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Do you have what it takes – from follicle to healthy baby?Scott Nelson
Muirhead Chair in Obstetrics & Gynaecology
The big challenge of assessing variability
Melisa
Jane
Wallace and Kelsey PLOS One 2010
Oocytenumber
Age
Aim to demonstrate that:
Technical issues with AMH measurement are now resolved by Roche
Randomised controlled trials now confirm AMH better than all other biomarkers for ovarian response prediction
Optimising ovarian response is critical for optimal outcome
Measuring AMH
We had developed the global reference range
25,000 women 10,984 women
DSL assay Gen II assay
Nelson et al Fertil Steril 2011Nelson et al RBMOnline 2012Nelson et al Fertil Steril 2013
Different labs gave different resultsBi
as fr
om m
ean
(%)
Zuvela, et al Reprod Biol 2013
Average AMH concentration(pmol/L)
Different labs gave different results
Bias
from
sam
ple
mea
n (%
)
LaboratoryAverage AMH concentration(pmol/L)
Data from 10 laboratories for all samples analysed by that laboratory (each laboratory returned between 4 and 20 results)
Zuvela, et al Reprod Biol 2013
Bias
from
mea
n (%
)
Our previous AMH assay options
Iliodromiti, Anderson and Nelson Hum Reprod Update 2015
Manual assays show huge day to day variability
1.7
0.6
Is your lab ensuring you get reproducible results?
Beckman Coulter release an automated AMH assay
Beckman CoulterAccess 2 AMH
Iliodromiti, Anderson and Nelson Hum Reprod Update 2015
Supposed to give almost identical values to Gen II
Y = 0.968(x) + 0.11
Beckman Coulter Access AMH assay documentation
Beckman Coulter new assay does not behave as expected – again!
Nelson et al Fertil Steril (in press)
Slope: 0.781 (95% CI 0.758, 0.805)Intercept: 0.128 (95% CI 0.070, 0.198)
Roche release their automated assay
RocheElecsys/cobas
Iliodromiti, Anderson and Nelson Hum Reprod Update 2015
Multicentre study confirms Roche automated AMH assay reproducible
AMH (ng/ml)
Age (years)Anderson et al Fertil Steril 2015
Nelson et al Fertil Steril (in press)
Multicentre study confirms Roche automated AMH assay reproducible
AMH (ng/ml)
AFC
Age (years) Age (years)Anderson et al Fertil Steril 2015
Nelson et al Fertil Steril (in press)
Roche: sensitive robust automated AMH assay
Robust to type of collection
Elecsys AMH serum (ng/ml)
Elec
sys A
MH
Li H
epar
in (n
g/m
L)
Robust to sample storage temperature
Elec
sys A
MH
seru
m s
tress
ed
Elecsys AMH serum fresh
Robust to short and long-term storage
Elec
sys A
MH
Li H
epar
in s
tress
ed
Elecsys AMH serum fresh
Gassner and Jung Clin Chem Lab Med 2014
Factors that affect AMH
GWAS identified 3 major SNPs for AMH
Perry and Nelson submitted
N=2,815
Illumina HumanHap550 quad
113 SNPs
0.8% in girls
AMH is dynamic across the lifecourse
Dewailly et al Hum Repro Update 2014
We can measure AMH on any day of the cycle
Menses Follicular Ovulation Luteal
AMH
(ng/
mL)
4.5
1.0
0.5
4.0
3.5
3.0
2.0
2.5
1.5
5.0
0.0
≤20 years21–2526–3031–35>35
Kissell et al Hum Reprod 2014
AMH
(ng/
mL)
Menses Follicular Luteal
4.0
3.5
3.0
2.0
2.5
1.5
AMHOestradiolProgesterone
Ovulation
Ethnic differences may not exist in ovarian reserve
Bleil et al Fertil Steril 2013Bhide et al BJOG 2014
Geometric Mean AMH
Age (years)
GnRHa alters AMH in time dependent manner
Su et al JCEM 2013Anderson et al Hum Repro 2006
GnRHa
Months
Combined contraception reduces AMH
Kallio et al Fertil Steril 2013
combined OCs (ethinyl E2 [EE] and desogestrel), transdermal patches (EE and norelgestromin), or vaginal rings (EE and etonogestrel)
Smoking can reduce AMH independent of COCP
Dolleman et al JCEM 2013Age (years)
AMH (ng/ml)
Median AMH values in subgroups
PCOS women have higher AMH
Webber et al Lancet 2003Bhide et al Fertil Steril 2014Iliodromiti et al JCEM 2013
PCO ovary has x6 the density of pre-antral follicles compared with normal ovary
AMH
AFC
PCOS women have higher AMH
PCO ovary has x6 the density of pre-antral follicles compared with normal ovary
4.7ng/ml
Webber et al Lancet 2003Bhide et al Fertil Steril 2014Iliodromiti et al JCEM 2013
Disease can temporarily reduce your AMH
Van Dorp et al Hum Repro 2013
AMH at initial diagnosis relative to age matched controls
How does AMH compare to its competitors
The major competitor - AFC
Image from 2001 Image from 2009
Dewailly, et al. Hum Reprod Update 2013
We will always be improving US resolution
Year of data collection
Follicle numberper 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 Hum Reprod Update 2013
AFC normal ranges are just being established
Age
AFC
20 25 30 35 40 45
05
10
15
20
25
30
35
1st
5th
10th
25th
50th
75th 90th 95th 99th
20 25 30 35 40 45
510
15
20
Age
Pre
dic
ted A
FC
DonorInfertility
9,978 women
Infertility population
Age
AFC
20 25 30 35 40 45
510
15
20
25
30
35
1st
5th
10th
25th
50th
75th
90th
95th 99th
Oocyte donor population
5,724 women
Iliodromiti et al submitted
MRI determined AFC – the next step in resolution
Hagen et al JCEM 2014
MRI determined AFC strongly correlates with AMH
Hagen et al JCEM 2014
Are AMH and AFC equivalent?
