How to balance too much
vs too little?
Lecture Outline
Context ovarian stimulation
Impact ovarian stimulation on oocyte / embryo
Wider implications
Why ovarian stimulation ?
Retrieve multiple oocytes for IVF procedure
Have multiple embryos available to choose from
Compensate for suboptimal fertilisation and
implantation
Have access embryos for cryostorage
Improve IVF outcomes
Compounds ovarian stimulation (2)
approaches compounds
Stimulation Gonadotropins (urine, rec)
CC, aromatase inhibitors,
insulin sensitizers
Co-treatment (1) GnRH agonist, antagonist
Co-treatment (2) LH, hCG, androgens, GH, etc
Oocyte maturation
triggering
hCG, GnRH agonist bolus
Pre-stimulation GnRH agonist flare, OC,
Estrogens
Post-stimulation Prog, Estrogens, hCG, GnRHa
Sequela of ovarian
stimulation for IVF
(Oehninger & Hodgen. Baill Clin Obstet Gyecol 1990)
Consequences for luteal phase endocrinology
Endometrial receptivity
Embryo quality/aneuploidy
74% of failed IVF = failed implantation
started oocyte embryo pregnancy ongoing
cycle retrieval transfer pregn
92% 81%
27% (37% cum)
21% (27% cum)
Total 16.898 started cycle
48% ICSI
Cum = fresh+froozen ET
91% singleton pregnancies
IVF results, The Netherlands, 2010
Optimal number of oocytes for IVF
- the more the better ??
Patient
perspective
So
cie
ty
pers
pecti
ve
C
hild
pers
pectiv
e
Relevant studies in mice
Superovulation in mice causes
Reduced oocyte quality
Reduced embryo quality
Delayed pre-implantation embryo development
Reduced implantation
Fetal growth retardation
Abnormal methylation of imprinted loci
Negative impacts on oviductal and uterine milieu
Laprise, Mol Reprod & Dev 2009
Objective Chromosome error rate from oocytes
generated for ICSI in women < 35 yrs
Patients N=933 couples undergoing ICSI
Methods Polar body testing
chromosomes 13,16, 18, 21, 22
conclusions High yield of oocytes is associated with
increased chromosome error rate
Results; chromosome error rate in relation to Oocyte No.
Oocyte # 1-5 6-10 > 10
Chromosome
error rate 23+5% 35+4% 51+6%
Objective Study effects of FSH on
aneuploidy in IVM oocytes
Patients Male factor infertility, ICSI
(86 cycles, 252 oocytes)
Interventions FSH; 0.5; 5.5; 22; 100; 2000 ng/ml
Polar body biopsy; chrom 13, 16, 18, 21, 22
Results Aneuploidy rate;
27, 23, 37, 47, and 63%, respectively
conclusion High FSH concentrations during IVM
sign. increases first meiotic division error
Fertil Steril 2010
Oocyte # / PU 1 10 20 30 0
2
4
6
20
60
100
C
0
2
4
6
20
60
100
B
0
2
4
6
20
60
100
A
P < 0.01
Cumulative
pregnancies
Pregnant
Non-pregnant
JCEM 2003
Embryo quality in relation to ovarian stimulation,
pregnancy chances in relation to embryo quality
Hohmann, JCEM 2003
Embryo quality and embryo selection
- the bigger picture
Female age
PCOS
Ovarian stimulation
Follicle /
oocyte development
Sperm quality
Embryo culture
conditions
Morphology criteria
Day of transfer
Time laps monitoring
Omics
# embryos transferred
Cryotechnology
ET technology
Endometrial receptivity
GnRH agonist (long prt)
rFSH (225 IU/d)
CD 2 5 foll > 14 mm
GnRH antag
rFSH (150 IU)
PGS: 2 blastomeres 10 chromosomes 1, 7, 15, X, and Y 13, 16, 18, 21, 22
111 Patients 528 fertilized oocytes 302 embryos FISHed
RCT
40 33 N =
% a
bn
orm
al
em
bry
os d
iag
no
se
d
100%
80%
60%
40%
20%
0%
Conventional
Mild
Embryo aneuploidy for
mild vs conventional stimulation
P = 0.016
F&S 2014
Study
objective
Evaluate dose response new rFSH
Study influence of initial AMH
Design
RCT, 7 centers,
265 women undergoing IVF/ICSI,
AMH stratified
F&S 2014
Study objective Evaluate dose response new rFSH
Study influence of initial AMH
Design RCT, 7 centers, 265 women undergoing IVF/ICSI,
AMH stratified
Results
Dose dependent increase in oocyte No in relation to rFSH
dose
Slope dose response differed in relation to AMH
Fertilization rate and blastocyst/oocyte ratio decreased
with increasing rFSH
No linear releationship between rFSH dose and
blastocyst No
conclusion
Increasing rFSH results in linear increase in oocyte No
Increase in oocyte number dependent on initial AMH
Blastocyst number less dependent on rFSH or AMH
Ovarian hyperstimulation for IVF
- the bigger picture
Ovarian
stimulation
cost Burden of treatment
Drop out (cum
outcomes)
monitoring
complex
Complications (OHSS)
contribute to success?
Drop out Access to
treatment