Do you have what it takes – from follicle to healthy baby? Scott Nelson Muirhead Chair in...

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


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


Multicentre study confirms Roche automated AMH assay reproducible

AMH (ng/ml)

Age (years)Anderson et al Fertil Steril 2015


Multicentre study confirms Roche automated AMH assay reproducible

AMH (ng/ml)

AFC

Age (years) Age (years)Anderson et al Fertil Steril 2015


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)


MEGASET Trial (n=749)

Nelson et al Fertil Steril 2015

At each clinic AMH better than AFC

Alt. 1)


MERIT Trial (n=623)Alt. 1)


Correlation coefficient

Alt. 1)


MEGASET Trial (n=749)


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


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


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


AMH (pmol/L)


Standard treatment


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


AMH (pmol/L)


Standard treatment


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


AMH (pmol/L)


Standard treatment


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

Do you have what it takes – from follicle to healthy baby? Scott Nelson Muirhead Chair in...

Documents

Transcript of Do you have what it takes – from follicle to healthy baby? Scott Nelson Muirhead Chair in...