100
1:14000
35 - 39
1:200
1:2400
1:4800
40 - 44
1:60
1:700
1:1600
•Mendelien Disease Screening
•Increase implantation rates
%15.6
% 26.6
% 14
% 4.3
•Increase pregnancy rates
•Decrease abortion rates
J Ass Reprod Genet 1998
Human Reprod 1999
Preimplantation Genetic
Diagnose
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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
Mono Genetic Disease
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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
Oocyte Donations
Indıcations:
35.
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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
Oocyte Donation Success
Human Reprod 1999
Oocyte Donation Success
Recipient Age and Clinical PRs, Live Births
Oocyte Donation and Embryo Quality
Fertil Steril 2001
Oocyte Donation Success
Endometrial Thickness and Clinical PRs, Live Births
Endometrial Pattern and Clinical PRs, Live Births
Fertil Steril 2001
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
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,
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,
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
Co-culture
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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
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,
Endometrial Cell Coculture
Results
Time of Endometrial Biopsy
(<5 versus >5 days from LH surge)
Endometrial Cell Coculture
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
Thank You