AMH: its role in selecting the Stimulation

protocol, Gonadotropin dosage and Egg

quality

Session Oocyte and Embryo Quality

MSRM-COGI meeting 24-26 april 2014, Barcelona

Frank J Broekmans

Professor Reproductive Medicine

University Medical Center Utrecht 12:30 - 30

Disclosures Member external advisory board Merck Serono Member external advisory board Gideon Richter Educational work MerckSharpDome Educational activities Ferring BV Consultancy work Roche

Take Homer 1

Individualisation in IVF:

Mostly personalised Cookery, only a bit of Science

Take Homer 2

Quality is….

Mostly Female age

And a bit Quantity

Agenda

• AMH and Ovarian Physiology

• Why predict and select in ART

• Can we really predict and select:

–FSH dosage

–Stim protocol

–Egg quality

• Conclusions

AMH - dimeric glycoprotein

member of the transforming growth factor β

(TGF-β) family of growth and differentiation

factors (Inhibins and Activins)

Produced from Mural Granulosa Cells

Basically a Paracrine Inhibitor

AMH Physiology

Ovarian AMH inhibits

a. Initial recruitment of primordial follicles into primary follicles

b. Sensitivity of Antral follicles to FSH

AMH Physiology – Paracrine!!

8-10 mm

2-7 mm

0,1-2 mm

Primordial pool

Primary follicles

Pre-antral follicles

Circulating AMH

?

The source of Serum AMH

Jeppesen, MHR 2013

Broer, COOG 2009

Agenda

• AMH and Ovarian Physiology

• Why predict and select in ART

• Can we really predict and select:

–FSH dosage

–Stim protocol

–Egg quality

• Conclusions

Live birth rate and oocyte yield

0

5

10

15

20

25

30

35

1 3 5 7 9 11 13 15 17 19 21 23 25

Oocyte number

LB

RLBR ↓

Costs↑

Burden↑

Discomfort ↑

Risks ↑

LBR ↓ Optimal

Predicting the variation:

Ovarian Response

Out of every 100

couples starting

IVF..

..only 50 will

achieve an

ongoing

pregnancy within

a 1 year treatment

period…

Lintsen, HR 2007

Predictable??

or..Preventable??

Predicting the variation:

Ongoing Pregnancy

Predict and select in ART

Can we..??

Agenda

• AMH and Ovarian Physiology

• Why predict and select in ART

• Can we really predict and select:

–FSH dosage

–Stim protocol

–Egg quality

• Conclusions

Predictors of Response and Pregnancy

1. Ovarian Reserve - Quantity

Continuous

Intermittent

AMH, AFC, basal FSH, basal Inhibin B: Quantity Markers

Ata, RBM 2012

With

increasing

female age the

proportion of

euploid

embryo’s goes

down from

~75% to ~25%

Predictors of Response and Pregnancy

2. Ovarian Reserve – Quality

OR marker = predictor

AMHGE

AUC AMH:

0.81 (0.77-0.84)

AUC age+AMH+AFC+FSH:

0.81 (075-0.86)

Prediction of Poor OR (< 5 oocytes)

Agonists N= 5800 Broer, HRU 2012

Cut off levels

AMH: 0.5 ng/ml

FSH: 13 IU/l

AFC(2-10): 7 fo

Arce, FS 2013

0

0.2

0.4

0.6

0.8

1

0 0.2 0.4 0.6 0.8 1Se

nsi

tivi

ty

1 - Specificity

Low response prediction

Age

AMH

BMI

Hamdine, Arant study, n=500

Prediction of Poor OR (< 5 oocytes)

Antagonists

Prediction Excessive OR (> 15 oocytes)

Agonists N= 5800 Broer, FS 2013

AUC AMH+AFC:

0.85 (0.80-0.90)

AUC age+AMH+AFC+FSH:

0.85 (080-0.90)

