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The Truth About Ovarian Hyperestimulation Syndrome and How to Avoid It
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  • Muchas gracias Orlando!

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  • EXCELENTE REVISION, MUY UTIL PARA GINECOLOGOS, QUE UTILIZAMOS TECNICAS DE REPRODUCCION ASISTIDA DE BAJA COMPLEJIDAD EN HOSPITALES DE REGIONES EN CHILE
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    The Truth About Ovarian Hyperestimulation Syndrome and How to Avoid It The Truth About Ovarian Hyperestimulation Syndrome and How to Avoid It Presentation Transcript

    • The Truth about OvarianHyperstimulation Syndromeand How to Avoid ItSandro Esteves, M.D., Ph.D.Director, ANDROFERTAndrology & Human Reproduction ClinicCampinas, BRAZILASPIRE III, June 14, Istambul, Turkey
    • Esteves, 2Know the NumbersAetiopathogenesisClinical AspectsWhat is in it for me?
    • Esteves, 3Singleton livebirth at termMaximizeTreatmentBeneficial EffectsMinimize Complications andRisksCycleCancellationMultiplePregnancy OHSS
    • Esteves, 4Incidence1:3-6% moderate OHSS~2% severe OHSSOHSS1Aboulghar. Fertil Steril. 2012;97:523-6; 2Confidential Enquiry into Maternal and Child Health,2007; 3ICMART (International Committee for Monitoring Assisted Reproductive Technologies): 3/100,000 cycles21.5 million cycles/year worldwide3~500 deaths in the last 10 years
    • Esteves, 5Low incidence and most cases are mild!!Real numbers not availableSeveral cases unreportedOI/CC: 13.5% of mild formsIUI: 2-8% cycle cancellation (OHSS risk)Cantineau et al., Cochrane Database Syst Rev. 2007; 18:CD005356; Delvigne &Rozenberg Hum Reprod Update. 2003;9:77-96.OHSS
    • HavingDifficultyConceiving1Boivin J, et al. Hum Reprod 2007;6:1506; 2Data on file, ObGyn Research 2003, EMD Serono;3Domar AD. Fertil Steril 2004;81:271TreatedbyInfertilitySpecialist20% discontinue treatment beforefinishing clomiphene citrate (CC)223% complete CC therapy and thendiscontinue treatment245% of infertile couples never seekmedical treatment1100Treated byObGyn553125-40% who come to IS for initialconsult do not initiate treatment260-65% who start treatment drop outbefore completing treatment3208
    • Esteves, 7Fluid Shift from Intravascular to Third SpacehCG Vascular PermeabilityProfound IntravascularVolume Depletion andHaemoconcentrationMassive ExtravascularTransudate AccumulationNo direct vasoactiveactivityVasoactiveSubstancesVEGFAetiopathogenesisAlbert et al. Mol Hum Reprod. 2002;8:409; Chen et al. Hum Reprod. 2000;15:1037; Gómez et al.Endocrinology. 2002;143:4339; Navot et al. Fertil Steril. 1992;58:249
    • Esteves, 8VascularEndothelialGrowthFactor1Yan et al, J Clin Endocrinol Metab 1993; 77:1723; 2Neulen et al, J Clin Endocrinol Metab1995; 80:1967; ; 3Wang et al, J Clin Endocrinol Metab 2002; 87:3300;4Pellicer et al, Fertil Steril 1999; 71:482;Induces endothelial cellproliferationIncreases capillary permeabilityVEGF and OHSS:• VEGF is expressed in human ovaries1• VEGF mRNA expression increases ingranulosa cells after hCG administration2,3• Elevated VEGF levels detected in serum,plasma, and peritoneal fluids of women withOHSS4
    • Esteves, 9Early onset Late onsetLyons CA et al., Hum Reprod 1994, 9:792.; Mathur RS, Fertil Steril 2000, 73:901;Papanikolaou et al.,Hum Reprod. 2005; 20:636.ClinicalAspectsExogenous hCGadministered for finaloocyte maturationEndogenous hCGproduced byimplanting blastocyst3–7 days after hCG 12 -17 days after hCGPredicted by high numberof growing follicles andelevated E2 levelsPredicted by number ofgestacional sacs(multiple pregnancy)Higher risk of preclinicalmiscarriageMore likely to besevere
