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Doha, Qatar
Amman, Jordan
Tehran, Iran
2013

Optimizing Treatment
Outcome in ART
Sandro C. Esteves, MD, PhD
Director, ANDR...
Maximize
Beneficial Effects

Minimize Complications
and Risks
Cycle
Multiple
Cancellation Pregnancy
Risk of OHSS
Poor Resp...
High-quality
Gametes and
Embryos

Individualization of
Controlled Ovarian
Stimulation
(iCOS)

Optimal
Endometrial Receptiv...
Outline
Predictors of pregnancy in IVF
Individualization of COS
Cumulative live birth rates

Esteves, 4

ANDROFERT, Referr...
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

Live birth rate (%)

Observed live birth rate
45%
40%
35%
30%
25%
20%
15...
...in all Age Groups

Esteves, 7

ANDROFERT, Referral Center for Male Reproduction
Key Points (1)
There is a strong association between the
number of oocytes retrieved and live birth
rates in IVF
The optim...
How can we tailor COS?

Esteves, 9

ANDROFERT, Referral Center for Male Reproduction
Define Who is Who

Esteves, 10

ANDROFERT, Referral Center for Male Reproduction
Who is Who in ART
Young and older patients
Polycystic ovaries/PCOS
High basal FSH/small ovaries

Easily
Recognized

Previo...
AFC AMH

No. pre-antral and small
antral follicles (≤4-8mm)

2D-TVUS early follicular phase
2-10 mm (mean diameter)
No. AF...
Non-growing
follicles (NGF)
recruited per
month

Kelsey et al. Mol Hum Reprod 2012
Esteves, 13

ANDROFERT, Referral Center...
Evidence
Level
1a

Esteves, 14

ANDROFERT, Referral Center for Male Reproduction
Low Inter-cycle Fluctuations (Fanchin et al. Hum Reprod 2005)

AMH

ICC: 0.89; 95% IC: 0.83–0.94

Esteves, 15

ICC: 0.55; ...
Biomarkers in COS
In a group of 131 women
undergoing conventional
COS after pituitary downregulation for IVF:
Population

...
Optimize the number of
oocytes retrieved
Esteves, 17

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

Esteves, 18

ANDROFERT, Referral Center for Male Reproduction
Rec-hFSH has greater potency compared
to both uFSH and HP-HMG
Evidence
Level
1b

↑ 1.5 oocytes (GnRH antagonist cycles)
De...
Protein content in solution
by mass (FbM)

Protein
content

hMG
hMG-HP

Specific
activity
(IU/mg protein)

Injected
protei...
Accurate dose delivery
Adjustments by small increments
Self-administration
75%
Easy of use

58%

Dosing mechanism

43%

Le...
Individualize COS
protocol
Esteves, 22

ANDROFERT, Referral Center for Male Reproduction
iCOS using AMH vs cCOS
High Responders
(N=70)
AMH >2.1
60
50
40
30
20
10
0

57.0
39.3

cCOS

*p<0.05

*

14.3

18.5

*

14...
Evidence
Level
1a

GnRH Antagonists in High
Responders

9 RCT; 966 PCOS women
GnRH Antagonist X Agonist

Weight Mean Diffe...
GnRH-agonist vs hCG: 11 RCT – 1,055 women
Live birth
Fresh autologous
cycles (8 RCT)

Pregnancy

Moderate/
severe OHSS

OR...
LH Trigger with GnRH-agonist
Modified Luteal Support
hCG bolus OPU day (1,500 UI) or 3x 500 UI
boluses; recLH; intense pro...
Evidence-based Strategies to
Optimize COS in High Responders
Intervention

Outcome

Evidence

Identify who are at risk

1a...
Ovarian Aging
Impaired Oocyte Quality
Reduced Fertilization Rate
Reduced Embryo Quality
Increased Miscarriage Rates
Wester...
Evidence
Level
1a

Adjuvant Therapy in Poor
Responders

Intervention
Growth Hormone
Testosterone

Effect on
Pregnancy

Met...
Evidence
Level
1a

GnRH Antagonists in Poor
Responders
14 RCT (1,127 patients)
Duration of
stimulation
-1.9 days
(-3.6; -0...
Evidence
Level
1b