We thought AMH and AFC were interchangeable
Poor Excessive
IMPORT Consortia Hum Repro Update 2013Export Consortia Fertil Steril 2014
Only AMH predicted oocyte yield in antagonist RCT
Arce et al Fertil Steril 2013
AFC performed poorly
At each clinic AMH better than AFC
Alt. 1)
Clinic AMHa AFC Clinic AMHb AFC1 0.21 -0.16 1 0.26 -0.042 0.31 0.28 2 0.37 0.23 Highest3 0.32 -0.01 3 0.49 0.354 0.49 0.37 4 0.51 0.33 Lowest5 0.50 0.16 5 0.51 0.576 0.53 0.37 6 0.52 0.457 0.53 0.46 7 0.54 0.478 0.55 0.49 8 0.57 0.199 0.56 -0.09 9 0.57 0.5110 0.56 0.58 10 0.59 0.4411 0.59 -0.06 11 0.59 0.5112 0.60 0.23 12 0.61 0.4113 0.61 0.59 13 0.65 0.2714 0.62 0.39 14 0.65 0.4615 0.65 0.75 15 0.65 0.4816 0.68 -0.18 16 0.67 0.7517 0.68 0.35 17 0.71 0.4918 0.68 0.44 18 0.75 0.2619 0.77 0.34
Correlation coefficient
Alt. 1)
Clinic AMHa AFC Clinic AMHb AFC1 0.21 -0.16 1 0.26 -0.042 0.31 0.28 2 0.37 0.23 Highest3 0.32 -0.01 3 0.49 0.354 0.49 0.37 4 0.51 0.33 Lowest5 0.50 0.16 5 0.51 0.576 0.53 0.37 6 0.52 0.457 0.53 0.46 7 0.54 0.478 0.55 0.49 8 0.57 0.199 0.56 -0.09 9 0.57 0.5110 0.56 0.58 10 0.59 0.4411 0.59 -0.06 11 0.59 0.5112 0.60 0.23 12 0.61 0.4113 0.61 0.59 13 0.65 0.2714 0.62 0.39 14 0.65 0.4615 0.65 0.75 15 0.65 0.4816 0.68 -0.18 16 0.67 0.7517 0.68 0.35 17 0.71 0.4918 0.68 0.44 18 0.75 0.2619 0.77 0.34
MEGASET Trial (n=749)
Nelson et al Fertil Steril 2015
At each clinic AMH better than AFC
Alt. 1)
Clinic AMHa AFC Clinic AMHb AFC1 0.21 -0.16 1 0.26 -0.042 0.31 0.28 2 0.37 0.23 Highest3 0.32 -0.01 3 0.49 0.354 0.49 0.37 4 0.51 0.33 Lowest5 0.50 0.16 5 0.51 0.576 0.53 0.37 6 0.52 0.457 0.53 0.46 7 0.54 0.478 0.55 0.49 8 0.57 0.199 0.56 -0.09 9 0.57 0.5110 0.56 0.58 10 0.59 0.4411 0.59 -0.06 11 0.59 0.5112 0.60 0.23 12 0.61 0.4113 0.61 0.59 13 0.65 0.2714 0.62 0.39 14 0.65 0.4615 0.65 0.75 15 0.65 0.4816 0.68 -0.18 16 0.67 0.7517 0.68 0.35 17 0.71 0.4918 0.68 0.44 18 0.75 0.2619 0.77 0.34
MERIT Trial (n=623)Alt. 1)
Clinic AMHa AFC Clinic AMHb AFC1 0.21 -0.16 1 0.26 -0.042 0.31 0.28 2 0.37 0.23 Highest3 0.32 -0.01 3 0.49 0.354 0.49 0.37 4 0.51 0.33 Lowest5 0.50 0.16 5 0.51 0.576 0.53 0.37 6 0.52 0.457 0.53 0.46 7 0.54 0.478 0.55 0.49 8 0.57 0.199 0.56 -0.09 9 0.57 0.5110 0.56 0.58 10 0.59 0.4411 0.59 -0.06 11 0.59 0.5112 0.60 0.23 12 0.61 0.4113 0.61 0.59 13 0.65 0.2714 0.62 0.39 14 0.65 0.4615 0.65 0.75 15 0.65 0.4816 0.68 -0.18 16 0.67 0.7517 0.68 0.35 17 0.71 0.4918 0.68 0.44 18 0.75 0.2619 0.77 0.34
Correlation coefficient
Alt. 1)
Clinic AMHa AFC Clinic AMHb AFC1 0.21 -0.16 1 0.26 -0.042 0.31 0.28 2 0.37 0.23 Highest3 0.32 -0.01 3 0.49 0.354 0.49 0.37 4 0.51 0.33 Lowest5 0.50 0.16 5 0.51 0.576 0.53 0.37 6 0.52 0.457 0.53 0.46 7 0.54 0.478 0.55 0.49 8 0.57 0.199 0.56 -0.09 9 0.57 0.5110 0.56 0.58 10 0.59 0.4411 0.59 -0.06 11 0.59 0.5112 0.60 0.23 12 0.61 0.4113 0.61 0.59 13 0.65 0.2714 0.62 0.39 14 0.65 0.4615 0.65 0.75 15 0.65 0.4816 0.68 -0.18 16 0.67 0.7517 0.68 0.35 17 0.71 0.4918 0.68 0.44 18 0.75 0.2619 0.77 0.34
