reproductive medicine : an update
DESCRIPTION
Limits and Interfaces in Science HumboldtKolleg Sao Paulo, Brasil 28.-30. November 2009. Reproductive Medicine : an update. T. Cordes and K. Diedrich Dept. of Obstetrics & Gynecology University of Schleswig-Holstein, Campus Lübeck, Germany. City of Lübeck. City of Lübeck. - PowerPoint PPT PresentationTRANSCRIPT
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Reproductive Medicine:Reproductive Medicine:
an updatean update
T. Cordes and K. DiedrichDept. of Obstetrics & Gynecology
University of Schleswig-Holstein, Campus Lübeck, Germany
Limits and Interfaces in ScienceHumboldt KollegSao Paulo, Brasil
28.-30. November 2009
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City of Lübeck
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City of Lübeck
... around christmas time
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Milestones in reproductive medicine• 1960 - ovarian stimulation with clomifene and gonadotrophins
- radioimmunoassay• 1970 - secretion, synthesis, mechanism of GnRH a. gonadotrophins
- in vitro fertilisation• 1980 - cryopreservation• 1990 - recombinant gonadotrophins
- preimplantation genetic diagnosis- intracytoplasmatic sperm injection (ICSI)
- GnRH-antagonists and gonadotrophins• 2000 - in vitro maturation of oocytes
- embryonic stemcells- SET (single embryo transfer)
- vitrification
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Once upon a time…
07/78 Louise Brownwas born
Birth after reimplantation of a human embryo
Steptoe P.C. / Edwards R.G.Lancet 2 (1978): 366
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Number of infertile couples in Germany:
approx. 15 - 20% of all couples(1.2 – 1.6 Millions)
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Probability of successfull infertility treatmentafter: Dor et al., 1996
cause of infertility pregnancy rate
ovarian 57.7%
tubal 63.3%
male 71.4%
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Children born after ART until 2006
birth rate
per cycle
worlwide: 3.9 Mio 26%
in Germany : 148.000
(1982-2006)
21%
after in vivo fertilization 24%
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New Developments in Reproductive Medicine
• Ovarian stimulation: GnRH-antagonists and long acting FSH
• Elective single embryotransfer (eSET)
• Blastocyst transfer
• Preimplantation genetic diagnosis and screening
• In-vitro-maturation
• Cryopreservation and vitrification
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History of ovarian stimulation• 1970 Clomifen
hMG
• 1980 GnRH-agonist / hMG
• 1990 recFSHGnRH-antagonist / hMG or recFSH
• 2000 long acting FSH
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Efficiancy of ovarian stimulation with hMG
endogeneous LH surge (progesterone): 22%
(Stanger et al. 1985)
oocyte qualityembryo qualitypregnancy rate
incidence after down regulation: <2%
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0
2
4
6
8
AmpoulesGonadotropins
d 6
Menses
Cetrorelix
OPU
HCG
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
ET
day of cycle
-16 -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16
0
2
4
6
8
Ampoules HMG
OPU
d -14
LHRH-agonist: daily injection/ depot/ nasal spray
Menses
ET
HCG
17 day of cycle
„long protocol“
„Lübeck protocol“
GnRH-agonist and antagonist protocol
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Gonadotrophins & GnRH-antagonist
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Does the probability of live birth after ovarian stimulation and IVF depend on the type of GnRH-
analogue used?
A systematic review and meta-analysis
G Griesinger, J Collins, B Tarlatzis, P Devroey, K Diedrich, EM Kolibianakis
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Citation Year Effect Lower Upper PValue
Albano 2000 ,829 ,444 1,547 ,556
European 2000 ,748 ,519 1,078 ,119
Olivennes 2000 ,799 ,336 1,901 ,612
North American 2001 ,777 ,470 1,284 ,324
Middle East 2001 ,973 ,604 1,568 ,910
Akman 2001 ,760 ,177 3,263 ,712
Hohmann 2003 ,929 ,398 2,169 ,865
Martinez 2003 1,569 ,307 8,011 ,587
Franco 2003 ,545 ,065 4,562 ,573
Hwang 2004 1,105 ,347 3,526 ,866
Sauer 2004 1,067 ,334 3,409 ,913
Xavier 2005 ,845 ,288 2,484 ,760
Loutradis 2005 ,704 ,271 1,827 ,469
Malmusi 2005 1,000 ,257 3,888 1,000
Marci 2005 10,358 ,533201,451 ,062
Cheung 2005 1,550 ,242 9,940 ,642
Check 2005 1,818 ,518 6,382 ,347
Barmat 2005 ,651 ,262 1,621 ,356
Bahceci 2005 ,839 ,436 1,613 ,598
Badrawi 2005 ,803 ,320 2,015 ,640
Schmidt 2005 1,000 ,181 5,533 1,000
Lee 2005 ,696 ,229 2,114 ,522
FixedCombined (22) ,859 ,722 1,021 ,085
0,1 0,2 0,5 1 2 5 10
Favor agonists Favor antagonists
