ANTI-ANTI-MMULULLLERIAN ERIAN HORMONE IN IN THE THE ... · •The inhibitory effects of AMH are...

ANTIANTI--MULLERIAN HORMONE MULLERIAN HORMONE

IN THE PREDICTION IN THE PREDICTION

OF OVARIAN RESPONSEOF OVARIAN RESPONSE

VuongVuong ThiThi Ngoc Ngoc LanLanDepartment of OB/GYN Department of OB/GYN

University of Medicine and Pharmacy of HCMCUniversity of Medicine and Pharmacy of HCMC

Ho Chi Minh City, VietnamHo Chi Minh City, Vietnam

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What is the definition of ovarian What is the definition of ovarian response?response?

lOvarian response can be defined as the

endocrine and follicular reaction of the

ovaries to a stimulus

¡ Qualitative meaning: achieving ovulation in

anovulatory women

¡ Quantitative meaning: the extent of

multifollicular development in patients

undergoing IVF


Ovarian response in IVFOvarian response in IVF

Normo –response

Poor-response

Hyper-response

Low number of eggs

and poor outcome

Appropriate number of eggs and good

outcome

High number of eggs and risk of OHSS


What is the optimal number of What is the optimal number of oocytesoocytesto harvest in a stimulation cycle?to harvest in a stimulation cycle?

Van der Gaast et al., RBMOnline, 2006

Pregnancy rate Live birth rate

131515

Sunkara et al., Hum Reprod, 2011


How to achieve the optimal number How to achieve the optimal number of of oocytesoocytes in a stimulation cycle?in a stimulation cycle?

Ovari

an

resp

on

se

Ovarian stimulation

Hyper-response = danger

Poor-response = poor outcome

?The need for

more individualized

controlled ovarian

stimulation (iCOS)


Individualization of COSIndividualization of COS

l iCOS is designed to treat women based upon their capacity of ovarian response

Pregnancy potential

Clinical safety

2 major components are required:- An accurate mean of predicting ovarian response- An appropriate strategic approach to COS adapted to that response


iCOSiCOS has proven difficult…has proven difficult…

lThe variability in the chronological decline

of the total follicular cohort between

individuals

lThe limited ability of ovarian reserve tests

to detect extremes of response to COS

Faddy, 2000Broekmans et al., 2006

Fauser et al., 2008


How to predict ovarian response? How to predict ovarian response? Proposed measuresProposed measures¡ Day 3 FSH

¡ AFC

¡ AMH

¡ Inhibin B

¡ Basal estradiol

¡ Ovarian volume

¡ Clomiphene citrate challenge test

¡ Exogenous FSH test

¡ GnRH agonist stimulation test

¡ Multivariate models

¡ Previous response


Comparison of characteristics of the most Comparison of characteristics of the most widely used markers of ovarian reservewidely used markers of ovarian reserve

La Marca et al., Hum Reprod Update 2010


How can we optimize ovarian How can we optimize ovarian response?response?

l Age

l Biomarkers

¡ Functional biomarkers: AFC

¡ Hormonal biomarkers: AMH

l Predictive models


AgeAge--related related normogramnormogram for AFC: for AFC: McGill Reference GuideMcGill Reference Guide

Almog et al., Fertil Steril 2011 All antral follicles of 2 – 10mm in diameter


Broekmans et al., Fertil Steril 2009

Use of AFC to Use of AFC to predict the predict the outcome of outcome of ovarian ovarian stimulationstimulation


ANTIANTI--MULLERIAN HORMONEMULLERIAN HORMONEa member of TGF β

•The inhibitory effects of AMH are shown in (a) on the initial recruitment

of primary follicles from the resting primordial follicle and (b) on the

sensitivity of antral follicles for FSH

•Serum AMH is produced from antral follicles up to 7mm, other smaller

follicles may also contributeLa Marca et al., Hum Reprod Update 2010


AMH strongly correlated with ageAMH strongly correlated with age

AMH concentrations decline with increasing reproductive age in a manner optimally described by a quadratic model (n = 4590) – DSL assay

Nelson et al., Fertil Steril 2011


AMH strongly correlated with AMH strongly correlated with ovarian response ovarian response

La Marca et al., Hum Reprod Update 2010


Kwee et al., Fertil Steril 2008

Nelson et al., Hum Reprod 2007Buyuk et al., Fertil Steril 2011

AMH strongly correlated with AMH strongly correlated with ovarian response ovarian response


AMH and AFC for the prediction of AMH and AFC for the prediction of excessive responseexcessive response

Broer et al., Hum Reprod Update 2010

• No consensus definition: 14-

21 oocytes or development of

OHSS

• AMH cut-off value 3.5ng/ml

(DSL assay)

• AFC: no common definition

as different AFC counts used

(2-5mm or 2-10mm)