    • Esteves, 10Delvigne & Rozenberg. Hum Reprod Update 2003, 9:77–96;Fiedler & Ezcurra. Reprod Biol Endocrinol 2012, 10:32ClinicalAspectsMany proposed systems according to severityof symptoms, signs and laboratory findingsRabal et al., 1967Schenker and Weinstein, 1978Golan et al., 1989Navot et al., 1992Rizk & Aboughar, 1999
    • Esteves, 11Abdominaldistension ordiscomfortMild nausea,vomitingDiarrheaEnlargedovariesNo relevantlaboratorialalterationLacking clinicalsignificanceFiedler & Ezcurra. Reprod Biol Endocrinol 2012, 10:32OHSS-ClassificationSimilar to Mild +Evidence ofAscitesHct >41%WBC >15,000HypoproteinemiaRequire carefulmonitoringIntractable nausea/vomitingSevere dyspnea; HydrothoraxOliguria/anuria; Tense ascitesLow central venous pressureRapid weight gain; syncopeSevere abdominal painVenous thrombosisHct >55%; WBC >25,000Creatinine >1.6Creat. Clearance <50 mL/minHyponatremia: <135 mEq/LHyperpotassemia: >5 mEq/LElevated liver enzymesHospitalization;Intensive care unitMild Moderate Severe
    • Esteves, 12Fiedler & Ezcurra. Reprod Biol and Endocrinol 2012, 10:32; Papanikolaou et al.,HumReprod. 2005; ;20:636-41; Humaidan et al., Fertil Steril. 2010; 94: 389-400.However…Psychological burden for both patients AND doctorsAssociated with high cycle cancellation ratesHigher risk of preclinical miscarriageThe TRUTH is that OHSS must be PREVENTEDrather than treatedMore severe cases may progressAcute renal failureArrhythmiaThromboembolismPericardial effusionMassive hydrothoraxArterial thrombosisSepsisAdult respiratorydistress syndromeComplications
    • Esteves, 13Identify patients at riskMild ovarian stimulationCycle cancellationGnRH-agonist for LH triggerHowtoAvoidOHSSIntravenous colloidsDopamine agonistAntagonist in the luteal phasePrimary Prevention:Secondary Prevention:
    • Esteves, 14Young patientsLow body mass indexPolycystic ovariesPCOSPrevious OHSSSensitive ovariesEasilyRecognizedFiedler & Ezcurra. Reprod Biol and Endocrinol 2012, 10:32;Humaidan et al., Fertil Steril. 2010; 94:389-400.HowtoAvoidOHSSBIOMARKERS ofOvarian Response
    • Esteves, 15The Rotterdam ConsensusPolycystic ovary:Ultrasound showing ≥12 follicles (2-9 mm)AND/OR ovarian volume >10 cm3Polycystic Ovary Syndrome: 2 out of 3Oligo‐ and/or anovulationClinical and/or biochemical hyperandrogenismPolycystic OvaryOHSS Risk: PCOS > isolated PCOS characteristicsRotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group.Hum Reprod. 2004; 19:41-7.; Humaidan et al., Fertil Steril. 2010; 94:389-400HowtoAvoidOHSS
    • Esteves, 16Which are the Biomarkers?Biomarkers●Hormonal Biomarkers: FSH, Clomiphenecitrate challenge test, Inhibin-B,Anti-Mullerian Hormone (AMH);●Functional Biomarkers:Antral Follicle Count (AFC);●Genetic Biomarkers: Single NucleotidePolymorphisms for FSH-R; LH/LH-R; E2-R;AMH-R.HowtoAvoidOHSS
    • Esteves, 17 La Marca et, Hum Reprod 2009;24:2264; Fleming et al, Fertil Steril 2012;98:1097.What is known?Dimeric glycoprotein; ~140KDaProduct of GCs of early folliclesPre-antral and small antral (≤4-8mm)Direct Biomarker of Ovarian Reserve:AMH
    • Esteves, 18AMH Low Inter-cycle Fluctuations (Fanchin et al, Hum Reprod 2005;20:923)Understanding BiomarkersLow Intra-cycle Fluctuations (Hehenkamp et al. JCEM 2006;91:4057)ICC: 0.89; 95% IC: 0.83–0.94 ICC: 0.55; 95% IC: 0.39–0.71Max. Variation: 17.4% Max. Variation: 108%Can be assessed at any cycle daywith a single measurement
    • Esteves, 19 Broekmans et al. Fertil Steril, 2010; 94:1044-51; Scheffer et al. Hum Reprod 2003;18:700Direct Biomarker of FunctionalOvarian Reserve:Sum of antral follicles in both ovaries byTVUS at early follicular phase (D2-D4):• 2-10 mm (mean diameter)• Greatest 2D-planeReflect the number of antral follicles inthe ovaries at a given time that can bestimulated by exogenousgonadotropinsAFCWhat is known?
