Tailoring Ovarian Stimulation
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Transcript of Tailoring Ovarian Stimulation
Sandro C. Esteves, MD, PhD Director, ANDROFERT
Andrology & Human Reproduction Clinic Campinas, Brazil
Tailoring Ovarian Stimulation
Advances in OBGYN Conference, Oman 2013
Individualization of Controlled Ovarian
Stimulation (iCOS)
Optimal Endometrial Receptivity
Maximize beneficial effects of
treatment
Minimize complications
and risks
Central Paradigm
High-quality Gametes and
Embryos
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Singleton live birth at
term
Maximize Beneficial Effects
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.
Multiple Pregnancy
Cycle
Cancellation Risk of OHSS
Poor Response
OHSS
Minimize Complications and Risks
Reproductive Hormones Report - GCC Countries (Feb 2011) Bologna criteria: Ferraretti et al. Hum Reprod 2011.
Esteves, 4
Up to 68%
Infertile Patients (WHO II) with PCO in Clinical Practice
Up to 45% Patients Aged ≥35 have Poor
Response to Stimulation
Who is Who in ART
How to Tailor Ovarian Stimulation for IVF Using Ovarian Biomarkers
Esteves, 5
Know the best biomarkers Understand how they work How to use them in COS
http://www.androfert.com.br/review
Tailoring Ovarian Stimulation Esteves SC – Oman Conference Nov 2013
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Know the Biomarkers
Hormonal Biomarkers FSH, Clomiphene citrate challenge test, Inhibin-B, Anti-Mullerian Hormone (AMH)
Functional Biomarkers Antral Follicle Count (AFC) Genetic Biomarkers Single Nucleotide Polymorphisms for FSH, LH, E2 and AMH receptor genes
Evidence Level 1a
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How AMH and AFC Work
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La Marca et al, Hum Reprod 2009;24:2264; Fleming et al, Fertil Steril 2012;98:1097; Broekmans et al. Fertil Steril, 2010; 94:1044-51; Scheffer et al. Hum Reprod 2003;18:700
.
Reflect No. pre-antral and small antral follicles
(≤4-8mm)
AMH
AF
C 2D-TVUS early follicular phase 2-10 mm (mean diameter)
No. AF at a given time that can be stimulated by medication
Esteves, 11
AMH
Low Inter-cycle Fluctuations (Fanchin et al, Hum Reprod 2005;20:923)
Low Intra-cycle Fluctuations (Hehenkamp et al. JCEM 2006;91:4057)
ICC: 0.89; 95% IC: 0.83–0.94 ICC: 0.55; 95% IC: 0.39–0.71
Max. Variation: 17.4% Max. Variation: 108%
Can be assessed at any cycle day with a single measurement
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Serum Levels: Peak at age 25 and decrease with aging Early marker of diminished ovarian reserve
Non-growing follicles (NGF) recruited per month
Kelsey et al. Mol Hum Reprod 2012;18:79
AMH
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AM
H
Fleming et al. RBM online 2013;26:130; Nelson SM. Fertil Steril. 2013 Jan 8; Nelson & La Marca. RBM online 2011;23:411;
ELISA assays with different performances:
DSL and Immunotech Beckman-Couter gen II (AB DSL + Curves Im.)
Fully automated ELISA (to be released)
Lack international standardization and EQC
Sample instability; measured levels altered by handling
Collection in EDTA Storage at room temperature (up to 40% increase)
No separation of serum from blood before postage
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AFC
Moderate to Low Inter-cycle Fluctuations van Disseldorp et al, Hum Reprod 2010;25:221
ICC: 0.71 (95% CI: 0.63–0.77); 29% individual cycle
variation
High Inter- and Intra-observer Reproducibility Scheffer et al. Ultrasound Obstet Gynecol 2002;20:270
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AFC
1Nelson SM. Fertil Steril. 2013 Jan 8; 2Broekmans et al., Fertil Steril, 2010; 94(3):1044-51;
3Raine-Fenning et al., Fertil Steril 2009;91:1469.