AMH and AFC for the prediction of AMH and AFC for the prediction of poor responsepoor response

Broer et al., Fertil Steril 2009

• The AMH cut-off

value ranges from 0.5

– 1.1 ng/ml

• The AFC cut-off

value ranges from 5-7


The issues about AMH in IVFThe issues about AMH in IVF

l Cut-off values for prediction of the extreme reponses: varied, no standard reference

¡ Different assays used to measure AMH level

¡ Variations in AMH level between races and ethnicity (Seifer et al., 2008)

¡ Lower AMH level in obese women (Su et al., 2008)

¡ Higher AMH level in PCOS (La Marca et al., 2004)

¡ Lower AMH level in smoking (Freour et al., 2008) or alcohol use (Nardo et al., 2007)

l Correlation with oocyte quality?

l Prediction of initial dose of rFSH? (Nelson et al., 2007)


AMH will be measured in one AMH will be measured in one commercial assay commercial assay –– AMH Gen IIAMH Gen II

• DSL assay gives lower values than

IOT assay (Freour et al., 2007)

• DSL reported in pmol/l; IOT ng/ml

• ng/ml to pmol/l * 7.14

• AMH Gen II has been calibrated with IOT standards

• AMH Gen II assay will give values about 40% higher

than DSL assay (Wallace et al., 2011)


AMH and ovarian response in AMH and ovarian response in Vietnamese patientsVietnamese patients

l 820 patients undergoing IVF treatment

l AMH Gen II assay was used

l Inclusion criteria:

¡Age 18 – 45

¡BMI ≤ 23kg/m2

¡Number of attempts ≤ 2

¡Use GnRH antagonist for COS

¡Had oocyte pick-up

l Exclusion criteria

¡ Donor cycles, IVM, PCOS, hyperprolactinemia

VTN Lan và cs., 2011


Patient characteristics (n=820)Patient characteristics (n=820)

Mean age (years) 32.1 ± 4.8 (19 – 45)

Mean BMI (kg/m2) 20.1 ± 1.4 (18 – 23)

Indications

Tubal

Male

Endometriosis

Advanced age

Ovulation disorder

Unexplained

315 (38.4%)

361 (44%)

7 (0.9%)

41 (5%)

41 (5%)

55 (6.7%)

Duration of infertility (years) 5.3 ± 3.5 (1 – 20)


Cycle characteristics (n = 820)Cycle characteristics (n = 820)

Mean AFC 8.7 ± 4.4 (1 – 24)

Mean AMH (ng/ml) 3.5 ± 3.4 (0.01 – 19.9)

Duration of stimulation (days ) 10.7 ± 1.7 (6 – 19)

Total dose of FSH used (IU) 2243 ± 837 (900 – 5325)

Number of oocytes retrieved 13.9 ± 7.2 (1 – 41)

Number of embryos 7.7 ± 5.1 (0 – 31)

Number of embryos transferred 2.4 ± 1.4 (1 – 5)

Endometrial thickness on day of

hCG (mm)

11.1 ± 2.5 (5 – 21)


Pregnancy outcomesPregnancy outcomes

Pregnancy rate / embryo

transfers

39.1% (257/657)

Miscarriage rate /

embryo transfers

1.4% (9/657)

Ectopic pregnancy rate /

embryo transfers

0.6% (4/657)


AMH and female ageAMH and female age

R = - 0.37

R squared = 0.14

P = 0.000


AMH and number of AMH and number of oocytesoocytes retrievedretrieved

r = 0.74R squared = 0.55P = 0.000


AMH in predicting poor responseAMH in predicting poor response

Poor response < 5 oocytes Cut-off: 1.51ng/ml

Sen: 91%

Spe: 92%

PPV: 82%

NPV: 96%

LR+: 11

LR -: 0.09

< 0.5 – 1.1 ng/ml (ESHRE, 2010)

AUC 0.96P = 0,000


AMH in predicting hyperAMH in predicting hyper--response response

Hyper-response > 15 oocytes Cut-off: 3.97ng/ml

Sen: 82%

Spe: 81%

PPV: 57%

NPV: 93%

LR+: 4.3

LR -: 0.22

3.5 ng/ml (Nelson, 2007)

Sen: 57%, Spe: 96%

AUC 0,88P = 0,000


ConclusionsConclusions

l Oocyte number is a robust prognostic marker of clinical

pregnancy and live birth rate

l AMH and AFC are equally effective in determining ovarian

response to FSH

¡ AFC requires standardization in a center and across centers to be meaningful

¡ A single AMH assay (AMH Gen II) is now commercially available

l The use of AMH to tailor stimulation protocols to improve

outcomes and reduce adverse effects and costs in IVF:

more studies are awaited


THANK YOU


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