Reproductive Reproductive Medicine: Medicine: an update an update T. Cordes and K. Diedrich Dept. of Obstetrics & Gynecology University of Schleswig-Holstein, Campus Lübeck, Germany Limits and Interfaces in Science HumboldtKolleg Sao Paulo, Brasil 28.-30. November 2009
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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
City of Lübeck
City of Lübeck
... around christmas time
Milestones in reproductive medicine• 1960 - ovarian stimulation with clomifene and gonadotrophins
- radioimmunoassay• 1970 - secretion, synthesis, mechanism of GnRH a. gonadotrophins
• 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
Blastocyst
Cochrane , 2007
Blastocyst culture
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 (??)
PGS: a metaanalysis
Mastenbroek et al. 2008, Hum. Reprod. 23
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.
• 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
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
Early oocyte retrieval from antral follicles before
selection and atresia . . .
Physiological basics of IVM
day 3 day 8 - 12
d>10mm
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
• 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
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
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
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
Methods of cryopreservation
slow cooling
vitrification
-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
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.
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.
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
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
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,