Top Five Problems You Have with Ovulation Induction and How to Solve Them

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  • 1. The Top Five Problems YouHave With Ovulation Inductionand How to Solve ThemSandro Esteves, M.D., Ph.D.Director, ANDROFERTAndrology & Human Reproduction ClinicCampinas, BRAZILKhobar & Gassim, KSA – June, 2013
  • 2. Esteves, 2The Top Five Problems You HaveWith Ovulation Induction andHow to Solve ThemEsteves SC – June 2013Review this Lecture at:http://www.androfert.com.br/review
  • 3. Esteves, 3Level Type of evidence1a Obtained from meta-analysis of randomised trials1b Obtained from at least one randomised trial2a Obtained from one well-designed controlledstudy without randomisation2b Obtained from at least one other type of well-designed quasi-experimental study3 Obtained from well-designed non-experimentalstudies (comparative and correlation studies, caseseries)4 Obtained from expert committee reports or opinionsor clinical experience of respected authoritiesModified from Sackett et al. Oxford Centre for EBM Levels of Evidence (2009)Level ofEvidence Information applied to OI and IUI population Evidence-based MedicineGrade Arecommendation• Good andconsistentscientific evidence
  • 4. Esteves, 4Is there a need to individualize the protocolper patient?Clomiphene citrate for how many cycles andhow?Is there any advantage of recombinant versusurinary gonadotropins?Is there any advantage of recombinant versusurinary hCG for triggering LH surge?Is there a need of LH supplementation in OIcycles?What is in it for me?
  • 5. Esteves, 5Is There a Need toIndividualize theProtocol per Patient?
  • 6. Esteves, 6Singletonlive birth attermMaximizeTreatmentBeneficialEffects1Delvigne & Rozenberg Hum Reprod Update. 2003;9:77-96; 2Cantineau et al., Cochrane DatabaseSyst Rev. 2007; 18:CD005356; 2Tur et al, Fertil Steril. 2005; 83: 116-121;3Aboulghar. Fertil Steril. 2012;97:523-6.MultiplePregnancy210-40%Minimize Complications andRisks in OI and IUICycleCancellation12-8%Risk of OHSSOHSS3Severe 2%Moderate 3-6%
  • 7.  Demographics andanthropometrics(Age, BMI, Race) Genetic profile Cause of Infertility Years of Infertility Health status Nutritional statusEsteves, 7
  • 8. 1Reproductive Hormones Report - GCC Countries (Feb 2011)2Bologna criteria: Ferraretti et al. Hum Reprod 2011.Esteves, 8• Prevalence of Patientswith Poor Response toOvarian Stimulation20510152025303540< 30years30-35years36-39years40-42years>42years Cancellation Rate < 4 oocytesUp to68%Prevalence of InfertilePatients (WHO II) with PCOin Clinical Practice1Up to 45% InfertilityPatients aged 35 orabove1
  • 9. Esteves, 9La Marca et al, Hum Reprod 2009;24:2264; Fleming et al, Fertil Steril 2012;98:1097;Broekmans et al. Fertil Steril, 2010; 94:1044-51; Scheffer et al. Hum Reprod 2003;18:700Reflect No. Pre-antral and Small AntralFollicles(≤4-8mm); gonadotropin-independentLow inter and intra-cycle variationassessment at any cycle day in asingle measurementAMHAFCTVUS at early follicular phase (D2-D4)2-10 mm (mean diameter); 2D-planeReflect No. AF at a given time that can bestimulated by gonadotropinsLow inter-cycle variation
  • 10. Esteves, 10EvidenceLevel1aBiomarkers
  • 11. 1Lee et al. Hum Reprod 2008; 2Checa et al. Fertil Steril. 2010; 3Broer et al. Hum Reprod Update2011; 3Nelson et al. Hum Reprod. 2009; *Bologna criteria: Ferraretti et al. Hum Reprod 2011Esteves, 11Response toOvarianStimulationAnti-MullerianHormone(ng/mL)AntralFollicleCountFalsePositiveRateRisk of OHSS1,2≥ 3.4 > 16~15%Risk of PoorResponse*3 < 1.1 < 5pmol/L X1000/140Level2a
  • 12. Esteves, 12Clomiphene Citrate forHow Many Cycles andHow?
