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
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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
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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
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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)
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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
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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
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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
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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
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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
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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
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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
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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
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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
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AMH strongly correlated with AMH strongly correlated with ovarian response ovarian response
La Marca et al., Hum Reprod Update 2010
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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
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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)
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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
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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)
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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)
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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
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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)
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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)
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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)
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AMH and female ageAMH and female age
R = - 0.37
R squared = 0.14
P = 0.000
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AMH and number of AMH and number of oocytesoocytes retrievedretrieved
r = 0.74R squared = 0.55P = 0.000
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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
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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
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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
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