afc/amh and ovarian reserve: are they competitors or …cme-utilities.com/mailshotcme/material for...
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AFC/AMH and ovarian reserve: are they competitors or complemenary?
ART/PGD Department Arnaud de Villeneuve hospital
University-hospital of Montpellier, INSERM U 1203Montpellier-34295, France
Pr. Samir Hamamah
Chair: Reproductive/PGD Department
Head: ART/PGD DivisionDirector: INSERM U 1203
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de Bruin et te Velde 2004
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Societal and Behavioral Shifts…
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• Ovarian reserve (OR)
• Bio markers of OR
• Tow major competitors - AFC and AMH
Pre- ART assessment of female partner
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- Serum assays (D2-3):
Conventional bio markers of OR
- Clinical:
• age: oocyte quality++
• FSH, Estradiol, Inhibine B• Anti-Müllerian Hormone (AMH)
- US measurements:• Antral follicule count (AFC)
(2-10 mm)
Normal si > 10 follicules !
• Ovarian volume
Kwee et al, FS 2008
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Others factors affects OR
BMI
Ethnicity
Age
Smoking
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Does AMH and AFC for OR assessment will be competitors
or complementary ?
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Our Tools
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Sonographic Evaluation of OR
I- Antral follicle count (AFC)
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• Antral follicle counts (AFC)
• Ovarian volume (not recommended by ASRM, 2015)
• Doppler imaging techniques
Sonographic Evaluation of OR
Antral follicle count (AFC)
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Improving US resolution
Year of data collection
Follicle number
per ovary
Max
Transducer
Freq (MHz)
2
4
6
8
10
12
14
16
18
1992 1994 1996 1998 2000 2002 2004 2006 2008 2010 2012
677.588.5912
Dewailly, et al HRU 2013
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Antral Follicle Counts (AFC)
• 2-10 mm antral follicles
• Typically measured on Day 2 or 3
• Correlates with d3 FSH, amount of total gonadotropin used, peak E2 level and # oocytes Chang et al. 1998
• Predictor beyond patient age, d3 FSH level Beckers, et al. 2000
or inhibin B level Fauser, 2000; Laszlo et al. 2002
• Normal responders typically have > 10 antral follicles vs. < 5 for poor responders Beckers, et al. 2000; 2002
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AFC normal ranges are just being established
Age
AFC
20 25 30 35 40 45
05
1015
2025
3035
1st
5th
10th
25th
50th
75th 90th 95th 99th
20 25 30 35 40 45
510
1520
Age
Pre
dict
ed A
FC
Donor
Infertility
9,978 women
Infertility population
Age
AFC
20 25 30 35 40 45
510
1520
2530
35
1st
5th
10th
25th
50th
75th
90th
95th 99th
Oocyte donor population
5,724 women
Iliodromiti et al JCEM, 2016
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Iliodromiti et al, JCEM. 2016
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Hagen et al JCEM 2014
MRI determined AFC MRI determined AFC strongly correlates with AMH
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Intraobserver variability
Diffe
rence
betw
een
paired m
easu
rem
ents
Mean of two counts
Interobserver variability
Mean of two counts
Diffe
rence
betw
een
paired m
easu
rem
ents
◼ ◼
Deb et al, 2009
Why is AFC not reliable? the variability is huge
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Individualized dosing based on AFC
. does not improve LBR
. may improve safety for high responder patients
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Antral follicle count (AFC)
• Widely used ultrasound measure of OR
• Transvaginal, early follicular phase
• Probably the best predictor of ovarian response to COS
• Thresholds for a low AFC definition vary
• Most use the combined number of 2-9 or 2-10 mm follicles on each ovary
• There is an age-related decline in AFC
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II- Anti Müllerian Hormone - AMH -
• Produced only in ovarian GC• Its serum concentration reflect the pool of ovarian follicules (preantral and small antral)• AMH levels are 2 to 3 times higher in PCOS patients compared to normal adult women
