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Frank J Broekmans Professor Reproductive Medicine and Surgery University Medical Center Utrecht -20-30 Checking AMH as an initial evaluation of ovarian.

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Presentation on theme: "Frank J Broekmans Professor Reproductive Medicine and Surgery University Medical Center Utrecht -20-30 Checking AMH as an initial evaluation of ovarian."— Presentation transcript:

1 Frank J Broekmans Professor Reproductive Medicine and Surgery University Medical Center Utrecht -20-30 Checking AMH as an initial evaluation of ovarian reserve Midwest Reproductive Symposium Chicago, USA June 19-21, 2014

2 Coming to Chicago

3 Disclosures Member external advisory board Merck Serono Member external advisory board Gideon Richter Educational work MerckSharpDome Educational activities Ferring BV Consultancy work Roche

4 Learning Objectives Appreciate the biology of Ovarian Reserve Know the limitations of predicting Poor and Excessive Ovarian Response by using AMH Believe the very limited relation ship between FSH dosage and Ovarian Response Appreciate the inability of AMH to predict Quality

5 Initial evaluation of ovarian reserve For what purpose? 1.Assessment of Time to Menopause/future fertility 2.Predicting prognosis for spontaneous pregnancy in Infertility 3.Predicting Pregnancy after ART 4.Prediction Ovarian response ART 5.Ovarian Damage quantification (chemo, UAE, ovarian surgery) 6.POI diagnosis

6 Initial evaluation of ovarian reserve For what purpose? 1.Assessment of Time to Menopause/future fertility 2.Predicting prognosis for spontaneous pregnancy in Infertility 3.Predicting Pregnancy after ART 4.Prediction Ovarian response ART 5.Ovarian Damage quantification (chemo, UAE, ovarian surgery) 6.POI diagnosis

7 Agenda AMH and Ovarian Physiology AMH in Infertility Work Up Why predict and select in ART Can we really predict and select: –FSH dosage –Stim protocol –Egg quality Conclusions

8 AMH - dimeric glycoprotein member of the transforming growth factor β ( TGF-β ) family of growth and differentiation factors (Inhibins and Activins) Produced from Mural Granulosa Cells Basically a Paracrine Inhibitor AMH Physiology

9 Ovarian AMH inhibits a. Initial recruitment of primordial follicles into primary follicles b. Sensitivity of Antral follicles to FSH AMH Physiology – Paracrine!!

10 8-10 mm 2-7 mm 0,1-2 mm Primordial pool Primary follicles Pre-antral follicles Circulating AMH ? The source of Serum AMH Jeppesen, MHR 2013 Broer, COOG 2009

11 AMH processing Signal peptide Proregion 55 kD Mature peptide 12.5 kD Signal peptide cleavage Dimerization Cleavage by proprotein convertases Furin, PC5 RAQR Serum Granulosa Cell

12 DSL-I AMH assay - enzymatically amplified two-site immunoassay. 2/6 detector AB 9/6 capture AB detector ABcapture AB F2B/7A detector AB F2B/12H capture AB DSL-II 0.006-0.017 ng/ml. Detection limit 0.078 ng/ml. Beckman-Coult Gen II 0.08 ng/ml. ultra-sensitive 2 ng/ml Immunotech-Beckman traditional 0.1 ng/ml

13 Serum AMH declines with.. Ovarian Stimulation Pituitary/gonadal suppression by Oral contraceptive GnRH agonist Smoking Pregnancy Li, JARG 2013 Koninger RBE 2013 Hagen, FS 2012 Dolleman, JCEM 2013

14 Use your Own or the Same Laboratory Standardise Storage and Shipping conditions: Deep Frozen -80 is best…?? Reference values based on your own data..and check pill and smoking GEN II = DSL + 40% AMH assay BC Gen II system Do’s and don’t’s F2B/7A detector AB F2B/12H capture AB

15 Agenda AMH and Ovarian Physiology AMH in Infertility Work Up Why predict and select in ART Can we really predict and select: –FSH dosage –Stim protocol –Egg quality Conclusions

16 Infertility Tubal Pathology Severe Male factor Anovulation Unexplained: 60% What is wrong here?? Advanced Ovarian Ageing?? Poor Gamete Quality?? Poor Implantation Conditions?