  • 13. PituitaryGnRHFSH/LHestrogenHypothalamusOvaryClomipheneCitrateEsteves, 13Structurally similar to estrogenbinds to estrogen receptors (ER)1CC binds to ER for extendedperiods of timedepleting ER concentrations1Ovulatory women: CC increasesGnRH pulse frequency2PCOS: CC increases GnRH pulseamplitude3frequency is already highHowitWorks?1Clark & Markaverich. Pharmacol Ther 1982;15:467; 2Kerin JF et al. J Clin Endocrinol Metab1985;61:265; 3Kettel et al. Fertil Steril 1993;59:532; 4Ibrahim et al. Arch Gynecol Obstet.2012;286:1581; 5Annapurna et al. Int J Fertil Womens Med 1997;42:215.Negative Effect onEndometrium4 andCervical Mucus5
  • 14. ClomipheneCitrateEsteves, 14How to Use?2 3 4 5 76 8 9 10 11 12 131Dose: 50 mg/d for 5 daysMensesStart dayUltrasoundCCAdapted form the ASRM Practice Committee. Fertil Steril 2003;5:1302–8Ultrasound
  • 15. Points to ConsiderClomipheneCitrateEsteves, 15PCOS: >75% of anovulatory infertility~25% CC-resistant (mainly obese & hyperandrogenic)~15% who ovulate have thin endometrium/poor mucusUltrasound monitoring:1. Dose can be adjusted, if necessary, in subsequentcycles.2. Allows endometrial evaluation.In IUI, endometrial appearance/thickness more important thanfollicle size for hCG administration3. Assessment for risk of OHSS.
  • 16. 50 mg/d 100 mg/d 150 mg/dOvulationOvulation2 – 3 cycles with the same doseOvulationNoOvulationNoOvulationNoOvulationHow Many cycles?No pregnancySuboptimal Endometrium(Endometrial thickness <7mm)InjectableGonadotropinsClomipheneCitrateEsteves, 16HypogonadotropicHypogonadismAdapted from the ASRM Practice Committee. Fertil Steril 2003;5:1302–8
  • 17. Esteves, 17 Cantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356Higher PR with gonadotropins (28%)compared with CC (18%)without increased risksGonadotropinsinOI/IUI No.StudiesNo.ParticipantsOdds-ratioPregnancy 7 556 OR: 1.76(95% CI 1.16 to 2.66)Miscarriage 4 120 OR: 1.2(95% CI: 0.67 to 1.9)MultiplePregnancy4 120 OR: 0.73(95% CI: 0.32 to1.67)OHSS 2 200 OR: 4.44(0.48 to 41.25)Level1a
  • 18. Esteves, 18Low Dose Step-up StimulationGonadotropinsinOI/IUI Starting dose: 37.5-50 IU (rec-hFSH); Adjust (by 37.5 IU) if nofollicles >10mm after 7-10 stimulation days;Adjust every 7 days until dominant follicle appear; hCG ≥18mmand endometrium ≥7mm2 3 4 5 76 8 9 10 11 12 131UltrasoundMensesStart day14 15• >70% ovulatory cycles; >85% monofollicular development• Threshold to produce a dominant follicle: 37.5 to 75 IU (~75%)• Average stimulation duration: 15 days• CPR after 6 cycles: ~60%• No OHSS; ~10-15% cancellation (multifollicular development)ResultsInPCOS
  • 19. Points to ConsiderEsteves, 19GonadotropinsinOI/IUI2. Be patient!It may take 10 days or more for a dominant follicle toappear during the first treatment cycle with low-dosegonadotropin.1. TVUS scan before starting:if endometrium thickness >8 mm, a short course of aprogestin (medroxyprogesterone acetate, 5-10 mg/d) isgiven to induce a withdrawal bleed.