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Anti Müllerian Hormone - AMH -
• Technical issues with AMH measurement are now resolved
• RCT now confirm AMH better than all other biomarkers for ovarian response prediction
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Anti Müllerian Hormone - AMH -
Measuring AMH
Nelson et al FS 2011Nelson et al RBMO 2012Nelson et al FS 2013
Global reference range
Different labs gave different results Zuvela, et al Reprod Biol 2013
Iliodromiti et al, HRU 2015Multicentre study confirms Roche automated AMH assay reproducible Anderson et al FS 2015
Nelson et al FS 2016
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Anti Müllerian Hormone - AMH -
Measuring AMH
VIDAS® AMH quantitatif measurement of circulating AMH using ELFA (Enzyme Linked Fluorescence Assay)
Roche or BioMerieux release their automated test VIDAS® AMH
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Anti Müllerian Hormone - AMH -
Measuring AMH
Competitor assayCuurently on the market
VIDAS® AMH
Assay typeTests / kitSample type
Automate30Serum, plasma (Li Hep)
Minimum sample volume 200 µl
Incubation time 35 min
Limit of detection 0.02 ng/mL
Units ng/ml – pmol/L
Measuring rangeCalibratios and controls frequency
0.02 – 9.00 ng/mL28 days
BioMérieux Values
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Anti Müllerian Hormone - AMH -
Factors that affect AMH
• 3 major SNPs for AMH identifiedPerry and Nelson 2015
• AMH is dynamic across the lifecourseDewailly et al, HRU 2014, 2018
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AMH can be measured on any day of the cycle
Menses Follicular Ovulation Luteal
AM
H (
ng/m
L)
4.5
1.0
0.5
4.0
3.5
3.0
2.0
2.5
1.5
5.0
0.0
≤20 years
21–25
26–30
31–35
>35
Kissell et al HR 2014
AM
H (
ng/m
L)
Menses Follicular Luteal
4.0
3.5
3.0
2.0
2.5
1.5
AMH
Oestradiol
Progesterone
Ovulation
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Ethnic differences may not exist in OR relate to AMH
Bleil et al FS 2013Bhide et al BJOG 2014
Geometric Mean AMH
Age (years)
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Smoking can reduce AMH
Dolleman et al JCEM 2013
Age (years)
AMH (ng/ml)
Median AMH values in subgroups
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Webber et al Lancet 2003Bhide et al FS 2014Iliodromiti et al JCEM 2013
PCOS patients ovary has x6 the density of pre-antral follicles compared with normal patients ovary
AMH
AFC
PCOS women have higher AMH
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• AMH decreases throughout reproductive life• Undetectable AMH levels after spontaneous menopause• Stable throughout the menstrual cycle
La Marca et al, 2006a
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di Clemente et al, 2014
Age-Specific Normal Reference Range for Serum AMH in Healthy Chinese Han
Women: A nationwide Population-Based Study.
Du et al, Reprod Sci 2016, 2017
• Serum AMH concentrations declined progressively with age• Median AMH levels were 6.23, 5.65, 4.55, 3.74, 2.78, and 1.09 ng/mL for the 20 ≤ age < 25, 25 ≤ age
< 30, 30 ≤ age < 33, 33 ≤ age < 37, 37 ≤ age < 40, and 40 ≤ age < 55 groups, respectively
• AMH levels were positively correlated with AFCs and T, LH, PRL and PRG levels and negatively correlated with BMI and FSH levels and were not significantly correlated with E2
AMH decreases with age
2.6 years
P<0.001
2055 women, aged 20 to 55 years, from 6 different regions in China
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How does AMH compare to its competitors ?
The major competitor - AFC
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Hagen et al JCEM 2014
MRI determined AFC strongly correlates with AMH
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Are AMH and AFC equivalent in COS ?
AMH AFC
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Why no consensus with either US or AMH?
• Population issues
– Patient populations
– Control populations
• Technical issues
– Different ultrasound machines (<≥8MHz)
– Different ways of counting/measuring
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How AMH can inform clinical practice ?