17 Diagnosis Prognosis Indication for ART IUI mild stimulation IVF/ICSI/ Oocyte donation Start Indicated treatment Cycle 1Cycle 3Cycle 2 Spontaneous Pregnancy ART related ongoing Pregnancy Drop Out The Success of your patient(s) Time No Pregnancy, Miscarriage Assessment of Success

18 The Infertile Couple Inf Work Up IUI ±StimIVF ICSI AMH ?? Diagnosis AMH ?? TreatmentExpectant Prognosis Unexplained Mild Semen Unexplained Mild Semen Moderate Semen Unexplained All Semen Tubal

19 Hunault Model prediction for chance of spontaneous Live Birth Does AMH or other ORT add value?? Prognostic Model – Who treatment? Who wait?

20 In 42 (1.3%) de probability for Ongoing pregnancy shifts from > 30% into < 30%, if basal FSH is added to the Hunault model These 42 couples would have been advised “TREATMENT” in stead of “EXPECTANT” N=3219 vd Steeg, 2007 Will an ORT add anything to the Hunaull Prediction Model

21 No such data on AMH Will AMH add anything to the Hunaull Prediction Model

22 N=474 - In 20 cases (5.4%) the probability of ongoing pregancy shifts from ≥ 30% into < 30%, if bFSH is added to the Hunault model. Haadsma, HR 2009 Will an ORT add anything to the Hunaull Prediction Model

23 The Infertile Couple Inf Work Up IUI ±StimIVF ICSI AMH ?? Diagnosis AMH ?? TreatmentExpectant Prognosis Diagnosis Unexplained Mild Semen Unexplained Mild Semen Moderate Semen Unexplained All Semen Tubal

24 ORT before starting IUI/Stim? Only Few studies, and not on AMH The aim could be: skip IUI/Stim if prognosis is too poor for succes in thta treatment modality and proceed directly to IVF

25 FSH and CCCT useful in IUI/stim?? Cases with 30-50% reduction in cumulative chance of pregnancy can be identified. Skip the treatment?? 3 Cumulative cycles… Magendzo, 2006

26 AFC prior to IUI with ovarian stimulation - No consistent data The significance of antral follicle count in controlled ovarian stimulation and intrauterine insemination. Ng EH, et al, JARG 2005 N=107 cases AFC< 5 fo Sens 19% Spec 96% LR+ 3.2 Post test prob of non pregn: 95% Abn test 16% N=150 cases AFC< 6 fo Sens 23% Spec 83% LR+ 1.3 Post test prob of non pregn: 88% Abn test 22% One cycle studies…

27 ORT when indication for IUI/Stim No consistent prediction of poor prognosis cases Should we skip IUI/STIM in women over 38 and/or abnormal ORT, and then do…. direct IVF….????? Or The PRORAILS study: AFC and AMH as predictors of response and outcome

28 The Infertile Couple Inf Work Up IUI ±StimIVF ICSI AMH ?? Diagnosis AMH ?? TreatmentExpectant Prognosis Unexplained Mild Semen Unexplained Mild Semen Moderate Semen Unexplained All Semen Tubal Diagnosis

29 Agenda AMH and Ovarian Physiology AMH in Infertility Work Up Why predict and select in ART Can we really predict and select: –FSH dosage –Stim protocol –Egg quality Conclusions

30 LBR ↓ Costs↑ Burden↑ Discomfort ↑ Risks ↑ LBR ↓ Optimal Predicting the variation: Ovarian Response

31 Out of every 100 couples starting IVF....only 50 will achieve an ongoing pregnancy within a 1 year treatment period… Lintsen, HR 2007 Predictable?? or..Preventable?? Predicting the variation: Ongoing Pregnancy

