1 / 47

Optimizing success in ovarian stimulation for IVF-ICSI

Optimizing success in ovarian stimulation for IVF-ICSI. Dr. E. Bosch. Instituto Valenciano de Infertilidad Valencia, Spain ebosch@ivi.es www.ivi.es. Aim in Ovarian Stimulation for IVF-ET: Embryo implantation.

tekli
Download Presentation

Optimizing success in ovarian stimulation for IVF-ICSI

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Optimizing success in ovarian stimulation for IVF-ICSI Dr. E. Bosch Instituto Valenciano de Infertilidad Valencia, Spain ebosch@ivi.es www.ivi.es

  2. Aim in Ovarian Stimulation for IVF-ET: Embryo implantation • Obtain enough mature and good quality oocytes to ensure a nice embryo cohort for a maximum quality embryo transfer • Provide an adequate endocrine milieu for optimizing endometrial receptivity

  3. Optimizing ovarian response Ongoing PR *p < 0.000001 * M-H test for trend

  4. 0.90 (0.76-1.05) 0.95 (0.72-1.24) 0.80 (0.60-1.06) 0.65 (0.48-0.87)* 0.54 (0.40-0.74)* 0.54 (0.38-0.76)* 0.38 (0.24-0.59)* 0.38 (0.23-0.63)* 0.19 (0.07-0.47)* Optimizing ovarian response OR (CI 95%) 0.69 (0.52-0.91)* OR

  5. P4 E2 Variation of hormonal profile in COH for IVF MULTIPLE FOLLICULAR DEVELOPMENT PREMATURE LUTEINIZATION

  6. Normal Responder High Responder No. cycles 114 63 Age 33.1 ± 3.8* 30.3 ± 2.8 Dose of gonadotropins 25.5 ± 6.8 24.7 ± 5.5 E2 day hCG (pg/ml) 1410 ± 780* 3194 ± 1637 Oocytes 8.5 ± 2.8 25.7 ± 9.6* Fertilization rate (%) 65.5 ± 24.1 59.6 ± 25.2 Embryos transferred 3.1 ± 1.4 3.3 ± 1.2 No.pregnancies (%) 38/114 (33.3)* 10/61 (16.4) Implantation (%) 48/432 (11.1)* 14/258 (5.4) *P<0.05 IVF outcome according to ovarian response Simón et al. Hum Reprod 1995;10:2432

  7. IVF outcome and serum E2 levels % 60 Pregnancy (%) Implantation (%) 50 40 30 20 10 0 <500 <1000 <1500 <2000 <2500 <3000 <3500 >3500 Serum E2 Simón et al. Hum Reprod 1995 ; 10:2432

  8. Normal High responder responder Cycles 216 108 Age 36.7 ± 0.3 36.1 ± 5.5 Oocytes 8.1 ± 0.1 8.2 ± 2.9 Fertilization (%) 71.3 ± 17.2 76.5 ± 20.2 Embryos transferred 4.0 ± 0.1 4.1 ± 1.0 Pregnancies/cycle 114/216 (52.8) 58/108 (53.7) Implantation (%) 157/880 (17.8) 77/517 (14.9) Ovum donation outcome according to origen of oocytes Simón et al. Hum Reprod 1995 ; 10:2432

  9. E2 / P Ratio from Day 0 (hCG) to Day 6 • Altered endocrine envoirenment: Increased serum E2 in the preimplantatory period. Lower implantation rates in high responders: evidence for an altered endocrine milieu during the preimplantation period Pellicer A. et al. Fertil. Steril. 1996; 65: 1190

  10. Step down regimen for ovulation induction Controlled ovarian stimulation Simón C., et al. . Fertil. Steril.1998; 70: 234

  11. Step down vs Standard Step-down Standard Patients 24 62 Age 31.6 ± 1.2 33.8 ± 0.3 Ampules of gonadotropins 22.4 ± 0.8 31.6 ± 1.6 Serum E2 (pg/ml) 1919 ± 477 5271 ± 613* Oocytes 18.1 ± 2.1 23.1 ± 1.6 Fertilization (%) 74.2 76.1 Embryos transferred 3.3 ± 0.2 3.4 ± 0.2 Pregnancy (%) 64.2 24.2* Implantation (%) 29.3 8.5* Hyperstimulation (%) 0 12.9* *p<0.05 Simón C., et al. Fertil. Steril.1998; 70: 234