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Arce et al FSl 2013
AMH predicted oocyte yield in antagonist RCT
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at each clinic AMH better than AFC
Alt. 1)
Clinic AMHa
AFC Clinic AMHb
AFC
1 0.21 -0.16 1 0.26 -0.04
2 0.31 0.28 2 0.37 0.23 Highest
3 0.32 -0.01 3 0.49 0.35
4 0.49 0.37 4 0.51 0.33 Lowest
5 0.50 0.16 5 0.51 0.57
6 0.53 0.37 6 0.52 0.45
7 0.53 0.46 7 0.54 0.47
8 0.55 0.49 8 0.57 0.19
9 0.56 -0.09 9 0.57 0.51
10 0.56 0.58 10 0.59 0.44
11 0.59 -0.06 11 0.59 0.51
12 0.60 0.23 12 0.61 0.41
13 0.61 0.59 13 0.65 0.27
14 0.62 0.39 14 0.65 0.46
15 0.65 0.75 15 0.65 0.48
16 0.68 -0.18 16 0.67 0.75
17 0.68 0.35 17 0.71 0.49
18 0.68 0.44 18 0.75 0.26
19 0.77 0.34
MERIT Trial (n=623) MEGASET Trial (n=749)
Correlation coefficient
AMH assay: aBeckman Coulter Innmunotech,
bBeckman Coulter Gen II
Alt. 1)
Clinic AMHa
AFC Clinic AMHb
AFC
1 0.21 -0.16 1 0.26 -0.04
2 0.31 0.28 2 0.37 0.23 Highest
3 0.32 -0.01 3 0.49 0.35
4 0.49 0.37 4 0.51 0.33 Lowest
5 0.50 0.16 5 0.51 0.57
6 0.53 0.37 6 0.52 0.45
7 0.53 0.46 7 0.54 0.47
8 0.55 0.49 8 0.57 0.19
9 0.56 -0.09 9 0.57 0.51
10 0.56 0.58 10 0.59 0.44
11 0.59 -0.06 11 0.59 0.51
12 0.60 0.23 12 0.61 0.41
13 0.61 0.59 13 0.65 0.27
14 0.62 0.39 14 0.65 0.46
15 0.65 0.75 15 0.65 0.48
16 0.68 -0.18 16 0.67 0.75
17 0.68 0.35 17 0.71 0.49
18 0.68 0.44 18 0.75 0.26
19 0.77 0.34
MERIT Trial (n=623) MEGASET Trial (n=749)
Correlation coefficient
AMH assay: aBeckman Coulter Innmunotech,
bBeckman Coulter Gen II
Nelson et al FS 2015
Alt. 1)
Clinic AMHa
AFC Clinic AMHb
AFC
1 0.21 -0.16 1 0.26 -0.04
2 0.31 0.28 2 0.37 0.23 Highest
3 0.32 -0.01 3 0.49 0.35
4 0.49 0.37 4 0.51 0.33 Lowest
5 0.50 0.16 5 0.51 0.57
6 0.53 0.37 6 0.52 0.45
7 0.53 0.46 7 0.54 0.47
8 0.55 0.49 8 0.57 0.19
9 0.56 -0.09 9 0.57 0.51
10 0.56 0.58 10 0.59 0.44
11 0.59 -0.06 11 0.59 0.51
12 0.60 0.23 12 0.61 0.41
13 0.61 0.59 13 0.65 0.27
14 0.62 0.39 14 0.65 0.46
15 0.65 0.75 15 0.65 0.48
16 0.68 -0.18 16 0.67 0.75
17 0.68 0.35 17 0.71 0.49
18 0.68 0.44 18 0.75 0.26
19 0.77 0.34
MERIT Trial (n=623) MEGASET Trial (n=749)
Correlation coefficient
AMH assay: aBeckman Coulter Innmunotech,
bBeckman Coulter Gen II
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ESTHER Trial
Anderson et al, 2017
AMH
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• AMH= good quantitative bio marker of OR• Can not be used alone (age, ovulatory status, AFC, BMI….)
• AMH= bad qualitative bio marker to predict conception. Low AMH=elevated FSH
• Age= best criteria for oocyte quality
• Normal AMH= non prognosis value
AMH as a Tool to choice ART!
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The Future
Circulating Nucleic Acids for evaluating Ovarian Reserve!
New markers in ART
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Applying Genomics medicine to ART
Ovarian reserve and Stress Predicting
Ovarian ResponsePredicting
Viable Embryo Selection
IW Detecting
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OR conventional biomarkers:AMH…CFA…FSH…LH…E2…
Which one more reliable?
Possibilities and limits of ovarian reserve testing in ARTLa Marca et al., Curr Pharm Biotechnol., 2012
Discrepancies between AMH and AFC?
Which one to choice for choicingCOS and predict protocols?
Identification of new biomarkers for OR and COS response
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RESEARCH ARTICLE
Cell-free DNA in Human FollicularMicroenvironment: New Prognostic
Biomarker to Predict in vitro Fertilization Outcomes
Sabine Traver, Elodie Scalici, Tiffany Mullet, Nicolas Molinari, Claire Vincens, Samir Hamamah
2014
2013
2015
2014
2016
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0.0
0.1
1.0
10.0
Normalovarianreserve
LFOR PCOS
cfD
NA (
ng/µ
l)
Ovarian reserve status
P=0.05
NS
P=0.045
*
• cfDNA level in serum was significantly higher in women with LFOR comparedwith normal OR (p=0.045).
• cfDNA level in serum tended to be higher in PCOS patients compared withnormal OR (p=0.05).