32 Agenda AMH and Ovarian Physiology AMH in Infertility Work Up Why predict and select in ART Can we really predict and select: –FSH dosage –Stim protocol –Egg quality Conclusions

33 Predictors of Response and Pregnancy 1. Ovarian Reserve - Quantity Continuous Intermittent AMH, AFC, basal FSH, basal Inhibin B: Quantity Markers

34 Ata, RBM 2012 With increasing female age the proportion of euploid embryo’s goes down from ~75% to ~25% Predictors of Response and Pregnancy 2. Ovarian Reserve – Quality

35 OR marker = predictor AMHGE

36 Predicting Poor OR (< 5 oocytes) AUC age: 0.60 (0.57-0.64) AUC age+FSH: 0.69 (0.66-0.72) AUC age+AFC: 0.76 (0.72-0.80) AUC age+AMH:0.80 (0.76-0.84) AUC AMH:0.81 (0.77-0.84) AUC age+AMH+AFC+FSH: 0.81 (075-0.86) Broer, IMPORT study, HRU 2013

37 Predicting Excessive OR (> 15 oocytes) AUC age: 0.61 (0.58-0.64) AUC age+AFC: 0.75 (0.71-0.79) AUC age+AMH:0.81 (0.77-0.85) AUC AMH:0.82 (0.77-0.86) AUC AMH+AFC:0.85 (0.80-0.90) AUC age+AMH+AFC+FSH: 0.85 (080-0.90) Broer, EXPORT study, HRU 2013

38 AMH in ANTA or AGO cycles Predicting With false negatives and positives Personalising Can we increase the antral follicle number mitigate excessive response = Accurate predictor of Response Category, …but…

39 Predict and select in ART Can we..??

40 Agenda AMH and Ovarian Physiology AMH in Infertility Work Up Why predict and select in ART Can we really predict and select: –FSH dosage –Stim protocol –Egg quality Conclusions

41 Dose – Response….? Sterrenburg, HRU 2009 Yajaprakasan, BJOG 2010 Berkkanoglu, FS 2010

42 No: predicted poor responders based on AFC (<5 [2–5 mm] follicles) did not have better pregnancy rates with 300 IU compared to 150 IU rec FSH (n=52) Klinkert ER, et al. Hum Reprod 2005 No: predicted poor response cases based on AMH (<14 pmol/L) did not have improvement of oocyte yield nor pregnancy rates when 150 IU rec FSH was compared to 200–300 IU in a pseudorandomized design (n=122) Lekamge DN, et al. J Assist Reprod Genet 2008 No: In cases with moderately decreased OR (FSH > 8.5 U/l) no benefit was observed from 400 versus 300 IU stimulation dose for response or pregnancy (n-48) Harrison R, et al Fertil Steril, 2001 No: In cases with AFC<12, no difference was observed in oocyte yield nor live birth rate comparing 300, 450 and 600 IU of FSH. Berkkanoglu FS 2010 Prediction of poor response Individualize dose of FSH?

43 Yes: an individual stimulation dose, based on a model with age, AFC, basal FSH and BMI suggests that reduced dosages mitigates response without effects on pregnancy rates (n=161) (wait for RCT, CONSORT) Olivennes, RBM 2009 Prediction of excessive response Individualize dose of FSH?

44 Predicted Poor Responders: and then do what? RCT design In cases with normal basal FSH, an individual stimulation dose, based on a model with AFC, ovarian volume, ovarian flow, female age and smoking resulted in reduced poor response rate and higher pregnancy rates compared to a standard dose (n=262) Popovic-Todorovic B, et al. Hum Reprod 2003

45 The OPTIMIST trial OPTIMisation of cost effectiveness through Individualised FSH Stimulation dosages for IVF Treatment: a randomised trial. Dutch RM consortium N=300 18 months treatment approach N=600 Completed March, 31st 1530 inclusions

46 Agenda AMH and Ovarian Physiology AMH in Infertility Work Up Why predict and select in ART Can we really predict and select: –FSH dosage –Stim protocol –Egg quality Conclusions