  • 20. Esteves, 20Low Dose Step-up StimulationCantineau et al., Cochrane Database Syst Rev. 2007; 18(2):CD005356Conventional vslow-dose step-up inIUI; 2 RCT (n= 297)OHSS 13% 2.7% 5.52(95% CI: 1.85-16.52)Pregnancy 31.1% 28.2% 1.15(95% CI: 0.69-1.92)Similar PR and Lower Risk of OHSS byUsing Low dose step-up in IUILevel1aGonadotropinsinOI/IUI
  • 21. Esteves, 21In general, 3 to 6 cyclesLevel2aBut recent evidence shows that Additional Testingshould be offered after 3 unsuccessful cyclesDiagnosticLaparoscopy(LPS)SpermChromatinIntegrity TestingBonneau et al. Eur J Obstet Gynecol Reprod Biol. 2012; 163: 57-61; Bungum et al. HumReprod 2007; 22: 174–9; Esteves et al. Arch Gynecol Obstet. 2012; 286: 217-29.
  • 22. Sperm Chromatin Dispersion Test:Sperm with absent “halos” haveDNA strand breaksSemen/SpermatozoaQuantitative (Normal <20%)Esteves et al. Arch Gynecol Obstet. 2012; 286: 217-29.19%1.5%Normal ElevatedLive Birth Rates withIntrauterine InseminationOR = 0.07[95% CI: 0.01-0.48]Bungum et al. HumReprod 2007; 22: 74–9
  • 23. Benefits of LPS:Gold standard for diagnosing tubal pathology, adhesions andendometriosisAllow treatment of identified lesions  spontaneous conceptionIn poor prognosis, bypass OI/IUI IVFDiagnosticLaparoscopy(LPS)Esteves, 23Findings After 3 OI/IUI Failures inUnexplained Infertility1,2Pelvic disease 50 – 90%Adhesions 10 – 48.4%EndometriosisI/IIII/IV36 – 73%22 – 50%4.1 – 26.3%Tubal Disease 1-27%After LPS: PR = 68%114% - No treatment17% - OI/IIU37% - IVF/ICSI1Bonneau C et al. Eur J Obstet Gynecol Reprod Biol. 2012; 163: 57-61;2Jacobson. Cochrane Database of Systematic Reviews 2010;20;(1):CD001398.
  • 24. Response to OI depends on patient profile.Biomarkers, AMH and AFC, correctlyidentify “Who is Who” before OI.CC is usually the first line choice for OI/IIU.Switch to injectable gonadotropins:3 ovulatory cycles but no pregnancySuboptimal endometrium thickness (< 7mm)No response with CC 150 mg/dEsteves, 24
  • 25. Esteves, 25Injectable Gonadotropins yields HigherPR than CC without Increased Risks.Mild Stimulation with Low-dose Step-upProtocol is Advantageous.Consider Sperm Chromatin Testing andDiagnostic LPS after 3 Failed OI/IUICycles.
  • 26. Is There Any Advantage ofRecombinant versusUrinary Gonadotropinsfor OI?