  12. Dose of E2 EEC To analyze the effect of estradiol on the embryonary adhesion phase in vitro Human endometrium biopsy Embryo culture Valbuena et al Fertil Steril 2001

  13. Day 7(adhesión) Day 2 Day 5 Blast 1. Effect of estradiol on endometrium and embryo EEC E2 Blast EEC 2. Effect of estradiol on endometrium E2 Emb EEC 3. Effect of estradiol on the embryo E2 Dose-response experiments Valbuena et al Fertil Steril 2001

  14. Endometrium and embryo are treated Only the endometrium is treated 80 80 * 70 * 60 * 60 50 * 40 40 30 20 20 10 0 Control (0) E2: 10-8 M E2: 10-7 M E2: 10-6 M E2: 10-5 M E2: 10-4 M Dose of estradiol Only the embryo is treated Embryo development 0 100% Control (0) : 10-8 M 10-7 M 10-6 M : 10-5 M : 10-4 M 90 Dose of estradiol 90% * 80 80% * 70 70% 60 * 60% 50 50% 40 40% 30 30% 20 20% 10 10% 0 Control (0) E2: 10-8 M E2: 10-7 M E2: 10-6 M E2: 10-5 M 0% Control E2: 10-8 E2: 10-7 E2: 10-6 E2: 10-5 E2: 10-4 Dose of estradiol Hatched Hatching Extended Cavited Early Degen. Effect of estradiol on the embryonary adhesion phase in vitro

  15. CONTROL E2 10-8 E2 10-7 E2 10-6 E2 10-5 E2 10-4

  16. The predictive value of Estradiol:Oocyte in IVF/ICSI-ET outcome Retrospective analysis of 3152 cycles (until 42 years) GnRH agonists, long protocol GnRH Antagonists, daily doses 1,0 1,0 0,8 0,8 0,6 0,6 0,4 0,4 0,2 0,2 0,0 0,0 0,0 0,2 0,4 0,6 0,8 1,0 0,0 0,2 0,4 0,6 0,8 1,0 1 - Especificidad 1 - Especificidad AUC=0,54 (IC 95%: 0,51-0,57); p=0,011 AUC=0,53 (IC 95%: 0,50-0,55); p=0,049 Labarta et al (2006) Fertil Steril 86, Sup.2: S435 B: GnRH antagonist daily protocol Sensibility 1-Specificity

  17. The predictive value of Estradiol:Oocyte in IVF/ICSI-ET outcome Pregnancy and implantation rates according to estradiol:oocyte ratio GnRH agonists, long protocol * p<0.05 GnRH antagonists, daily doses Labarta et al (2006) Fertil Steril 86, Sup.2: S435

  18. The predictive value of Estradiol:Oocyte in IVF/ICSI-ET outcome GnRH agonists GnRH antagonists

  19. LH FSH Impact of LH activity on ovarian response E2:Oocyte

  20. Summary: High serum E2 High E2 levels are associated to poor IVF outcome. Soft stimulation protocols improve implantation and pregnancy rates. The in vitro animal model shows a similar behaviour, where a progressive reduction in embryonic adhesion to monolayers of endometrial epithelial cells is observed There is a surprisingly negative effect on embryo development. E2 follicular production is related to LH activity

  21. Premature luteinization Serum Progesterone elevation (> 1.0-1.5 ng/mL) at the end of the follicular phase, before hCG administration *5-35 % of cycles with a GnRH agonist (Edelstein et al, 1990, Silverberg et al, 1991) *20-38% of cycles with a GnRH antagonist ( Ubaldi et al, 1996. Bosch et al, 2003)

  22. ng/mL Papanikolau et al 1.5 Bosch et al 1.2 Ubaldi et al 1.1 Check et al Shechter et al 1.0 Edelstein et al Siverberg et al Hoffmann et al Miller et al Moffitt et al Urman et al Martínez et al 0.9 Progesterone Premature luteinization: Threshold (ng/mL)