Lack of standardization1
• Inclusion criteria for antral follicles Ø e.g., 2–5 mm or 2–10 mm
• Method for counting and measuring follicles
• Variable scanning techniques • Image optimization Improved standardization
proposed2
Three-dimensional automated follicular tracking3
• Reduce intra- and inter-observer variability • Requires offline analysis • Costly
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Evidence Level 1a
AMH and AFC are not accurate for pregnancy prediction
Broer et al. Fertil Steril 2009 ; Broer et al. Hum Reprod Update, 17:46; 2011
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How to Use AMH and AFC to Tailor OS
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Population Cut-off Sensitivity Specificity Accuracy
AMH*ng/mL
High-responder1 2.1 85% 79% 0.82
Poor responder2 0.82 76% 86% 0.88
*Beckman-Couter generation II assay; 1>20 oocytes retrieved; 2≤4 oocytes retrieved
Biomarkers in OI
In a group of 131 women undergoing conventional COS after pituitary down-regulation for IVF:
Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013
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iCOS Using Biomarkers
High Responders
AMH >2.1
Poor Responders
AMH ≤ 0.82
rec-hFSH FbM 112.5 to 150 IU daily + GnRH antagonist
rec-hFSH FbM + 75 IU rec-hLH + GnRH antagonist
• Total daily dose: 262.5 to 375 IU
Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013
39.3
18.5 14.0
57.0
14.3 14.7 4.8
56.0
0
10
20
30
40
50
60
Observed Excessive
Response (%)
Oocytes retrieved (N)
OHSS (%) Pregnancy (%)
cCOS iCOS
1Excessive response: >20 oocytes retrieved; *Pts. received GnRH-a trigger + embryo vitrification; Mild/severe OHSS reported
p=0.03
p=0.04 p=0.38
p=0.92
iCOS Using AMH vs. cCOS High Responders (N=70)
Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013
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Low-starting FSH dose (150 UI)
AMH (ng/mL) >2.1¶ GnRH Agonist
(n=148) GnRH
Antagonist (n=34)
Days of Stimulation 13 (12-14) 9 (8-11)*
No. Oocytes retrieved (n) 14 (10-19) 10 (8.5-13.5)*
OHSS requiring hospitalization 20 (13.9%) 0 (0%)*
Cancellation 4 (2.7%) 1 (2.9%) CPR per transfer 40.1% 63.6%*
¶DSL assay; Adapted from Nelson SM et al . Anti-Müllerian hormone-based approach to controlled ovarian stimulation for assisted conception. Hum Reprod. 2009; 24(4):867-75.
*P ≤ 0.01
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Biomarkers for iCOS in High Responders
Evidence Level 2b
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AFC
Cut-off point of 4 Bancsi et al, Fertil Steril 2002;77:328
Moderate sensitivity (61%) and High specificity (88%) and to predict DOR2
Cut-off point of 14 Kwee et al, Fertil Steril 2008;90:737
High sensitivity (81%) and specificity (89%) to predict excessive response1
1>20 oocytes retrieved in conventional COS; 2≤4 oocytes retrieved
Accurate to Predict Ovarian Response
Evidence Level 1a
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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 OS -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; 24:6-22.
~40% reduction in moderate/severe OHSS by using antagonists rather than agonists
Impaired Oocyte Quality
Reduced Fertilization Rate
Reduced Embryo Quality
Increased Miscarriage Rates
Westergaard et al., 2000; Esposito et al., 2001; Humaidan et al., 2002
Ovarian Aging
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Balasch J, Fábreques F. Curr Opin Obstet Gynecol 2002, 14:265.