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Ce
llfr
ee
DN
A in
se
rum
(ng
/m
l)
Age (years)
Cell-free DNA level in serum according to patient’s age
• By including only patients withnormal OR (N=40)
• Linear RegressionR2=0.27, p=0.001
• By using cut off of 38 years:Significant higher cfDNA levels for women with ≥38 years compared to women with < 38 years (p=0.03)
Significant and positiveassociation between cfDNAlevels in serum at day 3and patient’s age
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Cell-free DNA level in serum at day 3 related to ovarian reserve status
Prediction of LOR (n=38)according to cfDNA at D3
Prediction of PCOS (n=30)according to cfDNA at D3
AUC=0.71 (0.59-0.81)P<0.001Se=68%Sp=73%
AUC=0.81 (0.69-0.90)P=0.01Se=70%Sp=68%
OR status based on AMH level and AFC at day 3.
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0.01
0.10
1.00
10.00
≤ 2 > 2
CfD
NA (
ng/µ
l)
AMH (ng/ml)
P=0.004*
cfDNA level was significantly higher in serum samples fromwomen with AMH ≤1 ng/ml or ≤ 2 ng/ml compared to those withAMH>1 ng/ml or > 2 ng/ml, respectively (p=0.004)
cfDNA according to AMH level
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Cell-free DNA levels in serum at D3 and COSCell
free D
NA in s
eru
m(n
g/m
l)
Number of retrieved oocytes
Ovarian response to stimulation based on nber oocytes collected at oocyte retrieval day
• By including patients undergoing IVF/ICSIprocedure (N=31)
• Linear RegressionR2=0.15, p=0.03
• Logistic regression: Prediction of retrievedoocytes by using mutivariate modelincluding AMH and cfDNA levels at day 3
Parameters Coeff. SE P
AMH 0,18 0,22 0,4 (NS)
CfDNA -0,01 0,006 0,03
CfDNA levels at day 3 can predict significantly the nbr of retrieved oocyte independently of AMH levels.
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Cell-free DNA versus AMH levels in serum at D3 for prediction of oocyte collection
Cell-free DNA
AMH
AUC=0.79 (0.60-0.91)P=0.001Se=73%Sp=82%
• Patients undergoing IVF/ICSI procedure
AUC=0.73 (0.54-0.87)P=0.02Se=67%Sp=81%
Cut off of 6 oocytes
CfDNA levels at D3 can predict significantly a poor ovarian response(<6 oocytes) to stimulation with higher Se and Sp than of AMH levels.
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Traver - Hamamah et al 2015
Comparison of cell-free DNA levels betweenwomen with normal OR, and PCOS
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0
1
2
3
4
8-12mm 13-18mm >18mm
0
1
2
3
4
8-12mm 13-18mm >18mm
AD
N lib
re
(ng/m
l)
*
Follicle size
*
AD
N lib
re
(ng/m
l)
Follicle size
*p=0.024
*p=0.007
Significant and negative correlation betweenintra-follicular cfDNA levels and follicle sizeRelationship with dynamic and functionnal
follicle state.
Significant associations between intra-follicularcell-free DNA levels and follicle size
High cell-free DNA levels
Low cell-free DNA levels
Scalici…Hamamah et al., HR 2014
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0
1
2
3
4
≤ 10 > 10
cfD
NA
(n
g/µ
l)
Number of days of stimulation
0
1
2
3
< 3000 ≥ 3000
cfD
NA
(n
g/µ
l)
Total dose of gonadotropins (IU)
0
1
2
3
4
≤ 6 > 6
cfD
NA
(n
g/µ
l)Number of oocytes
*
*
*
*p=0.008
*p=0.01
*p=0.045
Traver…Hamamah et al., Plos One 2015
Significant associations between intra-follicularcfDNA levels and ovarian response to COS
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ROC curve for obtaining a clinical pregnancyaccording to cfDNA level
ROC curve to evaluate the predictive value of FF cfDNA level for clinical pregnancy outcome in a multivariate model :area under the curve = 0.73 [0.66–0.87], sensitivity = 60%, specificity = 88%
Traver - Hamamah et al 2015
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Scalici - Hamamah et al., HR 2014Traver - Hamamah et al., Plos One 2015
Schematic model summarizing the significant relationships between cf-DNA levels and:
infertility duration, OR status, ovarian stimulation, ovarian response to COS, embryo development and clinical pregnancy outcomes
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Conclusions
• We now have a robust automated AMH assay from Roche, BioMerieux…
• RCTs confirm that AMH is superior to AFC biomarker
• AMH can be used for prediction hypo/hyper ovarian response
• In case of discrepancies between AMH and AFC, cfDNA should be investigated…