MEGASET Trial (n=749)
Nelson et al Fertil Steril 2015
AMH is consistently better in both RCTsGnRH antagonist RCT
Nelson et al ASRM 2014
Gen II AMH assay
GnRH agonist RCT
DSL AMH assay
AFC adds little to prediction of oocyte yield
AMH
AFC
Nelson et al Fertil Steril 2015
GnRH agonist RCTGnRH antagonist RCT
Only AMH required in Xpect trial
Prediction of high responseAUROC
AMH 0.77AMH & AFC & FSH 0.80
Screening assessment of candidate
predictors
Baselineassessment of candidate
predictors
Stimulation day 1assessment of candidate
predictors
Cycle 1
Cycle 2Nyboe Andersen, et al Hum Reprod 2011
Smoking added to poor response prediction
Prediction of high response (>18 oocytes)AUROC
AMH 0.86AMH & AFC 0.88AMH, AFC, FSH & age 0.89
Only AMH required in the PURSUE trial
Corifollitropin alfa arm of the Pursue Study (n=686)Women aged 35 to 42 years, Body weight ≥50 kg, BMI ≥18 and ≤32 kg/m2 Oehninger, Nelson et al RBOnline (in press)
Only AMH required in novel recFSH Phase II trial
Arce et al Fertil Steril 2014
Oocytes retrieved
rhFSH (fixed daily dose, ug/day)
No added value of additional predictors
R2
AFC 26%AMH 35%
AMH & AFC 38%
Why is AFC so bad – the variability is huge
Intraobserver variability
Diffe
renc
e be
twee
npa
ired
mea
sure
men
ts
Mean of two counts
Deb, et al Ultrasound Obstet Gynecol 2009
Intraobserver variability
Diffe
renc
e be
twee
npa
ired
mea
sure
men
ts
Mean of two counts
Interobserver variability
Mean of two counts
Diffe
renc
e be
twee
npa
ired
mea
sure
men
ts
Deb, et al Ultrasound Obstet Gynecol 2009
Why is AFC so bad – the variability is huge
How AMH can inform clinical practice
Low AMH does not reduce short term fecundability
0 1 2 3 4 5 60
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Time from cessation of birth control (cycles)
Cu
mu
lativ
e p
rop
ort
ion
of w
om
en
ach
ievi
ng
pre
gn
an
cy
19 21 23 25 27 29 31 33 350
10
20
30
40
50
60
70
Age (years)
AM
H (
pm
ol/L
)
AMH quintiles, middle 3 combined
Hagen et al Fertil Steril 2012
AMH can individualize fertility prognosis for oncology patents
Courtesy of RA Anderson 2015
We can use AMH to individualize fertility preservation
Anderson and Cameron JCEM 2011Anderson and Nelson Maturitas 2012
Anderson et al Eur J Cancer 2013
Amenorrhea Menses0
10
20
30
40
50
60
Amenorrhea Menses0
2.5
5
7.5
Amenorrhea Menses02468
101214161820
Amenorrhea Menses30
40
50AMH Age
FSH Inhibin B
** *
pm
ol/L
Ye
ars
IU/L
pg
/ml
We can use AMH to predict the menopause
Dolleman et al JCEM 2013
Chloe
Zoe
We can use AMH for family planning
OK to delay family
Have a family or work for
Apple/Google
Anderson and Nelson Hum Repro 2012
Dawn
Ellie
AMH should not be used to exclude from treatment
Iliodromiti et al Hum Reprod Update 2014
Sens
itivity