  23. Premature luteinization: Effect on pregnancy rate Venetis et al, (2007) Hum Reprod Update 13: 343-55

  24. Premature luteinization: Effect on pregnancy rate 0.75 0.53-1.06 0.10 OR of Clinical PR -0.10 -0.22-1.02 0.10 RD for Clinical PR Venetis et al, (2007) Hum Reprod Update 13: 343-55

  25. Premature luteinization: Effect on pregnancy rate Bosch et al (2003) Fertil Steril 80: 1444-9

  26. Premature luteinization: Effect on pregnancy rate O.R. (CI 95%) = 0.30 (0.11-0.79); p=0.015 Bosch et al (2003) Fertil Steril 80: 1444-9

  27. Premature luteinization: Effect on pregnancy rate 0.534 (0.407-0.660) N.S. 0.581 (0.453-0.709) N.S. 0.672 (0.555-0.789) p=0.008. Bosch et al (2003) Fertil Steril 80: 1444-9

  28. Premature luteinization: Effect on pregnancy rate GnRH agonists n=368; Age: 33.1 ± 3.6 GnRH antagonists n=1321; Age: 35.5 ± 4.2 p=0.09 *p=0.04 170/313 540/1096 94/225 23/55 IVI Valencia 2003-2006

  29. Premature luteinization: Effect on pregnancy rate OR (CI 95%); p 0.74 (0.55-0.99); p=0.04 0.70 (0.34-1.08); p=0.09 IVI Valencia 2003-2006

  30. *p = 0.001 * MH test for trend Premature luteinization: Effect on pregnancy rate (n=1857; Age: 35.0 ± 4.2) IVI Valencia 2003-2006

  31. Premature luteinization: Effect on pregnancy rate OR (CI 95%) 0.92 (0.66-1.30) 0.85 (0.59-1.21) 0.58 (0.38-0.88)* 0.55 (0.35-0.93)* IVI Valencia 2003-2006

  32. Premature luteinization: Negative impact Oocyte Endometrium

  33. DONOR CYCLE with P4 ≥ 1.2 ng/ mL CYCLE with P4 < 1.2 ng/ mL Premature luteinization in GnRH agonist egg donation cycles Material and Methods Retrospective study (01/ 2003-12/ 2004) 289 egg donation cycles n= 148 n= 141 Melo et al (2006) Hum Reprod 21: 1503-7

  34. Premature luteinization in GnRH agonist egg donation cycles OOCYTE AND EMBRYO QUALITY P<1.2 ng/mL (n= 148) CHARACTERISTICS P≥1.2 ng/mL (n= 141) 16.9 ± 0.6 * 19.4 ±0.6 * MATURE OOCYTES 69.2 ±2.1 68.2 ±1.9 FERTILIZATION (%) 90.6 ±2.4 89.7 ±2.3 CLEAVAGE (%) 7.9 ±0.6 8.1 ±0.6 FRAGMENTATION (%) 45.9 ±13.3 45.7 ±10.3 BLASTOCYST (%) 1.9 ±0.02 2.0 ±0.03 # EMB. TRANSF 1.5 ±0.2 1.4 ±0.2 # EMB. CRYOPRSVD 24.0 ±2.9 IMPLANTATION (%) 26.6 ±3.3 56.5 PREGNANCY (%) 57.6 14.9 MISCARRIAGE (%) 7.6 * p< 0.05 Melo et al (2006) Hum Reprod 21: 1503-7

  35. Endometrium in gonadotropin stimulated cycles Kolibianakis et al, (2002), Fertil Steril, 78: 1025-29

  36. Premature luteinization: OriginOvarian stimulation FSH requirement Duration of FSH stimulation Venetis et al, (2007) Hum Reprod Update 13: 343-55

  37. Premature luteinization: OriginOvarian response Serum E2 on day of hCG Oocytes retrieved Venetis et al, (2007) Hum Reprod Update 13: 343-55