Odds ratio:0.859
p=0.085
LIVE BIRTH
Rate difference
2.7%
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Citation Year Rate1 Rate2 PValue Effect Lower Upper
Albano 2000 ,00 ,01 ,20 ,16 ,01 3,91
Badrawi 2005 ,04 ,04 1,00 1,00 ,15 6,82
Bahceci 2005 ,04 ,07 ,49 ,62 ,15 2,49
European 2000 ,01 ,02 ,07 ,33 ,10 1,17
Lee 2005 ,07 ,10 ,72 ,73 ,13 4,04
Middle East 2001 ,02 ,05 ,07 ,34 ,10 1,17
North American 2001 ,01 ,02 ,76 ,76 ,13 4,46
Olivennes 2000 ,02 ,05 ,25 ,34 ,05 2,35
RandomCombined (8) ,01 ,47 ,27 ,84
0,01 0,1 1 10 100
Favor agonists Favor antagonists
RR : 0.47~ 2 times less risk to be admitted due to OHSS with GnRH antagonists
Hospital admission due to OHSS
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- fits into the normal cycle(„the patients like it“)
- less side effects in comparison to the long protocol:1. Ø cysts2. Ø hormonal withdrawl3. less OHSS4. simple
- no significant difference in the probability of live birth between GnRH-agonists and antagonists
Advantages of GnRH-antagonists
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long acting FSH
1 2 3 4 5 6 7 8 9 10 11 12 13 14 ….
FSH-CTP
10000 IE hCG
follicle aspirationafter 36h
GnRH-Antagonist
LF 10 mm LF 14 mm LF 17mm
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New Developments in Reproductive Medicine
• Ovarian stimulation: GnRH-antagonists and long acting FSH
• Elective single embryotransfer (eSET)
• Blastocyst transfer
• Preimplantation genetic diagnosis and screening
• In-vitro-maturation
• Cryopreservation and vitrification
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Children after ART: 1997-2002
DIR 2001
IVF ICSI Total %
Singleton 11455 12096 23551 59.83
Twin 6782 6553 13335 33.87
Triplet 1228 1221 2449 6.22
Quadruplet 23 8 31 0.08
Total 19488 19878 39366 100
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Problems of multiple pregnancies
• pregnancy related diseases
• prematurity
• increase of neonatal morbidity and mortality
• costs
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Aims
1. To avoid multiple pregnancies
2. Improve the pregnancy and life birth rate
Solution: Transfer of one selected embryo
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Embryo selection
> 30% < 5%Implantation
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eSET = 40.3% pregnancy rate
1% gemini
eDET = 44% pregnancy rate
32% gemini
Pregnancy rate after elective single embryo transfer (eSET) and
elective double embryo transfer (eDET)
Gerris, 2005ESHRE
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§ 1, Abs. 1, Nr. 5„a person fertilizing more oocytes than he or she intends to tranfer in the course of one treatment cycle“
§ 1, Abs. 1, Nr. 3„a person transfering more than 3 embryos to the womb in the course of one treatment cycle“
Prison sentence up to three years or financial penalty for
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Germany vs. Sweden
No. of embryos / ET after IVF and ICSI, 2004
Deutschland Schweden
1 embryo 11.6% 67.4%
2 embryos 61.3% 32.5%
3 embryos 27.1% 0.1%
Andersen et al., 2008
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DIR 2004; Andersen et al., 2008
born children (IVF) / ET 18.3% 26.4%
gemini / ET 20.7% 5.6%
triplets / ET 1.1% 0.0%
Germany vs. Sweden:Multiple pregnancies after ART
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New Developments in Reproductive Medicine
• Ovarian stimulation: GnRH-antagonists and long acting FSH
• Elective single embryotransfer (eSET)
• Blastocyst transfer
• Preimplantation genetic diagnosis and screening
• In-vitro-maturation
• Cryopreservation and vitrification
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Blastocyst
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Cochrane , 2007
Blastocyst culture
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Preimplantation Genetic DiagnosisIndication: High risk of genetic diseases.
Preimplantation Genetic Screening (PGS)Aneuploidie-Screening improves the pregnancy rate and abortion rate especially in older women (??)
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PGS: a metaanalysis
Mastenbroek et al. 2008, Hum. Reprod. 23
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A careful review of the published studies of this technique led the ASRM Practice Committee to conclude that the available evidence does not support the use of PGS to improve live-birth rates in patients with advanced maternal age, previous implantation failure, recurrent pregnancy loss, or to reduce miscarriage rate in patients with recurrent pregnancy loss related to aneuploidy at this time.
