Transcript Titel van de Slide

Checking AMH as an initial
evaluation of ovarian reserve
Midwest Reproductive Symposium
Chicago, USA
June 19-21, 2014
Frank J Broekmans
Professor Reproductive Medicine and Surgery
University Medical Center Utrecht
-20-30
Coming to Chicago
Disclosures
Member external advisory board Merck Serono
Member external advisory board Gideon Richter
Educational work MerckSharpDome
Educational activities Ferring BV
Consultancy work Roche
Learning Objectives
Appreciate the biology of Ovarian Reserve
Know the limitations of predicting Poor and
Excessive Ovarian Response by using AMH
Believe the very limited relation ship between FSH
dosage and Ovarian Response
Appreciate the inability of AMH to predict Quality
Initial evaluation of ovarian reserve
For what purpose?
1. Assessment of Time to Menopause/future
fertility
2. Predicting prognosis for spontaneous
pregnancy in Infertility
3. Predicting Pregnancy after ART
4. Prediction Ovarian response ART
5. Ovarian Damage quantification (chemo, UAE,
ovarian surgery)
6. POI diagnosis
Initial evaluation of ovarian reserve
For what purpose?
1. Assessment of Time to Menopause/future
fertility
2. Predicting prognosis for spontaneous
pregnancy in Infertility
3. Predicting Pregnancy after ART
4. Prediction Ovarian response ART
5. Ovarian Damage quantification (chemo, UAE,
ovarian surgery)
6. POI diagnosis
Agenda
• AMH and Ovarian Physiology
• AMH in Infertility Work Up
• Why predict and select in ART
• Can we really predict and select:
– FSH dosage
– Stim protocol
– Egg quality
• Conclusions
AMH Physiology
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 – Paracrine!!
Ovarian AMH inhibits
a. Initial recruitment of primordial follicles into primary follicles
b. Sensitivity of Antral follicles to FSH
The source of Serum AMH
Circulating AMH
8-10 mm
2-7 mm
0,1-2 mm
?
Pre-antral follicles
Primary follicles
Jeppesen, MHR 2013
Broer, COOG 2009
Primordial pool
AMH processing
Signal
peptide
Granulosa Cell
Proregion
55 kD
Mature peptide
12.5 kD
Signal peptide cleavage
Dimerization
RAQR
Serum
Cleavage by proprotein
convertases Furin, PC5
AMH assay - enzymatically amplified
two-site immunoassay.
detector AB
capture AB
Detection limit
Immunotech-Beckman
traditional
2 ng/ml
ultra-sensitive
0.1 ng/ml
2/6
detector AB
9/6
capture AB
0.078 ng/ml.
DSL-I
F2B/7A
detector AB
DSL-II
Beckman-Coult Gen II
F2B/12H
capture AB
0.006-0.017 ng/ml.
0.08 ng/ml.
Serum AMH declines with..
• Ovarian Stimulation
• Pituitary/gonadal
suppression by
• Oral contraceptive
• GnRH agonist
• Smoking
• Pregnancy
Li, JARG 2013
Koninger RBE 2013
Hagen, FS 2012
Dolleman, JCEM 2013
AMH assay BC Gen II system
Do’s and don’t’s
Use your Own or the Same
Laboratory
Standardise Storage and
Shipping conditions: Deep
Frozen -80 is best…??
Reference values based on your
own data..and check pill and
smoking
GEN II = DSL + 40%
F2B/7A
detector AB
F2B/12H
capture AB
Agenda
• AMH and Ovarian Physiology
• AMH in Infertility Work Up
• Why predict and select in ART
• Can we really predict and select:
– FSH dosage
– Stim protocol
– Egg quality
• Conclusions
Infertility
Tubal Pathology
Severe Male factor
Anovulation
Unexplained: 60%
What is wrong here??
Advanced Ovarian Ageing??
Poor Gamete Quality??
Poor Implantation Conditions?
The Success of your patient(s)
Diagnosis
Prognosis
Indication for ART
IUI mild stimulation
IVF/ICSI/ Oocyte donation
Assessment of Success
Start Indicated
treatment
Cycle 1
Cycle 2
Cycle 3
Time
Spontaneous Pregnancy
ART related ongoing Pregnancy
Drop Out
No Pregnancy, Miscarriage
The Infertile Couple
Inf Work Up
Prognosis
AMH ??
AMH ??
AMH ??
Treatment
Expectant
IUI ±Stim
Diagnosis
Unexplained
Mild Semen
Unexplained
Mild Semen
Moderate Semen
IVF ICSI
Unexplained
All Semen
Tubal
Prognostic Model – Who treatment?
Who wait?
Hunault Model prediction for
chance of spontaneous Live
Birth
Does AMH or other ORT add
value??