Specificity
1.0
0.8
0.6
0.4
0.2
0
1.0 0.8 0.6 0.4 0.2 0
live birth DOR 2.39 (95%CI 1.85 – 3.08)
With Univfy we showed that AMH enhanced prediction
Nelson et al Fertil Steril 2015
Validation Parameters AMH-PM AFC-PM AMH-AFC-PM
AUC of Receiver-Operating Characteristic Analysis 0.716 0.706 0.716
Control AUC 0.674 0.674 0.674
AUC Improvement 6.3% 4.8% 6.3%
PLORA – log scale 29.1 22.5 28.3
PLORA Improvement 76.2% 59.0% 73.3%
% Reclassified to have higher LB rate 62% 71% 67%
% Reclassified to have lower LB rate 14% 8% 12%
Tier-specific prediction error – See next slide for details ≤ 4% ≤ 8% ≤ 4%
We now know 15 is an optimal oocyte yield
Live
birt
h ra
te (%
)
Oocyte yield Sunkara, et al Hum Reprod 2011Steward et al Fertil Steril 2014
40
30
20
10
10
5 10 15 2520 30 35 40
Plateau even in the US after 15 but OHSS increases
Steward et al Fertl Steril 2014256,381 in vitro fertilization cycles
AMH can optimise stimulationPo
pula
tion
%
Oocyte yield
Inadequategonadotrophin
exposure
IatrogenicPoor response
Excessivegonadotrophin
exposure
Iatrogenic OHSS
Optimal
We can use AMH to stratify care
AMH (pmol/L)
AntagonisthCG/GnRHa trigger
Standard treatment
Maximise oocyte yield
40
20
7
1Nelson et al Hum Reprod 2009
Yates et al Hum Reprod 2011
We can use AMH to stratify care
AMH (pmol/L)
AntagonisthCG/GnRHa trigger
Standard treatment
Maximise oocyte yield
40
20
7
1Nelson et al Hum Reprod 2007Nelson et al Hum Reprod 2009
10
20
30
Antagonist
% C
ycle
s
HighAMH>15
Pmol/L
P < 0.001
Reduced OHSS
Excessive response
We can use AMH to stratify care
AMH (pmol/L)
AntagonisthCG/GnRHa trigger
Standard treatment
Maximise oocyte yield
40
20
7
1Nelson et al Hum Reprod 2007Nelson et al Hum Reprod 2009
10
20
30
Antagonist
% C
ycle
s
HighAMH>15
Pmol/L
P < 0.001
Reduced OHSS
Excessive response
0
20
40
60
80
Live
Birt
h %
High AMH>15
Pmol/L
Antagonist
Agonist
P < 0.001Increased live births
We can use AMH to stratify care
AMH (pmol/L)
AntagonisthCG/GnRHa trigger
Standard treatment
Maximise oocyte yield
40
20
7
1 Pre-AMHLi
ve b
irth
rate
(%)
30
25
20
15
10
Post-AMHNelson, et al Hum Reprod 2009
Yates, et al Hum Reprod 2011
AMH may allow truly individualised dosing
Optimum range (8–14 oocytes)
≥20 oocytes
15–19 oocytes
4–7 oocytes
≤3
Prop
ortio
n of
sub
ject
s %
AMH (pmol/L)
5 10 15 20 25 30 35 40
100
80
60
40
20
0AMH (pmol/L)
FE
99
90
49
do
se
ta
rge
tin
g 1
1 o
oc
yte
s (
ug
/kg
)
15 20 25 30 35 40
0.1
00
.12
0.1
40
.16
0.1
80
.20
0.2
2
AMH pmol/L
FE 9
9904
9 (u
g/kg
)ta
rget
ing
11 o
ocyt
es
Ferring ESTHER-1 RCT ongoing
AMH will be the biomarker of choice for individualising stimulation
Iliodromiti, Anderson & Nelson Hum Repro Update 2014
Conclusions:
We now have a robust automated AMH assay from Roche
RCTs confirm that AMH is superior to all other biomarkers
AMH can be used to personalise reproductive potential and therapy