  • 27. Recombinant hFSH is more potent thanHP-Urinary FSHMeta-analysis Rec-hFSH vs HP-uFSH in IUI6 RCT; (N=713 pts; 1,581 cycles)Similar PR: 14.5% vs 14.9% with rec-FSH dose50% lower (RR: 0.970; 95% CI: 0.68-1.37)Esteves, 27Level1aMatorras et al. Fertil Steril. 2011;95(6):1937-423 RCT; “equal dose group”Higher PR with rec-hFSH (16.4% vs 12.3%)RR: 1.394 (95% CI: 1.00-1.96)
  • 28. Esteves, 28Up to 70%impurities
  • 29. Bassett et al. Reprod Biomed Online 2005;10:169–177.Purity(proteincontent)Mean specificactivity(IU/mg protein)LHactivity(IU/vial)Injectedprotein per 75IU (mcg)hMG < 5% ~100 75 ~750hMG-HP < 70% 2,000–2,500 75 ~33rec-hFSH* > 99% 13,645 0 6.1Esteves, 29GonadotropinsinOI/IUI*Follitropin alfa
  • 30. Esteves, 3068%25%Folitropin alfaprefilled ready-to-use penNeedle-freereconstitution,conventionalsyringePatient PreferencesEasy of use 58%Dosing mechanism 43%Less chance oferror26%ReasonsWeiss N. RBMonline 2007;15:31-7Level2a• Allowed injectionsat home• Improved pts.satisfaction (QOL)
  • 31. *Steelman-Pohley Rat Bioassay, 1953; Bassett et al. Reprod Biomed Online 2005;10:169–177; Driebergen et al. Curr Med Res Opin 2003;19:41–46.ConventionalBioassay*HighvariabilityRat ovaryweightgainUrinary gonadotropinsFollitropin betaEsteves, 31GonadotropinsinOI/IUIGonadotropin injected sc1x 3daysSacrifice day 4and collect OvariesOvaries are weighed anddata processed
  • 32. Bassett et al. Reprod Biomed Online 2005;10:169–177;Driebergen et al. Curr Med Res Opin 2003;19:41–46.FbM: Novelanalitycal methodProtein content insolution by massMinimal batch-to-batch variability(1.6%)Follitropin alfaEsteves, 32GonadotropinsinOI/IUISize Exclusion HighPerformance LiquidChromatography(SE- HPLC)37.5Mild Stimulationwith PreciseDoseAdjustments112.575.0
  • 33. Is There Any Advantage ofRecombinant versusUrinary hCG forTriggering Ovulation?
  • 34. Esteves, 34hCG Presentation ViaUrinary lyophilized vials (5,000-10,000 IU) IMRecombinantchoriogonadotropin alfapre-filled syringes (250 mcg ≅ 6,750 IU) SC1ASRM Practice Committee. Fertil Steril. 2008;90(Suppl 5):S13-20; 2Palatnik et al, Fertil Steril2012;97:1089–94; 3da Silva et al. Eur J Obstet Gynecol Reprod Biol. 2012;164:156-60.Tsoumpou et al. Reprod Biomed Online. 2009;19:52-8hCGtotriggerovulationinOI/IUIRecommended Dose: 5,000 IU (250 mcg for rec-hCG)Systematic review (2009) unable to define best hCG doseWhen: 19–30 mm (~25 mm)12D TVUSDominant Follicle Size Mean Diameter23-28 mm (988 IUIs with CC & Letrozole)2≥16 mm (620 IUIs with gonadotropins)3
  • 35. Recombinant vsUrinary hCG forTriggering OvulationRCT N EffectLive birth 6 1,019 OR: 1.04 (95% CI 0.79 to 1.37)Miscarriage 7 1,106 OR: 0.69 (95% CI: 0.41 to 1.18)SevereOHSS3 549 OR: 1.49 (95% CI: 0.54 to 4.1)Side Effects 3 374 OR: 0.39 (95% CI: 0.25 to 0.61)Level1aOR: odds ratio; MD: mean differenceYoussef et al. Cochrane Database Syst Rev. 2011; 13(4):CD003719.Esteves, 35ClinicalEfficacy
  • 36. Is There Any Advantage ofUsing Recombinant versusUrinary Products in OI/IUI?Recombinant products are more potent.Similar pregnancy rates using 50% less rec-hFSH.Higher PR using the same dose.Rec-hCG is better tolerated.Fewer side effects.
  • 37. Is There Any Advantage ofUsing Recombinant versusUrinary Products in OI/IUI?Other advantages of recombinants vsurinaries:Allow SC self-injectionHigher purity and specific activityPatient-friendlyLess time-consuming; less hospital/clinic visitsAllow mild stimulation by small doseadjustmentsHigher dose precision; FbM
  • 38. Is There a Need for LHSupplementation in OICycles?