  38. Premature luteinization: Origin Multivariate analysis: Logistic regression Included variables E2 on stimulation day 3 Days of stimulation Days with Antagonist Total dose of FSH Age LH on day of hCG E2 on day of hCG Significantly associated variables Total dose of FSH; p=0.009 E2 on day of hCG; p=0.02 Bosch et al (2003) Fertil Steril 80: 1444-9

  39. Premature luteinization: Origin Filicori et al, (2002), Hum Reprod, 17: 2009-15

  40. Cholesterol Progesterone Androgens Androgens Estrogens Premature luteinization: Origin LH FSH theca granulosa Cholesterol Progesterone x X At Luteinization androgens

  41. GnRH-Agonist Control with Purified FSH Circulating Progesterone in the follicular phase Factors Likely to influence progesterone in the blood include: The number of follicles (↑) The circulating FSH (drive to granulosa cells) (↑) The circulating LH (drive to theca and granulosa cells) (↓) Progesterone can derive from granulosa cells and theca cells, but theca cells have a further metabolic step. High progesterone concentrations will influence endometrial dating. Analysis of 40 consecutive cycles Adonakis et al, (1998), Fertil Steril, 69: 450-3

  42. GnRH-Agonist Control with Purified FSH >5Fols,FSH>12,<LH >FSH, <LH >FSH, nLH Normal Range: Day of LH peak Factors Affecting Progesterone: LH 3.5 3.0 2.5 Progesterone (ng/ml) 2.0 1.5 nFSH, >LH nFSH, nLH 1.0 0.5 -4 -3 -2 -1 HCG Adonakis et al, (1998), Fertil Steril, 69: 450-3

  43. Circulating Progesterone in the Follicular Phase The evidence indicates that both GCs and TCs contribute: - The GCs do so under FSH drive - The TCs do so when catabolism to androgens is reduced The main contributors are: The numbers of follicles (↑) The FSH drive (↑) The ability of LH to increase the catabolism of P4 (to androgens) in the theca cells (↓) Adonakis et al, (1998), Fertil Steril, 69: 450-3

  44. Premature luteinization: Summary There is a negative association between circulating progesterone levels in the late follicular phase in COH cycles for IVF, before hCG administration, and pregnancy rate. When progesterone > 1.5 ng/mL on day of hCG, pregnancy rate diminishes significantly. This negative association has shown to be statistically significant in GnRH antagonist cycles, while remains to be demonstrated in GnRH agonist cycles: The evaluation of larger series with an appropriate (higher) threshold progesterone value could lead to a similar outcome.

  45. Premature luteinization: Summary The evidence available suggests that the negative impact of premature luteinization on pregnancy rate is related to its influence on endometrial dating, diminishing its receptivity, rather than to a detrimental effect on oocyte quality. Increased serum progesterone is related to high circulating FSH concentrations that provide the development of more follicles augmenting total GC activity. Therefore, premature luteinization appears associated to high serum E2 levels the day of hCG. LH diminishes progesterone through its catabolism to androgens in TC.

  46. Conclusions Ovarian response of  8 oocytes ensures maximum ongoing PR Small changes in ovarian stimulation may have a capital influence on the hormonal milieu at the moment of embryo implantation High E2 (LH dependent) and P (FSH dependent) levels have a negative impact on cycle outcome due to their effect on embryo quality (high E2) and endometrial recpetivity (E2 and P) Soft stimulation protocols and a rational use of LH can provide an optimal endocrine milieu for implantation

  47. C.Albert • P. Buendía • Cobo • A. Delgado • M.J. De los Santos • J.M. De los Santos • M.J. Escribá • B. Gadea • A. Galán • P. Gámiz • A. Mercader • M. Meseguer • T. Pehlivan • J. Romero • C. Rubio • A. Tejera • T. Viloria • J. Zulategui • P. Alamá • J. Bellver • E. Bosch • E. Budak • G. Coelho • J. Crespo • J. Domingo • A. Fernández • M. Ferrando • J. Ferro • J. Giles • E. Labarta • M. Melo • Pellicer • J. Remohí • C. Simón • C. Vidal

More Related