IMPART, Dubai 2013

Number of Oocytes and
Progesterone Levels in IVF
Success
Do they matter?
Sandro C. Esteves, MD, PhD
Di...
Number of oocytes and
progesterone levels in IVF success
http://www.androfert.com.br/review

ANDROFERT

ANDROLOGY AND HUMA...
Learning Objectives
Importance of number of oocytes and its
relation to live birth
Differences between gonadotropin
prepar...
Evidence
Level
1a

Predictive factors for pregnancy
in ART

Female Age
Duration of infertility
Basal FSH
Type of infertili...
Number of oocytes retrieved and
live birth rates
Observed live birth rate

Predicted live birth rate

45%
number of oocyte...
...in all age groups

Esteves, 6

ANDROFERT, Referral Center for Male Reproduction
Gonadotropin Preparations
and Oocyte Yield

Esteves, 7

ANDROFERT, Referral Center for Male Reproduction
Evidence
Level
1b

RCT and meta-analyses comparing oocyte
yield with different gonadotropins
↑ 1.5 oocytes (GnRH antagonis...
It relates to the way the
drug is made, filled and
delivered

Protein content in
solution by mass
(FbM) in rec-FSH

Protei...
Quantity vs. Quality
which one come first?
• Oocyte/embryo quality?
• Endometrial receptivity?

Esteves, 10

ANDROFERT, Re...
Morphology-based embryo quality
and number of oocytes
Embryo quality score

Implantation rate (%)

A large oocyte
1,301 cy...
Aneuploidy and Oocyte Yield

Aneuploidy rate %

60

634 patients; 3,688 oocytes; PB biopsy

50

<35 years

40

35-40 years...
Aneuploidy and Oocyte Yield
• Array CGH analysis in D3 and D5 embryos
• 7753 embryos from 990 patients
• Linear regression...
What we have learned
There is a strong association between the
number of oocytes retrieved and live birth
rates in IVF
The...
What we have learned
Aneuploidy in oocytes increases with maternal
age, but it is unaffected by cohort size in
women aged ...
How to get the best results
oocyte quality vs. quantity

Increasing oocyte yield is an opportunity to have
more euploid em...
More is good, but does it affect
implantation?
• Oocyte/embryo quality?
• Endometrial receptivity?

Esteves, 17

ANDROFERT...
Effect of progesterone levels on
pregnancy in IVF – Do they matter?
Fresh

Frozen-thawed

Donor/recipient

P
ng/mL

63 stu...
Progesterone levels in
stimulated cycles
Number of oocytes
Estradiol levels
FSH dose
Rec-hFSH vs. hMG

positively
associat...
No CYP17
LH

Esteves, 20

FSH
LH
hMG

Grondal et al. 2009:

r-FSH

P levels with rec-hFSH and hMG
GCs gene expression in pts. treated with
hMG and rec-hFSH...
What we know about progesterone
levels in stimulated cycles
Most circulating Progesterone (95%) is produced in
the intrafo...
Progesterone levels
and pregnancy
Bosch et al. 2010 (N=4,032)
Irrespective of GnRH analogue;
Cut-off = 1.5 ng/mL
Xu et al,...
Do we need to measure P levels at hCG
day in stimulated cycles?
How often P4 rise:
Overall: 8.4%
Low-responder: 4.5%
High-...
Effects of progesterone levels at hCG day
on pregnancy
Intrafollicular P4 is a terminal product. It cannot be
converted to...
ANDROFERT

Number of oocytes and cumulative
live birth rate

Esteves, 26

+25.0%

Female Age ≤38
+18.8%

40,4%

ET #1 (fre...
Cumulative live birth to improve
treatment outcome in ART
Pillar #1 – IVF facilities

Esteves, 28

ANDROFERT, Referral Cen...
Esteves & Bento. RBM Online 2013
Esteves & Bento. RBM Online 2013
Cumulative pregnancy to improve
treatment outcome in ART
Pillar #2 – Blastocyst Culture
Identify the embryos with
optimal ...
Identification of Embryos with Optimal
Development Potential

Time-lapse Technology
Videomicrography + Computer Vision Sof...
Cumulative pregnancy to optimize
treatment outcome in ART
Pillar #3 – Vitrification
Vitrification vs. Slow-freezing
Ongoin...
Cumulative pregnancy rate as a
strategy to improve success in IVF
The most important endpoint
for the patient
Allow estima...
Conclusions (1)
The number of oocytes retrieved is a key factor for
optimizing live birth rates
COS should be tailored to ...
Conclusions (2)
Progesterone levels on hCG day are related to
number of follicles developed (GCs) and
oocytes retrieved
No...
Conclusions (3)
Cumulative live birth is a key strategy to
optimize success in ART
Stimulation Protocol and Number of Oocy...
obrigado

Thank You
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Number of oocytes and progesterone levels in IVF: Do they matter?