Increasing the Stimulation Dose
of Gonadotropin in Poor
Responders…
RCT

Manzi et al, 1994
Klinkert et ...
Evidence
Level
1a

LH Supplementation in OS
Regimen

Mochtar et al, 2007
3 RCT (N=310)
Poor responders

Bosdou et al, 2012...
Normal

LH “Window” Concept
• Normal androgen and estrogen biosynthesis
• Normal follicular growth and development
• Norma...
LH Supplementation in Poor Responders
Late follicular phase
Early follicular phase
TC: Androgen production
TC: Androgen
GC...
LH How to Use LH in S Who and How
supplementation:
Patients (≥35 years)
Diminished Ovarian Reserve (AMH ≤0.82 ng/mL)
Rec-L...
Individualized vs. Conventional COS
Poor Responders
(N=118)

rec-hFSH FbM + 75 IU rec-hLH
+ GnRH antagonist
• Total daily ...
Sources of LH Activity
Purity
(LH content)

hCG
content
(IU/vial)

LH activity
(IU/vial)

Specific activity
(LH/mg protein...
Evidence
Level
2a

Sources of LH Activity

Matched case-control study; N=4,719 IVF pts.
35
30

P=0.02

25

Duration of
Sti...
Sources of LH Activity
Sources of LH Activity
Beta unit
hCG

Carboxyl
terminal
segment

Longer in hCG Absent in LH and
pre...
hMG

Grondal et al. 2009:

r-FSH

Sources of LH Activity
GCs gene expression in pts. treated with
hMG and rec-hFSH
q  Low...
Evidence-based Strategies to
Optimize COS in Poor Responders
Intervention

Outcome

Evidence

Identify who are at risk

1a...
Cumulative live
birth as a key
strategy to optimize
outcome in IVF
Esteves, 42

ANDROFERT, Referral Center for Male Reprod...
Cumulative live birth rates
Are they critical for success?
Sperm Selection

• Hyaruronic acid binding
• Polarization microscopy
• MSOME
• Electroforet...
Cumulative pregnancy to optimize
treatment outcome in ART
Pillar #1 – IVF facilities

Esteves, 45

ANDROFERT, Referral Cen...
Esteves & Bento. RBM Online 2013
Esteves & Bento. RBM Online 2013
Cumulative pregnancy to optimize
treatment outcome in ART
Pillar #2 – Blastocyst Culture
Identification of embryos with
op...
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
Embryo and Oocyte
Vitrification vs. Sl...
Conclusions (1)
The number of oocytes obtained is a key factor
for optimizing Live Birth rates
COS should be tailored to t...
Conclusions (2)
AMH and AFC are currently the best tools to
predict ovarian response to COS
Similar accuracy to determine ...
Conclusions (3)
Cumulative pregnancy is a key strategy to
optimize success in ART
Stimulation Protocol and Oocyte Yield
La...
obrigado

Thank You
Optimizing Treatment Outcome in ART
Optimizing Treatment Outcome in ART
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Optimizing Treatment Outcome in ART

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Optimizing Treatment Outcome in ART