• Normal androgen and estrogen biosynthesis • Normal follicular growth and development • Normal oocyte maturation N
orm
al
LH “Window” Concept
Reduced ovarian
paracrine activity
Hurwitz & Santoro 2004
Androgen secretory capacity reduced
• Piltonen et al., 2003
Decreased numbers of functional
LH receptors
• Vihko et al. 1996
Reduced LH bioactivity
• Mitchell et al. 1995; Marama et al 1984
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LH Supplementation in DOR
Regimen Outcome Effect on Pregnancy
Mochtar et al, 2007 3 RCT (N=310) Poor responders
r-hFSH+rLH vs.
r-hFSH alone*OPR OR: 1.85
(95% CI: 1.10; 3.11)
Bosdou et al, 2012 7 RCT (N= 603) Poor responders
r-hFSH+rLH vs.
r-hFSH alone*
CPR
LBR (only 1 RCT)
RD: +6%, (95% CI: -0.3; +13.0)
RD: +19% (95% CI: +1.0; +36.0%)
Hill et al, 2012 7 RCT (N=902) Women advanced age ≥35 yrs.
r-hFSH+rLH vs.
r-hFSH alone
CPR
OR: 1.37 (95% CI: 1.03; 1.83)
*long GnRH-a protocol; OR=odds-ratio; RD=risk difference
Mochtar MH et al. Cochrane Database Syst Rev. 2007;2:CD005070; Bosdou JK et al, Hum Reprod Update 2012; 8(2):127-45. Hill MJ et al. Fertil Steril 2012; 97:1108-4. Esteves, 26
Level 1a
*derives from hCG
Purity (LH content)
hCG content (IU/vial)
LH activity (IU/vial)
Specific activity (LH/mg protein)
>99% 0 75 22,000 IU
3% ~70 75* ≥ 60 IU
Sources of LH Activity
Rec-hLH
hMG-HP*
Adapted from ASRM Practice Committee. Fertil Steril. 2008; 90:S13-20. Esteves, 27
Sources of LH Activity
19 14 14
31 26 25
0 5
10 15 20 25 30 35
Fixed 2:1 r-hFSH (150IU)/r-hLH
(75IU)
HMG rec-hFSH + HMG
Duration of Stimulation (days)
Mean No. oocytes retrieved
IR (%)
CPR per transfer (%)
Buhler KF, Fisher R. Gynecol Endocrinol 2011;1-6.
Matched case-control study; N=4,719 IVF pts.
P=0.02
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Beta unit
Carboxyl terminal segment
Longer in hCG;
(Higher receptor affinity)
Absent in LH and present in hCG
(Longer Half-life)
Sources of LH Activity Sources of LH Activity
hCG
LH
Grondal et al. 2009: 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 Grondal ML et al. Fertil Steril 2009; 91: 1820-1830.
Menon KM et al. Biol Reprod 2004; 70:861-866
Sources of LH Activity
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r-FS
H
hMG
Patients (≥35 years) Diminished Ovarian Reserve (AMH ≤0.82 ng/mL)
GnRH antagonist flexible protocol DOR: Recombinant FSH/LH (2:1 or 3:1 ratio) from stimulation D1;
2 3 4 5 7 6 8 9 10 11 1
Menses
12
How to Use LH in COS Our Method for LH supplementation
7 6 8 9 10 11 3 4 5
Normal ovarian reserve: 75 IU recLH added to rec-hFSH from D6 on
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72.0
3.5
45.0
20.0
46.6
4.8
23.3 26.8
0
20
40
60
80
Expected Poor Response (%)
Oocytes retrieved (N)
Cancellation (%) Pregnancy/cycle (%)
cCOS iCOS
p=0.02
p=0.03
p=0.06 p=0.51
iCOS Using AMH vs cCOS Poor Responders (N=49)
Leão RBF, Nakano FY, Esteves SC. #O-51: ASRM 2013
Poor response: <5 oocytes retrieved; Esteves, 32
Esteves, 33
AMH and AFC are currently the best biomarkers to predict ovarian response to COS.
AMH and AFC are direct biomarkers of ovarian reserve. Both markers have similar accuracy to predict who is at risk of excessive and poor response in COS.
After identifying ‘Who is Who’, mild stimulation and GnRH antagonists in pts. at risk of excessive response, and rec-hLH supplementation in DOR, are useful strategies to optimize outcomes in ART cycles.
Take Home Messages