  1. 1. IMPART, Dubai 2013 Number of Oocytes and Progesterone Levels in IVF Success Do they matter? Sandro C. Esteves, MD, PhD Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, Brazil
  2. 2. Number of oocytes and progesterone levels in IVF success http://www.androfert.com.br/review ANDROFERT ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION S ESTEVES, 2 2013 DECEMBER ANDROFERT androfert.com.br
  3. 3. Learning Objectives Importance of number of oocytes and its relation to live birth Differences between gonadotropin preparations in oocyte yield Effect of progesterone levels at the day of hCG administration on pregnancy chances Cumulative live birth rates as a measure of success in IVF Esteves, 3 ANDROFERT, Referral Center for Male Reproduction
  4. 4. Evidence Level 1a Predictive factors for pregnancy in ART Female Age Duration of infertility Basal FSH Type of infertility Indication Fertilization method Number of oocytes retrieved Number of embryos transferred Embryo quality Negative Predictors Positive Predictor van Loendersloot et al. Hum Reprod Update 2010 Esteves, 4 ANDROFERT, Referral Center for Male Reproduction
  5. 5. Number of oocytes retrieved and live birth rates Observed live birth rate Predicted live birth rate 45% number of oocytes that best optimized LBR was 15 Live birth rate (%) 40% 35% 30% 25% 450,135 IVF cycles 20% 15% 10% 5% 0% 1 Esteves, 5 2 3 4 5 6 7 8 9 10 11 12 13 14 15 20 25 30 35 40 Oocyte number Sunkara et al. Hum Reprod 2011 ANDROFERT, Referral Center for Male Reproduction
  6. 6. ...in all age groups Esteves, 6 ANDROFERT, Referral Center for Male Reproduction
  7. 7. Gonadotropin Preparations and Oocyte Yield Esteves, 7 ANDROFERT, Referral Center for Male Reproduction
  8. 8. Evidence Level 1b RCT and meta-analyses comparing oocyte yield with different gonadotropins ↑ 1.5 oocytes (GnRH antagonist cycles) Devroey et al., 2012 No. Oocytes retrieved higher with Rec-FSH vs. hMG, HP-hMG, and uFSH ↑ 2.1 oocytes (16 RCT; different protocols) Lehert et al., 2010 ↑ 3.1 oocytes (GnRH antagonist cycles) Bosch et al., 2008 ↑ 2.8 oocytes (GnRH agonist cycles) Hompes et al., 2008 ↑ 1.8 oocytes (GnRH agonist cycles) MERIT Study, 2006 Esteves, 8 ANDROFERT, Referral Center for Male Reproduction
  9. 9. It relates to the way the drug is made, filled and delivered Protein content in solution by mass (FbM) in rec-FSH Protein content hMG hMG-HP Specific activity (IU/mg protein) Injected protein per 75 IU (mcg) < 5% ~100 ~750 < 70% 2,000–2,500 ~33 13,645 Size Exclusion High Performance Liquid Chromatography (SE- HPLC) 6.1 rec-hFSH* > 99% *Follitropin alfa; Bassett et al. Reprod Biomed Online 2005 Esteves, 9 ANDROFERT, Referral Center for Male Reproduction
  10. 10. Quantity vs. Quality which one come first? • Oocyte/embryo quality? • Endometrial receptivity? Esteves, 10 ANDROFERT, Referral Center for Male Reproduction
  11. 11. Morphology-based embryo quality and number of oocytes Embryo quality score Implantation rate (%) A large oocyte 1,301 cycles 23 cohort was the 17 main factor that increased the 3,8 4,5 chance of having at least one good 1-6 oocytes embryo 7-15 oocytes 27 p<0.001 4,8 >15 oocytes Devreker et al Hum Reprod 1999 Esteves, 11 ANDROFERT, Referral Center for Male Reproduction
  12. 12. Aneuploidy and Oocyte Yield Aneuploidy rate % 60 634 patients; 3,688 oocytes; PB biopsy 50 <35 years 40 35-40 years >40 years 30 20 10 0 p<0.001 The higher the oocyte cohort, the higher the number of EUPLOID oocytes in all age groups 1-5 oocytes 6-10 oocytes >10 oocytes Haaf et al Fertil Steril 2009 Esteves, 12 ANDROFERT, Referral Center for Male Reproduction
  13. 13. Aneuploidy and Oocyte Yield • Array CGH analysis in D3 and D5 embryos • 7753 embryos from 990 patients • Linear regression analysis adjusted by maternal age Higher aneuploidy rate in older women irrespective of embryo number Higher number of euploid embryos with increased cohort size Ata et al Reprod Biomed Online. 2012 Esteves, 13 ANDROFERT, Referral Center for Male Reproduction