  • 39. Esteves, 39• Mild Stimulation(low dose rec-hFSH +GnRH ant.):• 5 oocytesretrieved;• IR = 31%• ConventionalStimulation :• 10 oocytesretrieved;• IR = 29%Verberg et al.Hum Reprod Update 2009; 15: 5–12.Promotion of Steroidogenesis(TCs) early Follicular Phase• Adequate estrogen production• Uterine/endometrial changesStimulation of final FollicularMaturation (GCs) late FPEsteves, 39 Alviggi et al. Reprod Biomed Online 2006;12:221.
  • 40. Balasch J, Fábreques F. Curr Opin Obstet Gynecol 2002, 14:265.Esteves, 40• Normal androgen and estrogen biosynthesis• Normal follicular growth and development• Normal oocyte maturationNormal• Suppression of GC proliferation• Follicular atresia (non-dominant follicles)• Premature luteinization• Oocyte development compromisedHigh• Insufficient androgen (and estrogen) synthesis• Follicular maturation impaired• Inadequate endometrial proliferationLow
  • 41. LH levels <1.2 UI/L (WHO group I)Higher follicular development pts. receiving LH(67% vs 20%; p=0.02): Shoham et al., 2008Similar follicular development HMG vs FSH + rLH; Highercumulative PR after 3 cycles in FSH + rec-hLH(56% vs 23%; p=0.01): Carone et al., 2012Level1bEsteves, 41WHO group IIClomiphene-resistant: fewer intermediate-sized follicles andOHSS in LH-supl. vs FSH group; similar ovulation rate;Plateau, 2006Previous over-response: higher monofollicular development inLH group (32% vs 13%; p=0.04); Hughes et al., 2005IUI: higher monofollicular development in LH group w/ointermediate-size (42% vs 11%; p=0.03); lower cyclecancellation due to OHSS (-7% difference); Segnella et al., 2011LHSupplementationinOI/IUI
  • 42. Esteves, 42• ~80% normogonadotropic womenundergoing Ovarian Stimulation1-3Normal• 15-20% of NG women have lesssensitive ovaries• Older patients (≥35 years)4• Poor responders5• Slow/Hypo-responders6• Deeply suppressed endogenous LHlevels (hypo-hypo; endometriosis treated withGnRH-a)7Low1. Alviggi et al. Reprod Biomed Online 2006;12:221; 2. Tarlatzis et al. Hum Reprod2006;21:90; 3. Esteves et al. Reprod Biol Endocrinol 2009;7:111; 4. Marrs et al. ReprodBiomed Online 2004;8:175;5. Mochtar MH, Cochrane Database, 2007; 6. Alviggi, et al.RBMOnline 2009; 7. De Placido et al. Clin Endocrinol (Oxf) 2004;60:637;LHSupplementationinOI/IUI
  • 43. ReducedovarianparacrineactivityHurwitz &Santoro 2004LHreceptorpoly-morphismsAlviggi et al.,2006Androgensecretorycapacityreduced• Piltonen et al.,2003Decreasednumbers offunctionalLHreceptors• Vihko et al. 1996ReducedLHbioactivitywhileimnuno-reactivityunchanged• Mitchell et al.1995; Marama etal 1984Action of LH at the follicular level increasesandrogen production for its lateraromatization to estrogens;May restore the follicular milieu in selected pts.to recover oocyte quality.LHSupplementationinOI/IUI
  • 44. Mochtar et al,20073 RCT (N=310)r-hFSH+rLH vs.r-hFSH alone*OPROR 1.85(95% CI: 1.10; 3.11)Bosdou et al,20127 RCT (N= 603)r-hFSH+rLH vs.r-hFSH alone*CPRLBR(only 1 RCT)RD: +6%,(95% CI: -0.3; +13.0)RD: +19%(95% CI: +1.0; +36.0%)Hill et al, 20127 RCT (N=902)r-hFSH+rLH vs.r-hFSH alone CPROR 1.37(95% CI: 1.03; 1.83)*long GnRH-a protocol; OR=odds-ratio; RD=risk differenceMochtar MH et al. Cochrane Database Syst Rev. 2007;2:CD005070; Bosdou JK et al,Hum Reprod Update 2012; 8(2):127-45. Hill MJ et al. Fertil Steril 2012; 97:1108-4.Esteves, 44
