Influence ovarian stimulation on oocyte and embryo quality. Prof.Dr. Bart CJM Fauser

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1 Influence ovarian stimulation on oocyte and embryo quality Prof.Dr. Bart CJM Fauser

2 How to balance too much vs too little? Lecture Outline Context ovarian stimulation Impact ovarian stimulation on oocyte / embryo Wider implications

3 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

4 Compounds ovarian stimulation (2) approaches Stimulation Co-treatment (1) Co-treatment (2) Oocyte maturation triggering Pre-stimulation Post-stimulation compounds Gonadotropins (urine, rec) CC, aromatase inhibitors, insulin sensitizers GnRH agonist, antagonist LH, hcg, androgens, GH, etc hcg, GnRH agonist bolus GnRH agonist flare, OC, Estrogens Prog, Estrogens, hcg, GnRHa

5

6 Conventional superovulation strategy for IVF (Oehninger & Hodgen. Baill Clin Obstet Gyecol 1990)

7 Sequela of ovarian stimulation for IVF (Oehninger & Hodgen. Baill Clin Obstet Gyecol 1990) Consequences for luteal phase endocrinology Endometrial receptivity Embryo quality/aneuploidy

8 74% of failed IVF = failed implantation 92% 81% Total started cycle 48% ICSI Cum = fresh+froozen ET 91% singleton pregnancies 27% (37% cum) 21% (27% cum) started oocyte embryo pregnancy ongoing cycle retrieval transfer pregn IVF results, The Netherlands, 2010

9 Society perspective Optimal number of oocytes for IVF - the more the better?? Child perspective Patient perspective

10 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

11 HR 2012 Iive birth in relation to oocyte yield

12 Objective Patients Methods conclusions Chromosome error rate from oocytes generated for ICSI in women < 35 yrs N=933 couples undergoing ICSI Polar body testing chromosomes 13,16, 18, 21, 22 High yield of oocytes is associated with increased chromosome error rate Results; chromosome error rate in relation to Oocyte No. Oocyte # > 10 Chromosome error rate 23+5% 35+4% 51+6%

13 Fertil Steril 2010 Objective Patients Interventions Results conclusion Study effects of FSH on aneuploidy in IVM oocytes Male factor infertility, ICSI (86 cycles, 252 oocytes) FSH; 0.5; 5.5; 22; 100; 2000 ng/ml Polar body biopsy; chrom 13, 16, 18, 21, 22 Aneuploidy rate; 27, 23, 37, 47, and 63%, respectively High FSH concentrations during IVM sign. increases first meiotic division error

14 2011

15 JCEM P < 0.01 A Pregnant Non-pregnant Cumulative pregnancies 6 4 B C Oocyte # / PU

16 Embryo quality in relation to ovarian stimulation, pregnancy chances in relation to embryo quality Hohmann, JCEM 2003

17 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

18 RCT GnRH agonist (long prt) rfsh (225 IU/d) GnRH antag rfsh (150 IU) CD 2 5 foll > 14 mm PGS: 2 blastomeres 10 chromosomes 1, 7, 15, X, and Y 13, 16, 18, 21, Patients 528 fertilized oocytes 302 embryos FISHed

19 Correlation between oocyte number and embryo aneuploidy Baart, HR 2007

20 Embryo aneuploidy for mild vs conventional stimulation % abnormal embryos diagnosed 100% 80% P = Conventional Mild 60% 40% 20% 0% N = 33 40

21 HR 2007 Average per patient ** * Conventional Mild 4 0

22 Lancet 2007

23 Implantation rate 2009 Mild stimulation Conventional stimulation

24 F&S 2014 Study objective Design Evaluate dose response new rfsh Study influence of initial AMH RCT, 7 centers, 265 women undergoing IVF/ICSI, AMH stratified

25 Oocyte # retrieved in relation to rfsh dose Arce, F&S 2014

26 Arce, F&S 2014 Oocyte No in relation to No good quality blastocysts

27 F&S 2014 Study objective Design Results conclusion Evaluate dose response new rfsh Study influence of initial AMH RCT, 7 centers, 265 women undergoing IVF/ICSI, AMH stratified 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 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

28 Ovarian hyperstimulation for IVF - the bigger picture Access to treatment cost Burden of treatment Drop out (cum outcomes) Drop out complex monitoring Ovarian stimulation contribute to success? Complications (OHSS)

29 Recent papers in favour of mild stimulation IVF

30 PhD s thesis mild IVF

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