47 Ongoing Pregnancy rate 16.2% 8.1% 8.1% Underpowered Significant The PRINT trial Sunkara FS 2014 The Poor Responder: AGO or ANTA or FLARE? Long Suppression Is MORE expensive Yields more ETs

48 Compared with GnRH agonist the GnRH antagonist protocol is associated with Fewer oocytes retrieved “Similar” Cancellation rates “Similar” Clinical Pregnancy rates Cancellation rate Oocyte number CP rate Xiao, FS 2013 Poor Responder: antagonist?? Meta-Analysis by Pu, HR 2011: Not fewer oocytes PR Anta: 22% Pr Ago: 19%

49 Predicted Excessive responders: antagonist with standard dose ?? Nelson, 2009, non randomised Antagonist is More SAFE More Efficacious

50 AMH based Personalised ART treatment historical cohort design 10 versus 8 oocytes Yates, HR 2011

51 Agenda AMH and Ovarian Physiology AMH in Infertility Work Up Why predict and select in ART Can we really predict and select: –FSH dosage –Stim protocol –Egg quality Conclusions

52 Predicting…

53 Prognosticating… 0% 15% 10%30% 50% 20% 5% 60% 8%

54 Individual Patient Data Analysis: the IMPORT study Female age with or without any ORT fails to predict accurately zero prognosis cases N=5500 ART Success Prediction one cycle AUC Age 0.57 AFC 0.50 AMH 0.55 Age + AFC 0.58 Age + AMH 0.57 Broer, HRU 2012

55 Female age Cumulative cycles Hendriks, RBM 2008

56 IPD data, n=1007 Broeze 2009 Age and AMH in concert indicate prognosis for live birth – one cycle agonist Useful for Counseling Couples Useful for IVF Program Restrictions

57 Agenda AMH and Ovarian Physiology AMH in Infertility Work Up Why predict and select in ART Can we really predict and select: –FSH dosage –Stim protocol –Egg quality Conclusions

58 Individualization of ovarian stimulation in IVF using ORTs: from theory to practice LaMarca, HRU 2013 Nelson Yates

59 Individualization of ovarian stimulation in IVF using ORTs: from theory to practice LaMarca, HRU 2013 Nelson Yates

60 Individualization of ovarian stimulation in IVF using ORTs: from theory to practice LaMarca, HRU 2013 No Evidence for 300 IU for Anta Evidence for 150 IU Some Evidence for Dose for Anta Nelson Yates

61 Take Homer Individualisation in IVF: We need more Science!! Use not more than 225 IU

62 Take Homer 2 Quality is…. Mostly Female age And (knowing) Quantity will help a bit

63 Frank Broekmans Professor Reproductive Medicine and Surgery University Medical Centre Utrecht The Netherlands Simone Broer Jeroen van Disseldorp Monique Sterrenburg Marieke Verberg Dave Hendriks Ellen Klinkert Ilse van Rooij Laszlo Bancsi Marlies Voorhuis Kim Broeze (AMC) Brent Opmeer (AMC) Madeleine Dolleman Ouijdane Hamdine Martine Depmann Bart Fauser Nick Macklon (Southampton) Ben W Mol (AMC) Nils Lambalk (VUMC) Thank You the IMPORT* studygroup Richard A. Anderson Mahnaz Ashrafi László Bancsi, Ettore Caroppo, Alan B. Copperman, Thomas Ebner, Talia Eldar-Geva, Mehmet Erdem, Ellen M. Greenblatt, Kannamannadiar. Jayaprakasan, Nick Raine-Fenning, Ellen Klinkert, Janet Kwee, Antonio La Marca, MyvanwyMcIlveen, Luis T. Merce, Shanthi Muttukrishna, Scott M. Nelson, Ernest H.Y. Ng, Biljana Popovic Todorovic, Jesper M.J. Smeenk, Candido Tomás Paul J.Q. Van der Linden, K.Vladimirov, Patrick Bossuyt Genetic Department Edwin Cuppen Epidemiology Department Yvonne vd Schouw Charlotte Onland-Moret


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