  1. 1. Doha, Qatar Amman, Jordan Tehran, Iran 2013 Optimizing Treatment Outcome in ART Sandro C. Esteves, MD, PhD Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, Brazil
  2. 2. Maximize Beneficial Effects Minimize Complications and Risks Cycle Multiple Cancellation Pregnancy Risk of OHSS Poor Response OHSS Singleton live birth at term Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96; Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356; Aboulghar. Fertil Steril. 2012;97:523-6. Esteves, 2 ANDROFERT, Referral Center for Male Reproduction
  3. 3. High-quality Gametes and Embryos Individualization of Controlled Ovarian Stimulation (iCOS) Optimal Endometrial Receptivity Esteves, 3 ANDROFERT, Referral Center for Male Reproduction
  4. 4. Outline Predictors of pregnancy in IVF Individualization of COS Cumulative live birth rates Esteves, 4 ANDROFERT, Referral Center for Male Reproduction
  5. 5. 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, 5 ANDROFERT, Referral Center for Male Reproduction
  6. 6. Number of Oocytes Retrieved and Live Birth Rates Live birth rate (%) Observed live birth rate 45% 40% 35% 30% 25% 20% 15% 10% 5% 0% Predicted live birth rate number of oocytes that best optimized LBR was 15 450,135 Cycles 1 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 Esteves, 6 ANDROFERT, Referral Center for Male Reproduction
  7. 7. ...in all Age Groups Esteves, 7 ANDROFERT, Referral Center for Male Reproduction
  8. 8. Key Points (1) 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 COS should be tailored to the individual phenotype, maximizing the number of oocyte yield for poor responders and fine-tuning for hyper-responders Esteves, 8 ANDROFERT, Referral Center for Male Reproduction
  9. 9. How can we tailor COS? Esteves, 9 ANDROFERT, Referral Center for Male Reproduction
  10. 10. Define Who is Who Esteves, 10 ANDROFERT, Referral Center for Male Reproduction
  11. 11. Who is Who in ART Young and older patients Polycystic ovaries/PCOS High basal FSH/small ovaries Easily Recognized Previous OHSS/poor response High/Decreased Ovary Sensitivity BIOMARKERS of Ovarian Response Fiedler & Ezcurra Reprod Biol and Endocrinol 2012; Humaidan et al. Fertil Steril. 2010. Esteves, 11 ANDROFERT, Referral Center for Male Reproduction
  12. 12. AFC AMH No. pre-antral and small antral follicles (≤4-8mm) 2D-TVUS early follicular phase 2-10 mm (mean diameter) No. AF at a given time that can be stimulated by medication La Marca et al. Hum Reprod 2009; Fleming et al. Fertil Steril 2012; Broekmans et al. Fertil Steril 2010; Scheffer et al. Hum Reprod 2003. .. Esteves, 12 ANDROFERT, Referral Center for Male Reproduction
  13. 13. Non-growing follicles (NGF) recruited per month Kelsey et al. Mol Hum Reprod 2012 Esteves, 13 ANDROFERT, Referral Center for Male Reproduction
  14. 14. Evidence Level 1a Esteves, 14 ANDROFERT, Referral Center for Male Reproduction
  15. 15. Low Inter-cycle Fluctuations (Fanchin et al. Hum Reprod 2005) AMH ICC: 0.89; 95% IC: 0.83–0.94 Esteves, 15 ICC: 0.55; 95% IC: 0.39–0.71 Can be assessed at any cycle day with a single measurement Low Intra-cycle Fluctuations (Hehenkamp et al. JCEM 2006) Max. Variation: 17.4% Max. Variation: 108% ANDROFERT, Referral Center for Male Reproduction
  16. 16. Biomarkers in COS In a group of 131 women undergoing conventional COS after pituitary downregulation for IVF: Population High- AMH* responder1 ng/mL Poor responder2 Cut-off Sensitivity Specificity Accuracy 2.1 85% 79% 0.82 0.82 76% 86% 0.88 *Beckman-Couter generation II assay; 1>20 oocytes retrieved; 2≤4 oocytes retrieved Esteves, 16 Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013
  17. 17. Optimize the number of oocytes retrieved Esteves, 17 ANDROFERT, Referral Center for Male Reproduction
  18. 18. Gonadotropin Preparations and Oocyte Yield Esteves, 18 ANDROFERT, Referral Center for Male Reproduction
  19. 19. Rec-hFSH has greater potency compared to both uFSH and HP-HMG Evidence Level 1b ↑ 1.5 oocytes (GnRH antagonist cycles) Devroey et al., 2012 ↑ 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, 19 ANDROFERT, Referral Center for Male Reproduction