ASRM Committee Report, 2008Präimplantationsscreening
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New Developments in Reproductive Medicine
• Ovarian stimulation: GnRH-antagonists and long acting FSH
• Elective single embryotransfer (eSET)
• Blastocyst transfer
• Preimplantation genetic diagnosis and screening
• In-vitro-maturation
• Cryopreservation and vitrification
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The Lancet 1965
„Oocytes from antral follicles can
finalize their meiotic maturation in
vitro in 24 – 48 hours“
R.G. Edwards et al.
First oocyte maturation in vitro
Edwards RG et al. 1965
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Early oocyte retrieval from antral follicles before
selection and atresia . . .
Physiological basics of IVM
day 3 day 8 - 12
d>10mm
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Development of IVM
1983 Veeck First birth after IVM
1991 Cha IVM on immature oocyte extracted by using ovarian biopsy during a cesarean section resulted in healthy twins
2000 Cha birth of 20 healthy children after IVM
2003 Mikkelsen birth of 33 healthy children after IVM
today >300 children after IVM
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• PCOS
• high responder with a risk for OHSS
• normo-cyclic patients
• cryopreservation of oocytes (oncology)
• low responder
• implantation failure
Therapeutic indications for IVM
Mikkelsen et al. 2003, Smitz 2005, von Otte 2005
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IVMoocyte
maturation (24 h)
Tag 1 2 3 4 5 6 7 8 9 10 ….
first Examination:
basicultrasound
and hormone
level
embryo
culture
(2- 3 days)
Embryotransfer 2-3 days after
ovum aspiration
Menses
Fertilizationvia ICSI
♂ Male: sperms
4 days
of low dose hMG
(„priming“ with
75IE hMG/day)
Exam. 2,3, …
ultrasound and
hormone level
primordial follicle
≥ 12mm and E ≥7mm
10.000 IE hCG
36h later aspiration of small antral
follicles
Estradot 100
Crinone 8%
Treatment protocol
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In vitro maturation of oocytes
number of patients 140
Metaphase II 57%
2 pronuclei after in vitro maturation and ICSI 47%
pregnancies 30
v. Otte 2007
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New Developments in Reproductive Medicine
• Ovarian stimulation: GnRH-antagonists and long acting FSH
• Elective single embryotransfer (eSET)
• Blastocyst transfer
• Preimplantation genetic diagnosis and screening
• In-vitro-maturation
• Cryopreservation and vitrification
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Methods of cryopreservation
slow cooling
vitrification
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-196-196
-80-80
-5-5
Tem
p D
egre
es C
T
emp
Deg
rees
C
RoomRoomtemperaturetemperature
Temps (min)Temps (min)
Vitrification vs slow coolingVitrification vs slow cooling
10 20 30
H2O
Storage
total dehydratation
> 25000°C/min> 25000°C/min
Storage
0.3 – 0.5°C/min0.3 – 0.5°C/min
H2O
V I T R I F I C A T I O N Slow freezing(equilibrated)
Storage
weak dehydratation
Weak dehydratation
-35-35
37°C37°C
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Slow cooling(Whittingham et al., Science 1972,Willmut et al., Life Science 1972)
- 0.3°C/min
Vitrification(Rall and Fahy 1985)
- 50.000°C/min
2 sec.
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In contrast to slow-rate freezing In contrast to slow-rate freezing protocols, during vitrification the entire protocols, during vitrification the entire
solution remains unchanged and the solution remains unchanged and the water does not precipitate, so no water does not precipitate, so no
ice crystals are formed.ice crystals are formed.
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Clin. pregnancies / ETafter cryo transfer
(1996-2004)
Cryo transfer 67,257
Clin. pregnancy / ET 15.5 %
Abortion rate after cryo transfer 21.64 %
German IVF Index 2004
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Lübeck Results (till 01/2007)
Slow-cooling Vitrifikation0%
20%
40%
60%
80%
100%
59%
91%
Slow-cooling Vitrifikation0%
10%
20%
30%
40%
50%
19%
34%
survival rate pregnancy rate
n=752 n=155
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Future of Reproductive Medicine• new embryo protection law (european?)
• improvement of pregnancy rate by the elective single embryo
transfer (morphological criteria)
• avoid multiple pregnancies
• vitrification
• in vitro maturation
• Fertility preservation for women with cancer
• aim of infertility treatment: simple, safe, comfortable,
successful and cheap
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AachenBerlin BonnBremenDresdenDüsseldorfDuisburgErlangenFrankfurtFreiburgGiessenGöttingen Greifswald HalleHamburgHannover Heidelberg
InnsbruckHomburgJenaKiel KölnLeipzigLübeck MagdeburgMainzMarburgMünchenMünsterRostockTübingenUlm Würzburgusw.
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Universitäres Kinderwunschzentrum Lübeck UKL
www.fertiprotekt.de
Thank you!