Will an ORT add anything to the Hunaull
Prediction Model
In 42 (1.3%) de probability for Ongoing pregnancy shifts from > 30%
into < 30%, if basal FSH is added to the Hunault model
100
90
Prediction by Model I (%)
80
These 42 couples would have
been advised
“TREATMENT” in stead of
“EXPECTANT”
70
60
50
40
30
20
10
0
0
10
20
30
40
50
60
70
80
Prediction by Model Hunault:(%)
90
100
N=3219
vd Steeg, 2007
Will AMH add anything to the Hunaull
Prediction Model
No such data on AMH
Will an ORT add anything to the Hunaull
Prediction Model
N=474 - In 20 cases
(5.4%) the
probability of
ongoing pregancy
shifts from ≥ 30%
into < 30%, if bFSH
is added to the
Hunault model.
Haadsma, HR 2009
The Infertile Couple
Inf Work Up
Diagnosis
Prognosis
AMH ??
AMH ??
AMH ??
Treatment
Expectant
IUI ±Stim
Diagnosis
Unexplained
Mild Semen
Unexplained
Mild Semen
Moderate Semen
IVF ICSI
Unexplained
All Semen
Tubal
ORT before starting IUI/Stim?
Only Few studies, and not on AMH
The aim could be: skip IUI/Stim if
prognosis is too poor for succes in thta
treatment modality and proceed directly
to IVF
FSH and CCCT useful in IUI/stim??
Cases with 30-50% reduction in cumulative chance of
pregnancy can be identified.
Skip the treatment?? 3 Cumulative cycles…
Magendzo, 2006
AFC prior to IUI with ovarian
stimulation - No consistent data
N=107 cases
AFC< 5 fo
Sens 19%
Spec 96%
LR+ 3.2
Post test prob of
non pregn: 95%
Abn test 16%
One cycle studies…
The significance of antral follicle count in
controlled ovarian stimulation and intrauterine
insemination.
Ng EH, et al, JARG 2005
N=150 cases
AFC< 6 fo
Sens 23%
Spec 83%
LR+ 1.3
Post test prob of non
pregn: 88%
Abn test 22%
ORT when indication for IUI/Stim
No consistent prediction of poor prognosis
cases
Should we skip IUI/STIM in women over 38
and/or abnormal ORT, and then do….
direct IVF….?????
Or The PRORAILS study: AFC and AMH as
predictors of response and outcome
The Infertile Couple
Inf Work Up
Diagnosis
Prognosis
AMH ??
AMH ??
AMH ??
Treatment
Expectant
IUI ±Stim
Diagnosis
Unexplained
Mild Semen
Unexplained
Mild Semen
Moderate Semen
IVF ICSI
Unexplained
All Semen
Tubal
Agenda
• AMH and Ovarian Physiology
• AMH in Infertility Work Up
• Why predict and select in ART
• Can we really predict and select:
– FSH dosage
– Stim protocol
– Egg quality
• Conclusions
Predicting the variation:
Ovarian Response
Live birth rate and oocyte yield
35
30
LBR ↓
Costs↑
Burden↑
LBR
25
Discomfort ↑
Risks ↑
LBR ↓
Optimal
20
15
10
5
0
1
3
5
7
9
11
13
15
Oocyte num ber
17
19
21
23
25
Predicting the variation:
Ongoing Pregnancy
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??
Agenda
• AMH and Ovarian Physiology
• AMH in Infertility Work Up
• 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
Predictors of Response and Pregnancy
2. Ovarian Reserve – Quality
With
increasing
female age the
proportion of
euploid
embryo’s goes
down from
~75% to ~25%
Ata, RBM 2012
OR marker = predictor
AMHGE
Predicting Poor OR
(< 5 oocytes)
Broer, IMPORT study,
HRU 2013
AUC age:
AUC age+FSH:
AUC age+AFC:
AUC age+AMH:
0.60 (0.57-0.64)
0.69 (0.66-0.72)
0.76 (0.72-0.80)
0.80 (0.76-0.84)
AUC AMH:
0.81 (0.77-0.84)
AUC age+AMH+AFC+FSH:
0.81 (075-0.86)
Predicting Excessive OR
(> 15 oocytes)
Broer, EXPORT study,
HRU 2013
AUC age:
AUC age+AFC:
AUC age+AMH:
AUC AMH:
AUC AMH+AFC:
0.61 (0.58-0.64)
0.75 (0.71-0.79)
0.81 (0.77-0.85)
0.82 (0.77-0.86)
0.85 (0.80-0.90)
AUC age+AMH+AFC+FSH:
0.85 (080-0.90)
AMH in ANTA or AGO cycles
= Accurate predictor of
Response Category, …but…
Predicting
With false negatives
and positives
ROC Curve
1,00
,75
,50
0.90
,25
0,00
0,00
,25
,50
,75
1 - Specificity
1,00
Personalising
Can we
• increase the antral
follicle number
• mitigate excessive
response
Predict and select in ART
Can we..??