  20. 20. Protein content in solution by mass (FbM) 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 6.1 rec-hFSH* > 99% Size Exclusion High Performance Liquid Chromatography (SE- HPLC) *Follitropin alfa; Bassett et al. Reprod Biomed Online 2005;10:169–177. Esteves, 20 ANDROFERT, Referral Center for Male Reproduction
  21. 21. Accurate dose delivery Adjustments by small increments Self-administration 75% Easy of use 58% Dosing mechanism 43% Less chance of error 26% 25% Folitropin alfa prefilled ready-touse pen Needle-free reconstitution, conventional syringe Weiss N. RBMonline 2007 Esteves, 21 ANDROFERT, Referral Center for Male Reproduction
  22. 22. Individualize COS protocol Esteves, 22 ANDROFERT, Referral Center for Male Reproduction
  23. 23. iCOS using AMH vs cCOS High Responders (N=70) AMH >2.1 60 50 40 30 20 10 0 57.0 39.3 cCOS *p<0.05 * 14.3 18.5 * 14.7 56.0 iCOS 14.0 4.8 Observed Excessive Response (%) Esteves, 23 iCOS: rec-hFSH FbM 112.5 to 150 IU daily + GnRH antagonist Oocytes retrieved (N) OHSS (%) Pregnancy (%) Excessive response >20 oocytes retrieved; Mild/severe OHSS reported; Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013. ANDROFERT, Referral Center for Male Reproduction
  24. 24. Evidence Level 1a GnRH Antagonists in High Responders 9 RCT; 966 PCOS women GnRH Antagonist X Agonist Weight Mean Difference (WMD)1; Relative Risk (RR)2 Duration of stimulation -0.74 (95% CI: -1.12; -0.36)1 Gonadotropin dose -0.28 (95% CI: -0.43; -0.13)1 Oocytes retrieved 0.01 (95% CI: -0.24; 0.26)1 Risk of OHSS (Moderate & Severe) 20% vs 32% 0.59 (95% CI: 0.45-0.76)2 Clinical PR 1.01 (95% CI: 0.88; 1.15)2 Miscarriage rate 0.79 (95% CI: 0.49; 1.28)2 Pundir J et al. RBM Online 2012 Esteves, 24 ANDROFERT, Referral Center for Male Reproduction
  25. 25. GnRH-agonist vs hCG: 11 RCT – 1,055 women Live birth Fresh autologous cycles (8 RCT) Pregnancy Moderate/ severe OHSS OR 0.44 (0.29 - 0.68) OR 0.45 (0.31 - 0.65) OR 0.10, (0.01 to 0.82) Risk for OHSS markedly reduced: 3% ! 0%-2.6% Chance of Pregnancy also reduced: 30% ! 12%-22% Youssef et al. Cochrane Database Syst Rev. 2011 Esteves, 25 ANDROFERT, Referral Center for Male Reproduction
  26. 26. LH Trigger with GnRH-agonist Modified Luteal Support hCG bolus OPU day (1,500 UI) or 3x 500 UI boluses; recLH; intense progesterone + estradiol; combined Risk Difference for Pregnancy (hCG vs. GnRHa) 18% (Before) vs 6% (After) Modified LPS Humaidan et al. Fertil Steril 2012; Engmann & Benadiva Fertil Steril 2012 Embryo cryopreservation Meta-analysis of 5 RCT Vitrification vs. Slow-freezing OPR = 35% x 27%; OR: 1.82; 95% CI: 1.04-3.20 IR = 29% x 24%; OR: 1.49, 95% CI: 1.03-2.15 AbdelFahez et al . RBM Online 2010 Esteves, 26 ANDROFERT, Referral Center for Male Reproduction
  27. 27. Evidence-based Strategies to Optimize COS in High Responders Intervention Outcome Evidence Identify who are at risk 1a Oocyte yield 1a Fine-tune COS + oocyte yield 1b GnRH Antagonists OHSS 1a GnRH Agonist for LH Triggering OHSS 1a Two-step IVF OHSS 1b Ovarian biomarkers Recombinant rather than urinary gonadotropins Biomarkers + low starting doses of rec-hFSH FbM Esteves, 27 ANDROFERT, Referral Center for Male Reproduction
  28. 28. Ovarian Aging Impaired Oocyte Quality Reduced Fertilization Rate Reduced Embryo Quality Increased Miscarriage Rates Westergaard et al., 2000; Esposito et al., 2001; Humaidan et al., 2002 Esteves, 28 ANDROFERT, Referral Center for Male Reproduction
  29. 29. Evidence Level 1a Adjuvant Therapy in Poor Responders Intervention Growth Hormone Testosterone Effect on Pregnancy Meta-analyses Kyrou et al,20091 Kolibianakis et al, 20092 Duffy et al, 20103 Bosdou et al , 2012 Higher LBR1,2,3 Higher PR2 Higher CPR3 Higher LBR Higher CPR Kolibianakis et al, Hum Reprod Update 2009,15:613-22; Kyrou et al, Fertil Steril 2009;91: 749–66; Duffy et al, Cochrane Database Syst Rev 2010;1:CD000099; Bosdou JK et al, Hum Reprod Update 2012;8:127-45; Esteves, 29 ANDROFERT, Referral Center for Male Reproduction