Cut off levels

AMH: 2.5 ng/ml

AFC(2-10): 16 fo

Prediction Excessive OR (> 15 oocytes)

Antagonists

Hamdine, Arant study, n=500 Arce, FS 2013

0

0.2

0.4

0.6

0.8

1

0 0.2 0.4 0.6 0.8 1

Sen

siti

vity

1 - Specificity

High response prediction

Age

AMH

BMI

AMH in ANTA or AGO cycles

ROC Curve

1 - Specificity

1,00,75,50,250,00

Sensi

tivity

1,00

,75

,50

,25

0,00

0.90

Predicting

With false negatives

and positives

Personalising

Can we

• increase the antral

follicle number

• mitigate excessive

response

= Accurate predictor of

Response Category, …but…

Agenda

• AMH and Ovarian Physiology

• Why predict and select in ART:

• Can we really predict and select:

–FSH dosage

–Stim protocol

–Egg quality

• Conclusions

Dose – Response….? Sterrenburg, HRU 2009

Yajaprakasan, BJOG 2010

Berkkanoglu, FS 2010

No: predicted poor responders based on AFC (<5

[2–5 mm] follicles) did not have better pregnancy rates with 300 IU compared to 150 IU

rec FSH (n=52)

Klinkert ER, et al. Hum Reprod 2005

No: predicted poor response cases based on AMH

(<14 pmol/L) did not have improvement of oocyte yield nor pregnancy rates when 150 IU

rec FSH was compared to 200–300 IU in a pseudorandomized design (n=122) Lekamge DN, et al. J Assist Reprod Genet 2008

No: In cases with moderately decreased OR (FSH > 8.5 U/l) no benefit was observed

from 400 versus 300 IU stimulation dose for response or pregnancy (n-48)

Harrison R, et al Fertil Steril, 2001

No: In cases with AFC<12, no difference was observed in oocyte yield nor live birth rate

comparing 300, 450 and 600 IU of FSH. Berkkanoglu FS 2010

Prediction of poor response Individualize dose of FSH?

Yes: an individual stimulation dose, based on a model with age,

AFC, basal FSH and BMI suggests that reduced dosages

mitigates response without effects on pregnancy rates (n=161)

(wait for RCT, CONSORT) Olivennes, RBM 2009

Prediction of excessive response Individualize dose of FSH?

The OPTIMIST trial

OPTIMisation of cost effectiveness through Individualised FSH Stimulation

dosages for IVF Treatment: a randomised trial. Dutch RM consortium

N=300

N=300

N=300

18 months treatment approach

N=600

Completed

March, 31st

1530 inclusions

Agenda

• AMH and Ovarian Physiology

• Why predict and select in ART:

• Can we really predict and select:

–FSH dosage

–Stim protocol

–Egg quality

• Conclusions

Ongoing Pregnancy rate 16.2% 8.1% 8.1% Underpowered

Significant

Significant

The PRINT trial Sunkara FS 2014

The Poor Responder: AGO or ANTA or FLARE?

Long Suppression

Is MORE expensive

Yields more ETs

Compared with GnRH agonist

the GnRH antagonist protocol is

associated with

• Fewer oocytes retrieved

• “Similar” Cancellation rates

• “Similar” Clinical Pregnancy

rates

Cancellation rate

Oocyte number

CP rate

Xiao, FS 2013

Poor Responder:

antagonist??

Meta-Analysis by Pu, HR 2011:

Not fewer oocytes

PR Anta: 22%

Pr Ago: 19%

Predicted Excessive responders:

antagonist with standard dose ??

