Infertility Management in Advanced Age

Prof Cihat Ünlü

Bakırköy Acıbadem Hospital

Age Related Predictive Factors in Infertility

• 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. 2008Vagnini L et al. Reprod Biomed Online. 2007

Female Partner AgeMale Partner Age

Fecundability and Age of Female Partner

Human Reprod 2004

The Influence of Female Partner Age

Previous Pregnancy with ARTNo 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... • 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

Hum Reprod 2004

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,

2

> 38 age

< 38 age

group A, FSH <10 IU/ml; group B, 10.1±15 IU/ml group C,15.1±20 IU/ml

PRs, Live Births, > 38 age

½

Basal FSH and Age

Pregnancy Loss

Hum Reprod 2004

Prediction of Ovarian Response in ART

Sensitivity SpecifityPrognostic Significance

OD (Range, %95 CI)

Age % 73.58 % 55.56 % 72.171.21

(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

•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

Prediction of Oocyte Quality Solely by Age

Success in Prediction of

Inducible Oocyte nb

Prediction of Ovarian Reserve

Clin Exp Obstet Gynecol. 2004, Minerva Ginecol. 2003

Duration of Infertility

Fertıl Sterıl 2003

Duration of Infertility as age related factor

Decreased Success !> 3 years

Paternal and Maternal Age

Fertil Steril 2003

Paternal age ≥40 accepted as a key risk factor

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 TUNEL assay clearly demonstrates an increase in sperm DNA damage with age. sperm DNA damage with age.

Vagnini L et al. Reprod Biomed Online. 2007

DF -DF +

DNA hasarlarının (DF) akridin orange ile gösterilmesi

0

10

20

30

40

50

60

A CEmbriyo kalitesi

<%56 DF+

p<0.05

Ünlü C, Aydos K. 2006

DNA hasarı Normal morfoloji

<%56 %60

>%56 %21

0

10

20

30

40

50

60

70

80

<%56 >%56

DNA hasarlı spermatozoa

% Fertilizasyon

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. 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 Response6. 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?

Infertility Treatment Choicesin Advanced Age

• Ovulation Induction

• Sperm Insemination Techniques

– IUI

– ICI

– FSP

• IVF / ICSI

• Advanced Treatment Options

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

Efficacy of IUI in Advanced Age

IUI with OI has virtually no place in their treatment.Dovey S Fertil Steril 2008

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

4,199 cycles performed in 1,738 infertility patients

IVF/ ICSI and Advanced Age

Cumulative PRs Rate of Abortion• IVF-ET

> 38 16% 21% < 38 28% 13%

• ICSI> 38 9% 26%

< 38 27% 14%

Poor-responders

Clin Exp Obstet Gynecol. 2004, Reprod Biomed Online. 2003

PRs≤ 34 yaş 19.5%≥ 35- < 39 7.2% ≥ 40 yaş 1.5%

Normo-responders

Indications of IVF

• Tubal Infertility

• Tuboperitoneal Factor

• Endometriosis

• Unexplained Infertility

• Male Factor

• Immunological Infertility     

• Recurrent IUI Failure

• Preimplantation Genetic Diagnose(PGD)

Tubal Infertility

Mild

ModerateDistal Tubal Obst

Proximal Tubal Obst.

Age > 35

Poor Ovarian Reserve

Infertilite duration > 3 years

Additional Factor

Insurance ??

Hydrosalpinx +

ReconstructiveSurgery

ReconstructiveSurgery

IVF / ET 4-6 cyclesOI + IUI

Curr Opin Obstet Gynecol, 2004

6-12 monthsObservation

4-6 cyclesOI + IUI

6-12 monthsObservation

IVF / ET cost effective 4 cycles PR % 70

Unexplained Infertility???

Randolph 2000, Godon & Sperof 2002, Guzick et al 1998

0

5

10

15

20

25

PRs

/ cyc

le

•Fecundity rate % 1.3 !•Spontaneus Pregnancy ?????

Spontaneus Pregnancy

(Timed İntercourse)3 years 30-60% 5 years 50-80%

Unexplained Infertility

•< 35 age

•< 2 years

•Prior Pregnancy

Observation 6-12 ay

•> 35- 39 age

•< 2 years

Guzick 1998, Soules, 2000

CC / HMG + IUI 4 cycles

IVF / ET 6 cycles•> 40 age

•> 3 years

•Prior Treatment

•> 35- 39 age

•> 3 years

Influence of Age in Endometriosis

Stage of Endometriosis

Management in Endometriosis

Mild / Moderate (Stage I / II) Moderate / Severe (Stage III / IV)

Age < 38Duration of Infertility < 8 yearsNormal Ovarian Reserve Diagnose > 5 years

6 Months Expectant (% 50)

4-6 cycles OI + IUI

Age >38Duration of

Infertility > 8 yearsAdditional Factor

Poor Ovarian Reserve

Diagnose > 5 years

IVF / ET IVF / ETIVF / ET

Impossible Tubo-ovarianRestoration

Normal tubo-ovarian

restoration

Suboptimal resection

Fertil Steril 2002

Am J Obstet Gynecol 2003

Male Infertility

TMS > 5 x mil TMS 1.5 - 5 x mil TMS < 1.5 x mil

Male Age < 40 ?Female Age < 35Infertility duration < 2 yearsNo Additional Factor

İUİ 3-4 x

Normal Morphology

> 14

5-14 < 4

Male Age > 40 ? Female Age > 35Infertility duration > 3 yearsAdditional Factor

IVF4-6 x ICSI 4-6 xOehninger, Ombelet Reprod Bio Med 2003

Male Infertility

TESE PESAMESA

Ejaculatuar canal obs.Vas deferens obs.

Intratesticular obst.Epididymal obst.

CongenitalAquired

MIBPPC, Fertil Steril 2002

TURED

Microsurgery

Additional Factor+ Epididymal obst.Female Age > 35Duration of Infertility > 15 yearsDifficulties in surgery

Inflamation

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

Preimplantation Genetic Diagnose

• 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

•Increase pregnancy rates

•Decrease abortion rates % 14 % 4.3

J Ass Reprod Genet 1998Human Reprod 1999

Preimplantation Genetic Diagnose

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 deletionsUniparental Disomi (UDP)

• Genomic Imprinting

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

Oocyte Donations

35.• Premature ovarian failure, • Gonadal disgenesis (Turner send., etc), • Bilateral Ooforectomy, • Iatrogenic Ovarian Failure (Chemotherapy or

Radiotherapy) • IVF failures with risk of genetic disorders

Indıcations:

RCOG Guideline, 2001

Oocyte Donation Success

Human Reprod 1999

Oocyte Donation Success

Recipient Age and Clinical PRs, Live Births

Fertil Steril 2001

Oocyte Donation and Embryo Quality

Oocyte Donation Success

Endometrial Thickness and Clinical PRs, Live Births

Fertil Steril 2001

Endometrial Pattern and Clinical PRs, Live Births

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 derivedgenetic information

Co-culture with somatic cellsGrowth 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

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

•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

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.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, 1999Barmat et al. Fertil Steril 1998,Spandorfer et al. J Ass Reprod Genet, 2002

Somatic Cell CocultureSomatic 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