  30. 30. Evidence Level 1a GnRH Antagonists in Poor Responders 14 RCT (1,127 patients) Duration of stimulation -1.9 days (-3.6; -0.12) Number Oocytes Cycle cancellation retrieved -0.17 (-0.69; 0.34) 1.01 (0.71; 1.42) Clinical Pregnancy 1.23 (0.92, 1.66) ü  Limited Clinical Benefit Pu D et al. Hum Reprod. 2011 Esteves, 30 ANDROFERT, Referral Center for Male Reproduction
  31. 31. Evidence Level 1b Increasing the Stimulation Dose of Gonadotropin in Poor Responders… RCT Manzi et al, 1994 Klinkert et al, 2004 Berkkanoglu & Ozgur, 2010 Number oocytes retrieved Cycle Pregnancy cancellation rates …is not associated with better IVF outcome Manzi DL et al. Fertil Steril. 1994; Klinkert ER et al. Hum Reprod. 2005; Berkkanoglu & Ozgur Fertil Steril. 2010. Esteves, 31 ANDROFERT, Referral Center for Male Reproduction
  32. 32. Evidence Level 1a LH Supplementation in OS Regimen Mochtar et al, 2007 3 RCT (N=310) Poor responders Bosdou et al, 2012 7 RCT (N= 603) Poor responders Outcome Effect on Pregnancy r-hFSH+rLH vs. r-hFSH alone* OPR OR: 1.85 r-hFSH+rLH vs. r-hFSH alone* (95% CI: 1.10; 3.11) RD: +6%, CPR (95% CI: -0.3; +13.0) LBR (only 1 RCT) Hill et al, 2012 7 RCT (N=902) Age ≥35 yo. r-hFSH+rLH vs. r-hFSH alone CPR RD: +19% (95% CI: +1.0; +36.0%) OR: 1.37 (95% CI: 1.03; 1.83) *long GnRH-a protocol; OR=odds-ratio; RD=risk difference Mochtar et al. Cochrane Database 2007; Bosdou et al, Hum Reprod Update 2012; Hill et al. Fertil Steril 2012. Esteves, 32 ANDROFERT, Referral Center for Male Reproduction
  33. 33. Normal LH “Window” Concept • Normal androgen and estrogen biosynthesis • Normal follicular growth and development • Normal oocyte maturation Reduced ovarian paracrine activity Decreased numbers of functional LH receptors Reduced LH bioactivity Hurwitz & Santoro 2004 Esteves, 33 Androgen secretory capacity reduced •  Piltonen et al., 2003 •  Vihko et al. 1996 •  Mitchell et al. 1995; Marama et al 1984 ANDROFERT, Referral Center for Male Reproduction
  34. 34. LH Supplementation in Poor Responders Late follicular phase Early follicular phase TC: Androgen production TC: Androgen GC: Enhance FSH action (estrogen production production) and Progesterone synthesis Alviggi et al. Reprod Biomed Online 2006 Esteves, 34 ANDROFERT, Referral Center for Male Reproduction
  35. 35. LH How to Use LH in S Who and How supplementation: Patients (≥35 years) Diminished Ovarian Reserve (AMH ≤0.82 ng/mL) Rec-LH; GnRH antagonist flexible protocol DOR: Recombinant FSH/LH (2:1 or 3:1 ratio) from stimulation D1 Normal reserve: 75 IU recLH added to rec-hFSH since D6 3   1   2   4   5   6   7   8   9   10   11   3   4   5   6   7   8   9   10   11   12   Menses   Esteves, 35 ANDROFERT, Referral Center for Male Reproduction
  36. 36. Individualized vs. Conventional COS Poor Responders (N=118) rec-hFSH FbM + 75 IU rec-hLH + GnRH antagonist • Total daily dose: 262.5 to 375 IU AMH ≤ 0.82 80 60 40 20 72.0 * 46.6 45.0 *p<0.05 3.5 * cCOS * 23.3 20.0 iCOS 26.8 4.8 0 Expected Poor Oocytes retrieved Cancellation (%) Pregnancy/cycle Response (%) (N) (%) Poor response <5 oocytes retrieved; Leão RBF, Nakano FY, Esteves SC. Fertil Steril 2013; 100 (Suppl.): S16. Esteves, 36 ANDROFERT, Referral Center for Male Reproduction
  37. 37. Sources of LH Activity Purity (LH content) hCG content (IU/vial) LH activity (IU/vial) Specific activity (LH/mg protein) Rec-hLH >99% 0 75 22,000 IU hMG-HP* 3% ~70 75* ≥ 60 IU *derives from hCG Adapted from ASRM Practice Committee. Fertil Steril. 2008 Esteves, 37 ANDROFERT, Referral Center for Male Reproduction
  38. 38. Evidence Level 2a Sources of LH Activity Matched case-control study; N=4,719 IVF pts. 35 30 P=0.02 25 Duration of Stimulation (days) 31 26 20 15 25 19 14 10 14 Mean No. oocytes retrieved IR (%) 5 0 Fixed 2:1 r-hFSH (150IU)/r-hLH (75IU) HMG rec-hFSH + HMG CPR per transfer (%) Buhler KF, Fisher R. Gynecol Endocrinol 2011 Esteves, 38 ANDROFERT, Referral Center for Male Reproduction