  14. 14. What we have learned There is a strong association between the number of oocytes retrieved and live birth rates in IVF The optimum number of oocytes needed to maximize IVF outcomes seems to be about 15 Recombinant gonadotropin preparations are more potent and result in an increased oocyte yield Esteves, 14 ANDROFERT, Referral Center for Male Reproduction
  15. 15. What we have learned Aneuploidy in oocytes increases with maternal age, but it is unaffected by cohort size in women aged 35 or older Among young women, an increased incidence of aneuploid oocytes seems to be associated with higher oocyte cohort The higher the cohort size, the higher the number of euploid oocytes and embryos regardless of age Esteves, 15 ANDROFERT, Referral Center for Male Reproduction
  16. 16. How to get the best results oocyte quality vs. quantity Increasing oocyte yield is an opportunity to have more euploid embryos The goal is to obtain ~15 oocytes avoiding OHSS COS should be tailored to the individual phenotype, maximizing the number of oocyte yield for poor responders and fine-tuning for hyper-responders Esteves, 16 ANDROFERT, Referral Center for Male Reproduction
  17. 17. More is good, but does it affect implantation? • Oocyte/embryo quality? • Endometrial receptivity? Esteves, 17 ANDROFERT, Referral Center for Male Reproduction
  18. 18. Effect of progesterone levels on pregnancy in IVF – Do they matter? Fresh Frozen-thawed Donor/recipient P ng/mL 63 studies; N = 55,199 9 studies; N =7,229 8 studies; N = 1,330 LBR/OPR CPR CPR 0.8-1.1 OR: 0.72 OR: 1.18 (0.76 – 1.84) OR: 0.64 OR: 1.03 (0.79 – 1.34) OR: 0.83 (0.62 – 1.32) (0.64 – 4.05) OR: 0.62 (0.57 – 0.69) OR: 1.13 (0.97 – 0.69) - OR: 0.67 OR: 1.03 OR: 0.51 (0.55 – 0.81) (0.84 – 1.27) (0.12 – 2.19) 1.2-1.4 1.5-1.75 1.9-3.0 (0.56 – 0.94) (0.53 – 0.77) OR: 1.61 P levels not related to oocyte and embryo quality, nor with fertilization and cleavage rates Venetis et al., Hum Reprod Update 2013 Esteves, 18 ANDROFERT, Referral Center for Male Reproduction
  19. 19. Progesterone levels in stimulated cycles Number of oocytes Estradiol levels FSH dose Rec-hFSH vs. hMG positively associated with P levels Bosch et al. 2008, 2010; Xu et al, 2012; Kolibianakis et al 2012; Venetis et al. 2012; Griesinger et al 2013 Esteves, 19 ANDROFERT, Referral Center for Male Reproduction
  20. 20. No CYP17 LH Esteves, 20 FSH LH
  21. 21. hMG Grondal et al. 2009: r-FSH P levels with rec-hFSH and hMG GCs gene expression in pts. treated with hMG and rec-hFSH  Lower expression of LH/hCG receptor gene and other genes involved in steroids biosynthesis with hMG Down-regulation of receptors owed to constant ligand exposure to hCG (Menon et al. 2004) CYP11A activity decreased by 2.4-fold Lower steroids synthesis and P levels  Higher potency of rec-hFSH inducing more LH/hCG receptors Esteves, 21 Grondal ML et al. Fertil Steril 2009; 91: 1820-1830. Menon KM et al. Biol Reprod 2004; 70:861-866
  22. 22. What we know about progesterone levels in stimulated cycles Most circulating Progesterone (95%) is produced in the intrafollicular compartment by granulosa cells Higher serum P are related to more follicles developed (more GCs) and more oocytes retrieved Treatment with rec-hFSH results in higher P levels than hMG Rec-hFSH has higher FSH bioactivity (increased GCs and oocyte yield HMG induces underexpression of genes involved in steroids synthesis Bosch et al,. Hum Reprod. 2008 ;23(10):2346-51; Grøndahl ML, et al. Fertil Steril 2009; 91(5): 1820-30. Esteves, 22 ANDROFERT, Referral Center for Male Reproduction
  23. 23. Progesterone levels and pregnancy Bosch et al. 2010 (N=4,032) Irrespective of GnRH analogue; Cut-off = 1.5 ng/mL Xu et al, 2012 (N=11,055) GnRH agonist Ovarian response Number of oocytes Serum P threshold (ng/mL) Poor ≤4 1.5 Intermediate 5-19 1.75 High ≥20 ■ Fresh ■ FET 2.25 Esteves, 23 ANDROFERT, Referral Center for Male Reproduction
