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Sandro C. Esteves, MD, PhD Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, Brazil Tailoring Ovarian Stimulation Advances in OBGYN Conference, Oman 2013

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Page 1: 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

Page 2: Tailoring Ovarian Stimulation

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

Esteves, 2

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Esteves, 3

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

Page 4: Tailoring Ovarian Stimulation

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

Page 5: Tailoring Ovarian Stimulation

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

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http://www.androfert.com.br/review

Tailoring Ovarian Stimulation Esteves SC – Oman Conference Nov 2013

Esteves, 6

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Esteves, 7

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

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Evidence Level 1a

Esteves, 8

Page 9: Tailoring Ovarian Stimulation

Esteves, 9

How AMH and AFC Work

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Esteves, 10

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

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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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Esteves, 12

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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Esteves, 13

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

Page 14: Tailoring Ovarian Stimulation

Esteves, 14

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

Page 15: Tailoring Ovarian Stimulation

Esteves, 15

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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Esteves, 16

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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Esteves, 17

How to Use AMH and AFC to Tailor OS

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Esteves, 18

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

Page 19: Tailoring Ovarian Stimulation

Esteves, 19

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

Page 20: Tailoring Ovarian Stimulation

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

Esteves, 20

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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

Esteves, 21

Biomarkers for iCOS in High Responders

Evidence Level 2b

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Esteves, 22

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

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Evidence Level 1a

Esteves, 23

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

Page 24: Tailoring Ovarian Stimulation

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

Esteves, 24

Page 25: Tailoring Ovarian Stimulation

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

Esteves, 25

Page 26: Tailoring Ovarian Stimulation

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

Page 27: Tailoring Ovarian Stimulation

*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

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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

Esteves, 28

Page 29: Tailoring Ovarian Stimulation

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

Page 30: Tailoring Ovarian Stimulation

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

Esteves, 30

r-FS

H

hMG

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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

Esteves, 31

Page 32: Tailoring Ovarian Stimulation

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

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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