Agenda
• AMH and Ovarian Physiology
• AMH in Infertility Work Up
• 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
Prediction of poor response
Individualize dose of FSH?
• 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 excessive 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
Predicted Poor Responders: and then do
what? RCT design
In cases with normal basal
FSH, an individual
stimulation dose, based on
a model with AFC, ovarian
volume, ovarian flow,
female age and smoking
resulted in reduced poor
response rate and higher
pregnancy rates compared
to a standard dose
(n=262)
Popovic-Todorovic B, et al. Hum Reprod 2003
The OPTIMIST trial
OPTIMisation of cost effectiveness through Individualised FSH Stimulation
dosages for IVF Treatment: a randomised trial.
Dutch RM consortium
Completed
18 months treatment approach
March, 31st
N=300
N=300
1530 inclusions
N=600
N=300
Agenda
• AMH and Ovarian Physiology
• AMH in Infertility Work Up
• Why predict and select in ART
• Can we really predict and select:
– FSH dosage
– Stim protocol
– Egg quality
• Conclusions
The Poor Responder: AGO or ANTA or FLARE?
Significant
Significant
Ongoing Pregnancy rate
16.2%
Long Suppression
Is MORE expensive
Yields more ETs
8.1%
8.1%
Underpowered
The PRINT trial Sunkara FS 2014
Poor Responder:
antagonist??
Compared with GnRH agonist
Cancellation rate the GnRH antagonist protocol is
associated with
•Fewer oocytes retrieved
Oocyte number
•“Similar” Cancellation rates
•“Similar” Clinical Pregnancy
rates
Xiao, FS 2013
CP rate
Meta-Analysis by Pu, HR
2011:
Not fewer oocytes
Predicted Excessive responders:
antagonist with standard dose ??
Antagonist is
More SAFE
More Efficacious
Nelson,
2009,
non
randomised
AMH based Personalised ART treatment
historical cohort design
10 versus 8 oocytes
Yates, HR 2011
Agenda
• AMH and Ovarian Physiology
• AMH in Infertility Work Up
• Why predict and select in ART
• Can we really predict and select:
– FSH dosage
– Stim protocol
– Egg quality
• Conclusions
Predicting…
Prognosticating…
15%
60%
30%
10%
20%
0%
8%
5%
50%
ART Success Prediction one cycle
Individual Patient Data
Analysis: the IMPORT study
Female age
with or without any ORT
fails to predict accurately
zero prognosis cases
N=5500
AUC
Broer, HRU 2012
Age
0.57
AFC
0.50
AMH
0.55
Age + AFC
0.58
Age + AMH
0.57
Female age Cumulative cycles
Hendriks, RBM 2008
Age and AMH in concert indicate
prognosis for live birth – one cycle agonist
Age yrs
<31
n
31-35
n
36-38
n
38-40
n
>40
n
<0,4
16% (8-29%)
13
15% (8-28%)
21
14% (7-26%)
24
11% (5-23%)
22
5% (2-12%)
48
AMH pg/l
0,4-0,8
0,8-1,6
25% (15-39%)
31% (21-43%)
20
58
24% (15-37%)
30% (20-11%)
32
99
23% (13-35%)
28% (18-40%)
37
65
18% (10-32%)
23% (14-36%)
19
46
9% (4-18%)
11% (5-22%)
38
28
Useful for Counseling Couples
Useful for IVF Program Restrictions
1,6-2,8
32% (22-45%)
58
32% (21-43%)
74
29% (20-42%)
54
24% (14-39%)
18
12% (6-24%)
8
>2,8
34% (24-46%)
102
33% (23-46%)
74
31% (21-44%)
37
26% (15-41%)
7
13% (6-26%)
6
IPD data, n=1007
Broeze 2009
Agenda
• AMH and Ovarian Physiology
• AMH in Infertility Work Up
• 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
Nelson
Yates
LaMarca, HRU 2013
Individualization of ovarian stimulation in
IVF using ORTs: from theory to practice
Nelson
Yates
LaMarca, HRU 2013
Individualization of ovarian stimulation in
IVF using ORTs: from theory to practice
Nelson
Yates
Some Evidence
for Dose
for Anta
Evidence for
150 IU
No Evidence
for 300 IU
for Anta
LaMarca, HRU 2013
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
Thank You
Frank Broekmans
Professor
Reproductive Medicine and Surgery
University Medical Centre Utrecht
The Netherlands
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
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)