  24. 24. Do we need to measure P levels at hCG day in stimulated cycles? How often P4 rise: Overall: 8.4% Low-responder: 4.5% High-responder: 19% 6 RCT, N=1866; Antagonist cycles OPR not impaired in high responders with P elevation Ongoing PR: OR = 0.55 (0.37–0.81) Griesinger et al. Fertil Steril 2013 Esteves, 24 ANDROFERT, Referral Center for Male Reproduction
  25. 25. Effects of progesterone levels at hCG day on pregnancy Intrafollicular P4 is a terminal product. It cannot be converted to estradiol by GCs under the effect of gonadotropins containing hCG. The expression of CYP17 needed for this pathway is negligible Conflicting data on what levels Progesterone is detrimental to implantation in fresh transfers. P levels not so critical in women with high oocyte yield Adequate number of embryos for freezing and FET is an opportunity to overcome any detrimental effect of P4 on the endometrium Wickenheisser et al. Trends Endocrinol Metab. 2006; 17(2): 65-71; Nguyen PT et al. J Theor Biol. 2013; 332: 52-64. Esteves, 25 ANDROFERT, Referral Center for Male Reproduction
  26. 26. ANDROFERT Number of oocytes and cumulative live birth rate Esteves, 26 +25.0% Female Age ≤38 +18.8% 40,4% ET #1 (fresh) 822 332/822 50.5% 48,0% ET #2 (FET) 239 63/239 ET #3 (FET) 49 17/49 ANDROFERT, Referral Center for Male Reproduction
  27. 27. Cumulative live birth to improve treatment outcome in ART Pillar #1 – IVF facilities Esteves, 28 ANDROFERT, Referral Center for Male Reproduction
  28. 28. Esteves & Bento. RBM Online 2013
  29. 29. Esteves & Bento. RBM Online 2013
  30. 30. Cumulative pregnancy to improve treatment outcome in ART Pillar #2 – Blastocyst Culture Identify the embryos with optimal development potential Meta-analysis of eight RCT with 1,654 patients LBR with Blastocyst vs. Cleavage-stage ET 35% x 28%; OR: 1.39; 95% CI: 1.10-1.76 Papanikolaou E et al. Hum Reprod 2008 Esteves, 31 ANDROFERT, Referral Center for Male Reproduction
  31. 31. Identification of Embryos with Optimal Development Potential Time-lapse Technology Videomicrography + Computer Vision Software (Eeva; Auxogyn) Wong et al, 2010 Esteves, 32 ANDROFERT, Referral Center for Male Reproduction
  32. 32. Cumulative pregnancy to optimize treatment outcome in ART Pillar #3 – Vitrification Vitrification vs. Slow-freezing Ongoing PR: 35% x 27%; OR: 1.82; 95% CI: 1.04-3.20 Meta-analysis of five RCT with 765 cycles AbdelFahez et al . RBM Online 2010 Vitrification is simpler and faster than Slow Freezing Esteves, 33 ANDROFERT, Referral Center for Male Reproduction
  33. 33. Cumulative pregnancy rate as a strategy to improve success in IVF The most important endpoint for the patient Allow estimation of likelihood of delivery in relation to no. oocytes/embryos obtained and prognostic factors such as age Esteves, 34 ANDROFERT, Referral Center for Male Reproduction
  34. 34. Conclusions (1) The number of oocytes retrieved is a key factor for optimizing live birth rates COS should be tailored to the individual phenotype, maximizing the number of oocyte yield for poor responders and fine-tuning for hyper-responders Among gonadotropin preparations, recombinant FSH gives the highest oocyte yield Higher FSH bioactivity, which is related to the way the drug is made, filled and delivered Esteves, 35 ANDROFERT, Referral Center for Male Reproduction
  35. 35. Conclusions (2) Progesterone levels on hCG day are related to number of follicles developed (GCs) and oocytes retrieved No conclusive data on P levels detrimental to implantation in fresh transfers Progesterone cannot be converted to estradiol under the effect of gonadotropins containing LH activity Adequate number of viable embryos for freezing and FET can overcome any detrimental effect of P on the endometrium Esteves, 36 ANDROFERT, Referral Center for Male Reproduction
  36. 36. Conclusions (3) Cumulative live birth is a key strategy to optimize success in ART Stimulation Protocol and Number of Oocytes ART Facilities Tools to Identify the Most Viable Embryos Cryopreservation Program (Vitrification) Esteves, 37 ANDROFERT, Referral Center for Male Reproduction
  37. 37. obrigado Thank You
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