  • 45. Esteves, 451. PCOS w/previous excessive responsewith low dose step-up stimulationAdd 75 IU LH activity starting from D1 (min. 7 days)LHSupplementationinOI/IUI2. Hypo-hypo/Poor responders1:1 or 2:1 FSH/LH ratio from stimulation D1Add 75 IU LH activity starting on D62 3 4 5 76 8 9 10 11 12 131UltrasoundMenses14 15
  • 46. *derives primarily from hCG, which is concentrated duringpurification or added to achieve the desired LH-likebiological activity.Beta unit Carboxyl terminal segmentLonger in hCG; higherreceptor affinityAbsent in LH and present inhCG (Longer Half-life)Purity(LHcontent)hCGcontent(IU/vial)LHactivity(IU/vial)Specificactivity(LH/mgprotein)Rec-hLH >99% 0 75 22,000 IUhMG-HP 3% ~70 75* ≥ 60 IUAdapted from ASRM Practice Committee. Fertil Steril. 2008; 90:S13-20.Esteves, 46
  • 47. In Pts. Treated with HMG, expression of LH/hCGreceptor and other genes involved in steroidsbiosynthesis in GCs are loweredMay reflect LH receptors down-regulation:Constant ligand exposure during follicular phase due to longer halflife and higher binding affinity of hCG compared with rec-hLHMay explain the observed lower progesterone levels:Caused by lower LH-induced cholesterol uptake, a decrease inthe novo cholesterol synthesis and a decrease in steroidsynthesis.Trinchard-Lugan I et al. Reprod Biomed Online 2002; 4:106-115; Menon KM et al. BiolReprod 2004; 70:861-866; Grondal ML et al. Fertil Steril 2009; 91: 1820-1830.Esteves, 47Level2a
  • 48. Esteves, 48Individualized approaches maximize treatmentbeneficial effects and minimize complications andrisks.Biomarkers, AMH and AFC, are useful to predictovarian response and to define an individualizedstimulation.Mild stimulation with low-dose step-up gonadotropinprotocol is advantageous.Is there a need to individualize theprotocol per patient?The Top Five Problems With OI andHow to Solve Them
  • 49. Esteves, 49The Top Five Problems With OI andHow to Solve ThemCC for 3-6 cycles as the first line choice for OI/IIU.Injectable gonadotropin when:3 CC ovulatory cycles but no pregnancySuboptimal endometrium thickness (< 7mm) after CC-OINo response with CC 150 mg/dWHO I (hypo-hypo) anovulationInjectable gonadotropins yields higher PR than CCwithout increased risks.Consider sperm chromatin testing and diagnosticlaparoscopy after 3 failed OI/IUI cycles withgonadotropins.Clomiphene citrate for how many cyclesand how?
  • 50. Esteves, 50The Top Five Problems With OI andHow to Solve ThemRecombinants are safer, purer and more potent thanurinary gonadotropins.Similar pregnancy rates using 50% less rec-hFSH.Higher PR using the same dose.Recombinant, as pen injector devices, allows SC self-administration and individualized stimulation usingsmall dose adjustments with great precision.Recombinant hCG, as pre-filled syringes, allows SCself-administration and is better tolerated than u-hCG.Is there any advantage of recombinantversus urinary products for OI and LHsurge trigger ?
  • 51. Esteves, 51The Top Five Problems With OI andHow to Solve ThemIs there a need of LH supplementation inOI cycles?Crucial for adequate follicular development and endometrialproliferation in WHO I (~75 IU).Promotes monofollicular growth and decreases cancellation inWHO II (CC-resistent and hyper-responders).Increase androgen production for aromatization to estrogen. May restorefollicular millieu in less responsive ovaries (>35y-o, diminished ovarianreserve, slow responders).LH activity is hCG-dependent in urinaries and pure LH-dependent inrecombinants.Choice of formulations may influence oocyte and corpus luteumcompetence.