  39. 39. Sources of LH Activity Sources of LH Activity Beta unit hCG Carboxyl terminal segment Longer in hCG Absent in LH and present in hCG (Higher receptor affinity) (Longer Half-life) LH Esteves, 39 ANDROFERT, Referral Center for Male Reproduction
  40. 40. hMG Grondal et al. 2009: r-FSH Sources of LH Activity GCs gene expression in pts. treated with hMG and rec-hFSH q  Lower expression of LH/hCG receptor gene and other genes involved in steroids biosynthesis in hMG group 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 q  Higher potency of rec-hFSH inducing more LH/hCG receptors Esteves, 40 Grondal ML et al. Fertil Steril 2009; 91: 1820-1830. Menon KM et al. Biol Reprod 2004; 70:861-866
  41. 41. Evidence-based Strategies to Optimize COS in Poor Responders Intervention Outcome Evidence Identify who are at risk 1a Oocyte yield 1a Pregnancy rate 1a Duration of stimulation 1a LH supplementation Pregnancy rate 1a Biomarkers + rec-LH Oocyte yield/cancellation/PR 2a Pregnancy rate 2a Ovarian biomarkers Recombinant rather than urinary gonadotropin Adjuvant therapy GnRH antagonist protocol LH supplementation with rec-LH rather than hMG Esteves, 41 ANDROFERT, Referral Center for Male Reproduction
  42. 42. Cumulative live birth as a key strategy to optimize outcome in IVF Esteves, 42 ANDROFERT, Referral Center for Male Reproduction
  43. 43. Cumulative live birth rates
  44. 44. Are they critical for success? Sperm Selection • Hyaruronic acid binding • Polarization microscopy • MSOME • Electroforetic sperm isolation • Magnetic-activated cell sorting • Microfluids • Microarray technology • Proteomics Esteves, 44 Oocyte Selection Embryo Selection • Polscope • Oxygen consumption • Cumulus cells gene expression (mRNA transcripts) • Molecular mining of follicular fluid (metabolomics, proteomics) Metabolic Profile: • Glucose and pyruvate uptake • Amino acid turnover • Oxygen consumption Proteomics • Mass Spectroscopy • Raman Spectroscopy • Nuclear Magnetic Resonance Embryo biopsy • FISH, PCR, CGH, SNS microarray, Next-generation Sequencing (single gene), Quantitative Real-time PCR (qPCR) ANDROFERT, Referral Center for Male Reproduction
  45. 45. Cumulative pregnancy to optimize treatment outcome in ART Pillar #1 – IVF facilities Esteves, 45 ANDROFERT, Referral Center for Male Reproduction
  46. 46. Esteves & Bento. RBM Online 2013
  47. 47. Esteves & Bento. RBM Online 2013
  48. 48. Cumulative pregnancy to optimize treatment outcome in ART Pillar #2 – Blastocyst Culture Identification of 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, 48 ANDROFERT, Referral Center for Male Reproduction
  49. 49. Identification of Embryos with Optimal Development Potential Time-lapse Technology Videomicrography + Computer Vision Software (Eeva; Auxogyn) Wong et al, 2010 Esteves, 49 ANDROFERT, Referral Center for Male Reproduction
  50. 50. Cumulative pregnancy to optimize treatment outcome in ART Pillar #3 – Vitrification Embryo and Oocyte 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, 50 ANDROFERT, Referral Center for Male Reproduction
  51. 51. Conclusions (1) The number of oocytes obtained 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 COS with recombinant FSH results in an increased oocyte yield compared with hMG/uFSH Higher FSH bioactivity, which is related to the way the drug is made, filled and delivered Esteves, 53 ANDROFERT, Referral Center for Male Reproduction
  52. 52. Conclusions (2) AMH and AFC are currently the best tools to predict ovarian response to COS Similar accuracy to determine who is at risk of excessive and poor response Evidence-based strategies to optimize COS combine biomarkers and stimulation protocol Low recFSH doses and GnRH antagonists recLH supplementation Esteves, 54 ANDROFERT, Referral Center for Male Reproduction
  53. 53. Conclusions (3) Cumulative pregnancy is a key strategy to optimize success in ART Stimulation Protocol and Oocyte Yield Laboratory Facilities Identification Embryos with Development Potential Cryopreservation Program (Vitrification) Esteves, 55 ANDROFERT, Referral Center for Male Reproduction
  54. 54. obrigado Thank You

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