Nelson,

2009,

non

randomised

Antagonist is

More SAFE

More Efficacious

AMH based Personalised ART treatment

historical cohort design

10 versus 8 oocytes

Yates, HR 2011

Agenda

• AMH and Ovarian Physiology

• Why predict and select in ART:

• Can we really predict and select:

–FSH dosage

–Stim protocol

–Egg quality

• Conclusions

Searching for the ZERO prognosis patient

Individual Patient Data

Analysis: the IMPORT study

Female age

with or without any ORT

fails to predict accurately

zero prognosis cases

N=5500

ART Success Prediction one cycle

AUC

Age 0.57

AFC 0.50

AMH 0.55

Age + AFC 0.58

Age + AMH 0.57

Broer, HRU 2012

Female age Cumulative cycles

Hendriks, RBM 2008

IPD data, n=1007

Broeze 2009

<0,4 0,4-0,8 0,8-1,6 1,6-2,8 >2,8

<31 16% (8-29%) 25% (15-39%) 31% (21-43%) 32% (22-45%) 34% (24-46%)

n 13 20 58 58 102

31-35 15% (8-28%) 24% (15-37%) 30% (20-11%) 32% (21-43%) 33% (23-46%)

n 21 32 99 74 74

36-38 14% (7-26%) 23% (13-35%) 28% (18-40%) 29% (20-42%) 31% (21-44%)

n 24 37 65 54 37

38-40 11% (5-23%) 18% (10-32%) 23% (14-36%) 24% (14-39%) 26% (15-41%)

n 22 19 46 18 7

>40 5% (2-12%) 9% (4-18%) 11% (5-22%) 12% (6-24%) 13% (6-26%)

n 48 38 28 8 6

AMH pg/l

Age yrs

Age and AMH in concert indicate

prognosis for live birth – one cycle agonist

Useful for Counseling Couples

Useful for IVF Program Restrictions

Agenda

• AMH and Ovarian Physiology

• Why predict and select in ART:

• Can we really predict and select:

–FSH dosage

–Stim protocol

–Egg quality

• Conclusions

Individualization of ovarian stimulation in

IVF using ORTs: from theory to practice

LaMarca, HRU 2013

Nelson Yates

Individualization of ovarian stimulation in

IVF using ORTs: from theory to practice

LaMarca, HRU 2013

Nelson Yates

Individualization of ovarian stimulation in

IVF using ORTs: from theory to practice

LaMarca, HRU 2013

No Evidence

for 300 IU

for Anta

Evidence for

150 IU

Some Evidence

for Dose

for Anta

Nelson Yates

Take Homer

Individualisation in IVF:

We need more Science!!

Use not more than 225 IU

Take Homer 2

Quality is….

Mostly Female age

And (knowing)

Quantity will

help a bit

Frank Broekmans Professor

Reproductive Medicine and Surgery

University Medical Centre Utrecht

The Netherlands

Simone Broer Jeroen van Disseldorp Monique Sterrenburg Marieke Verberg Dave Hendriks Ellen Klinkert Ilse van Rooij Laszlo Bancsi Marlies Voorhuis Kim Broeze (AMC) Brent Opmeer (AMC) Madeleine Dolleman Ouijdane Hamdine Martine Depmann

Bart Fauser Nick Macklon (Southampton)

Ben W Mol (AMC) Nils Lambalk (VUMC)

Thank You

the IMPORT* studygroup

Richard A. Anderson

Mahnaz Ashrafi

László Bancsi,

Ettore Caroppo,

Alan B. Copperman,

Thomas Ebner,

Talia Eldar-Geva,

Mehmet Erdem,

Ellen M. Greenblatt,

Kannamannadiar.

Jayaprakasan,

Nick Raine-Fenning,

Ellen Klinkert,

Janet Kwee,

Antonio La Marca,

MyvanwyMcIlveen,

Luis T. Merce,

Shanthi Muttukrishna,

Scott M. Nelson,

Ernest H.Y. Ng,

Biljana Popovic Todorovic,

Jesper M.J. Smeenk,

Candido Tomás

Paul J.Q. Van der Linden,

K.Vladimirov,

Patrick Bossuyt

Genetic Department

Edwin Cuppen

Epidemiology Department

Yvonne vd Schouw

Charlotte Onland-Moret