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Frank J BroekmansProfessor Reproductive Medicine and SurgeryUniversity Medical Center Utrecht -20-30
Checking AMH as an initial evaluation of ovarian reserveMidwest Reproductive SymposiumChicago, USA June 19-21, 2014
Coming to Chicago
Disclosures Member external advisory board Merck SeronoMember external advisory board Gideon RichterEducational work MerckSharpDomeEducational activities Ferring BVConsultancy 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 - 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 folliclesb. 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 2013Broer, COOG 2009
AMH processing
Signal peptide
Proregion 55 kD
Mature peptide 12.5 kD
Signal peptide cleavage
Dimerization
Cleavage by proprotein convertases Furin, PC5
RAQR
Serum
Granulosa Cell
DSL-I
AMH assay - enzymatically amplified two-site immunoassay.
2/6detector AB
9/6capture AB
detector AB capture AB
F2B/7Adetector AB
F2B/12Hcapture AB
DSL-II0.006-0.017 ng/ml.
Detection limit
0.078 ng/ml.
Beckman-Coult Gen II 0.08 ng/ml.
ultra-sensitive
2 ng/ml
Immunotech-Beckmantraditional
0.1 ng/ml
Serum AMH declines with..
• Ovarian Stimulation• Pituitary/gonadal
suppression by• Oral contraceptive• GnRH agonist
• Smoking• Pregnancy Li, JARG 2013
Koninger RBE 2013Hagen, FS 2012Dolleman, JCEM 2013
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%
AMH assay BC Gen II systemDo’s and don’t’s
F2B/7Adetector AB
F2B/12Hcapture 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 PathologySevere Male factorAnovulation
Unexplained: 60%
What is wrong here??Advanced Ovarian Ageing??Poor Gamete Quality??Poor Implantation Conditions?
DiagnosisPrognosis
Indication for ARTIUI mild stimulationIVF/ICSI/ Oocyte donation
Start Indicated treatment
Cycle 1 Cycle 3Cycle 2
Spontaneous Pregnancy
ART related ongoing Pregnancy
Drop Out
The Success of your patient(s)
Time
No Pregnancy, Miscarriage
Assessment of Success
The Infertile Couple
Inf Work Up
IUI ±Stim IVF ICSI
AMH ??
Diagnosis
AMH ??AMH ??
Treatment Expectant
Prognosis
UnexplainedMild Semen
UnexplainedMild SemenModerate Semen
UnexplainedAll SemenTubal
Hunault Model prediction for chance of spontaneous Live BirthDoes AMH or other ORT add value??
Prognostic Model – Who treatment? Who wait?
Prediction by Model Hunault:(%)
0 10 20 30 40 50 60 70 80 90 100
Pre
dic
tio
n b
y M
od
el I (%
)
0
10
20
30
40
50
60
70
80
90
100
In 42 (1.3%) de probability for Ongoing pregnancy shifts from > 30% into < 30%, if basal FSH is added to the Hunault model
These 42 couples would have been advised “TREATMENT” in stead of “EXPECTANT”
N=3219vd Steeg, 2007
Will an ORT add anything to the Hunaull Prediction Model
No such data on AMH
Will AMH 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
Will an ORT add anything to the Hunaull Prediction Model
The Infertile Couple
Inf Work Up
IUI ±Stim IVF ICSI
AMH ??
Diagnosis
AMH ??AMH ??
Treatment Expectant
Prognosis
DiagnosisUnexplainedMild Semen
UnexplainedMild SemenModerate Semen
UnexplainedAll SemenTubal
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
The significance of antral follicle count in controlled ovarian stimulation and intrauterine insemination.
Ng EH, et al, JARG 2005
N=107 casesAFC< 5 foSens 19%Spec 96%LR+ 3.2Post test prob of non pregn: 95%Abn test 16% N=150 cases
AFC< 6 foSens 23%Spec 83%LR+ 1.3Post test prob of non pregn: 88%Abn test 22%
One cycle studies…
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
IUI ±Stim IVF ICSI
AMH ??
Diagnosis
AMH ??AMH ??
Treatment Expectant
Prognosis
UnexplainedMild Semen
UnexplainedMild SemenModerate Semen
UnexplainedAll SemenTubal
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
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
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 Pregnancy1. 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 Pregnancy2. Ovarian Reserve – Quality
OR marker = predictor
AMHGE
Predicting Poor OR(< 5 oocytes)
AUC age: 0.60 (0.57-0.64)AUC age+FSH: 0.69 (0.66-0.72)AUC age+AFC: 0.76 (0.72-0.80)AUC age+AMH: 0.80 (0.76-0.84)AUC AMH: 0.81 (0.77-0.84)
AUC age+AMH+AFC+FSH:0.81 (075-0.86)
Broer, IMPORT study, HRU 2013
Predicting Excessive OR (> 15 oocytes)
AUC age: 0.61 (0.58-0.64)AUC age+AFC: 0.75 (0.71-0.79)AUC age+AMH: 0.81 (0.77-0.85)AUC AMH: 0.82 (0.77-0.86)AUC AMH+AFC: 0.85 (0.80-0.90)
AUC age+AMH+AFC+FSH:
0.85 (080-0.90)
Broer, EXPORT study, HRU 2013
AMH in ANTA or AGO cycles
ROC Curve
1 - Specificity
1,00,75,50,250,00
Sensiti
vity
1,00
,75
,50
,25
0,00
0.90
PredictingWith false negatives and positives
PersonalisingCan we • increase the antral follicle number• mitigate excessive response
= Accurate predictor of Response Category, …but…
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 2009Yajaprakasan, BJOG 2010Berkkanoglu, 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?
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 trialOPTIMisation 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
• AMH in Infertility Work Up
• 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 expensiveYields 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 oocytesPR Anta: 22%Pr Ago: 19%
Predicted Excessive responders: antagonist with standard dose ??
Nelson, 2009, non randomised
Antagonist is More SAFEMore Efficacious
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…
0%
15%
10%30%50%
20% 5%
60%
8%
Individual Patient Data Analysis: the IMPORT study
Female age with or without any ORT fails to predict accuratelyzero prognosis casesN=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=1007Broeze 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 CouplesUseful for IVF Program Restrictions
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
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 BroekmansProfessorReproductive Medicine and SurgeryUniversity Medical Centre UtrechtThe Netherlands
Simone Broer Jeroen van DisseldorpMonique SterrenburgMarieke VerbergDave HendriksEllen KlinkertIlse van RooijLaszlo BancsiMarlies VoorhuisKim Broeze (AMC)Brent Opmeer (AMC)Madeleine DollemanOuijdane HamdineMartine Depmann
Bart FauserNick Macklon (Southampton)
Ben W Mol (AMC)Nils Lambalk (VUMC)
Thank You the IMPORT* studygroup Richard A. AndersonMahnaz 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 TomásPaul J.Q. Van der Linden,K.Vladimirov, Patrick Bossuyt
Genetic DepartmentEdwin CuppenEpidemiology DepartmentYvonne vd SchouwCharlotte Onland-Moret