    • Esteves, 20Cut-off: 3.36 ng/mLHigh sensitivity (90.5%)High specificity (70%)Lee et al., Hum Reprod 2008, 23:160–167AFCAFCAMHCut-off: 16 AFHigh sensitivity (100%)High specificity (93%)Prediction of excessive responsein IUI with 75 IU/d recombinant FSHCheca et al. Fertil Steril. 2010; 94:1105-7
    • Esteves, 21Low dose step-up protocol in pts. at riskStarting gonadotropin dose: 37.5 – 75 IUAdjustments according to ovarian responseSengoku et al. Hum Reprod. 1999; 14:349-53; Cantineau et al., Cochrane Database Syst Rev.2007; 18:CD005356., Humaidan et al., Fertil Steril. 2010; 94:389-400Pen devices:Precise dose delivery allowingadjustments by smallincrements and self-administrationHowtoAvoidOHSS
    • Esteves, 222 RCT (n= 297)Low dose step-up in IUICantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356Similar PRs and Lower Risk of OHSS byUsing Low dose Step-up in IUIHowtoAvoidOHSSOHSS 13% 2.7% 5.52(95% CI: 1.85 to 16.52)Pregnancy 31.1% 28.2% 1.15(95% CI: 0.69 to 1.92)
    • Esteves, 23HowtoAvoidOHSSGnRh-agonistrather than hCGfor LH triggerDrawbacks:Patient frustrationWaste of time and moneyRisk of spontaneous ovulation and patientnon-compliance with doctor´srecommendations to avoid intercourseRisk of multiple pregnancy and late onset OHSSCantineau et al., Cochrane Database Syst Rev. 2007;18:CD005356;Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96
    • Esteves, 24HowtoAvoidOHSSLH/FSH UnloadWhat and How:Triptorelin 0.2 mgLeuprolide acetate 1 mgBuserelin 0.2-0.5 mgGriesinger et al. Hum Reprod Update. 2006;12:159-68.When:Same criterion of hCG14 h20 h14 h48 h20 h4 hGnRHa LH surge vsnatural cycle
    • Reduced, if not eliminated, risk for OHSSIn specific high risk patients and egg donation programsis now the the choice.Esteves, 25GnRH-agonist vs hCG: 11 RCT – 1,055 womenLBR OPRModerate/severe OHSSFreshautologouscycles (8 RCT)OR 0.44(0.29 - 0.68)OR 0.45(0.31 - 0.65)OR 0.10,(0.01 to 0.82)Donorrecipientcycles (3 RCT)OR 0.90(0.57 - 1.42)OR 0.91(0.59 -1.40)OR 0.06(0.01 - 0.31)Youssef et al. Cochrane Database Syst Rev. 2011HowtoAvoidOHSS
    • Esteves, 26Aboulghar & Mansour. Hum Reprod Update 2003;9:275;Humaidan et al. Fertil Steril 2012 ;97:529; Engmann & Benadiva Fertil Steril 2012;97:531Challenge is to rescue luteal phase insufficiency:Modified luteal support improves delivery rate:hCG bolus OPU day (1,500 UI) or 3x 500 UI boluses;recLH; intense progesterone + estradiol; combinedRisk Difference for Pregnancy:18% (Before) vs 6% (After Modified Luteal Support)HowtoAvoidOHSSIVF: luteal phase is always altered estrogen/progesterone LH suppressed
    • Study N TriggerLutealsupportFindingsRomeu,1997761hCGX1.5 mgLeuprolideAcetate(2 doses12/12h)1,000- 2,500IU hCG D0,D2 and D4 ofluteal phase99% ovulation rate; No differencesin E2 and P4 levels, luteal phaseduration and miscarriage rates.Higher Pregnancy Rates withLA (27.3%) vs hCG (17.3%)(p=0.0007); No OHSS in LA groupRomeu et al. J Assist Reprod Genet. 1997; 14:518;Pirard et al. Hum Reprod. 2005; 20:1798; Diaz et al. J Reprod Med. 2008; 53:33.LHTriggerwithGnRHainIUIEsteves, 27Pirard,200524hCGX0.2 mgBuserelin0.1 mgBuserelindifferentschemesNo difference in luteal phaseduration.Higher P4 levels at D14 withevery day buserelinDiaz,200848hCGX0.2 mgTriptorelin-----Higher FSH and LH rise 24 h aftertriptorelin.Higher P4 levels 48h after triggerwith hCG
    • Esteves, 28Primary Prevention:Identify patients at riskMild ovarian stimulationCycle cancellationGnRH-agonist for LH triggerSecondary Prevention:Intravenous colloidsDopamine agonistAntagonist in the luteal phaseHowtoAvoidOHSS
