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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