    • Esteves, 291Gokmen et al. Eur J Obstet Gynecol Reprod Biol. 2001;96:187; 2Konig et al. Hum Reprod.1998;13:2421; 3Youssef et al. Cochrane Database Syst Rev. 2011;16:CD001302.Colloid administration during oocyte retrieval forprevention of severe OHSS in IVF/ICSI320% HumanAlbumin (50 mL)6% Hydroxyethylstarch (HES); 1LNo. Studies(patients)8 RCT(n=1,660)3 RCT(n=487)Severe OHSSOR: 0.67(95% CI: 0.45-0.99)OR: 0.12(0.04-0.40)CPROR: 0.76(0.48-1.21)OR: 1.2(0.49-2.95)OI and IUI: Data Not AvailableHowtoAvoidOHSS Increase serum oncotic pressure and reverse leakage of fluidsfrom the intravascular space; bind mediators of ovarian origin
    • Esteves, 30Prophylactic effect of Cabergoline versus NoTreatment in IVF/ICSI cyclesYoussef et al., Hum Reprod Update. 2010;16:459-66;Tang et al. Cochrane Database Syst Rev. 2012; 15;2:CD008605.Youssef, 20104 RCT (n=570)Tang, 20102 RCT (n=230)OHSSOR = 0.4195% CI: 0.25-0.66OR 0.4095% CI: 0.20-0.77SevereOHSSOR 0.50(0.20-1.26)OR 0.77(0.24-2.45)CPROR 1.07(0.70-1.62)OR 0.94(0.56-.59)MiscarriageRateOR 0.31(0.03-3.07)OR 0.31(0.03-3.07)HowtoAvoidOHSS
    • Esteves, 31Cabergoline, Quinagolide, Bromocriptinedopamine agonistsBasu et al. Nat Med 2001;7:569–74; Gomez et al. Endocrinology 2006; 147:5400–11.;Soares. Fertil Steril. 2012; 97:517-22.HowtoAvoidOHSSIn vitro studies:Activation of dopamine receptor-2 (Dpr2) causeinternalization of VEGFR-2 (becomeunreachable for VEGF);Cabergoline administration in rats:Phosphorylation of VEGFR-2 reduced by 42%;Inhibition of VEGF production in cultured granulosa cellsexposed to hCG.
    • Esteves, 32Most effective regimen: 0.5 mg daily for 8 daysStart on the day of hCG administration; ideally a fewhours before injection is givenSoares. Fertil Steril. 2012; 97(3):517-22.HowtoAvoidOHSSFair evidence demonstratethe efficacy of Carbegolineand other DAs to decreasethe incidence of early-onsetOHSS;No major complications reported;
    • Esteves, 331Minaretzis et al. J Clin Endocrinol Metab. 1995;80:430; 2Fridén & Nilsson. Acta Obstet Gynecol Scand.2005;84:812; 3Asimakopoulos et al. Fertil Steril. 2006;86:636; 4Taylor et al. J Endocrinol. 2004;183:1;5Lainas et al. Reprod Biol Endocrinol. 2012;10:69; 6Lainas et al. Hum Reprod. 2013; April 26.HowtoAvoidOHSS Supression of endogenous LH secretion (luteolytic effect)Decrease vasoactive cytokines production by corpus luteum1Direct effect on the ovary reducing VEGF production2,3,4Lainas et al., 2012540 pts.; early-onset severe OHSSGanirelix (0.25 mg) daily fromD5-D8 after oocyte retrieval +embryo freezingNO HOSPITALIZATION;Rapid resolution of OHSSLainas et al., 2013622 pts.; early-onset severe OHSSGanirelix (0.25 mg) daily from D5-D7after OPU + embryo transfer; 172controls at risk of OHSSNO HOSPITALIZATION;Rapid resolution of OHSS;No late-onset OHSS;LBR: 41% (Antag.) vs 43% (controls)
    • Esteves, 34OHSS has a dramatic psychological effectin patients’ life; those who suffer from itare unwilling to continue treatment.OHSS must be PREVENTED rather thantreated.Improving patients’ welfare starts atidentifying who are at risk for OHSS, andcontinues by individualization of theovulation induction protocol.KeyMessages The Truth about OHSSand How to Avoid It
    • Esteves, 35GnRH-agonists LH trigger virtuallyeliminates OHSS; in these cases lutealphase support will be required.Secondary prevention by albumin/HES andcarbegoline administration are useful butnot eliminate the risk.Antagonist GnRH antagonist administrationduring the luteal phase seems promisingto prevent progression of early-onsetOHSS.KeyMessages The Truth about OHSSand How to Avoid It