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Ovulation induction in patients with poor ovarian response Filippo Maria Ubaldi M.D. M.Sc .

www.generaroma.it. CLINICA VALLE GIULIA, Rome. SALUS, ASIMEDICAL, Marostica (VI). GENERA, Umbertide (PG). Ovulation induction in patients with poor ovarian response Filippo Maria Ubaldi M.D. M.Sc.

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Ovulation induction in patients with poor ovarian response Filippo Maria Ubaldi M.D. M.Sc .

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  1. www.generaroma.it CLINICA VALLE GIULIA, Rome SALUS, ASIMEDICAL, Marostica (VI) GENERA, Umbertide (PG) Ovulationinduction in patientswithpoorovarianresponse Filippo Maria Ubaldi M.D. M.Sc. 2nd International Meeting “New perspectives on ovulation induction” 3 – 4 June, 2010 Istanbul Turkey

  2. www.generaroma.it Introduction Ovarian superovulation is of paramount importance toobtain a goodreproductiveoutcome goals of the ovarian stimulation selection of the correct stimulation protocol In poor responders the induction of a multifollicular response is a challenge and a frustrating problem

  3. www.generaroma.it Introduction The lackof a uniformdefinitionofpoorresponders makesitdifficultto compare treatment outcomes and develop and assessprotocolsforprevention and management (Surrey 2000; Kailasam 2004; Franco 2006) FSH >10, E2 <900, <5 mature oocytes(Akman 2001) Age >37, FSH >9 (De Placido 2006) <4 oocyteswhen >300 IU FSH for >14 d. (Malmusi 2005) E2 <600, <3 oocytes(Marci 2005) FSH >10, <3 mature follicles(Cheung 2005) E2 <850, <4 follicles >15 mm (Schmidt 2005)

  4. www.generaroma.it Management of poor responders • High dosesofgonadotrophins • Additionof GH • LutealGnRH-a and itscessation at menses • GnRH-aflare-up • GnRHantagonists • Naturalcycle • Novelproposals High dosesofgonadotrophins

  5. the gonadotophin dose IMPROVES the ovarian response (Chong 1986; Crosignani 1989; Hofman 1989) the gonadotophin dose DOES NOT IMPROVE the ovarian response (Karande 1992; Land 1996; Manzi 1997) the gonadotophin dose WORSENS the ovarian response (Ben Rafael 1992) Althoughithasnotbeendefinined a maximal effective dose itseemsthatthereis no benefit touse >450 IU/ daily(Surrey 2000) www.generaroma.it High doses of gonadotrophins Increasing the dose ofgonadotrophinsis the obvious clinicalapproach in poorresponderpatients

  6. www.generaroma.it Management of poor responders • High dosesofgonadotrophins • Additionof GH • LutealGnRH-a and itscessation at menses • GnRH-aflare-up • GnRHantagonists • Naturalcycle • Novelproposals Additionof GH

  7. www.generaroma.it Addition of GH Rationale Significantlyreducedresponsetoovarianstimulation in micewith no GH receptors and GH-bindingprotein (Bachelot 2002). Itmayincrease the intra-ovarian pro- ductionof IGF-1 (Hsu and Hammond 1987; Yoshimura 1996) playinganimportantrole in ovarianfunction, stimula- tingfollicledevelopment, E production and oocyte ma- turation(Adashi 1985; Erickson 1989; Yoshimura 1996) Verylimitednumberofoldstudies

  8. Sistematic review and meta-analysisClinical pregnancy rate www.generaroma.it Addition of GH Kolibianakis, Hum Reprod Update, Nov-Dec 2009

  9. Sistematic review and meta-analysis: conclusions www.generaroma.it Addition of GH Considerableclinicalvariability in the eligiblestudies: a) the definitionofpoorresponse b) the protocolof GH administration c) the protocolusedtoinhibit premature LH surge d) the protocolusedfor COH and lutealsupport FurtherwelldesignedRCTsmightincrease the robustness oftheseresults, mightassess the optimal dose and sche- me of GH administration and itssafety Kolibianakis, Hum Reprod Update, Nov-Dec 2009

  10. www.generaroma.it Management of poor responders • High dosesofgonadotrophins • Additionof GH • LutealGnRH-a and itscessation at menses • GnRH-aflare-up • GnRHantagonists • Naturalcycle • Novelproposals LutealGnRH-a and itscessation at menses

  11. Indirectaction (?): GnRH-adecreasesblood flow (Aleem and Predanic, 1995) GnRH-aearlycessation, whilemaintainingpituitarysuppression, restores the diminishedperifollicularblood flow (Bhalet al., 1999) www.generaroma.it Cessation of GnRH-a administration AfterGnRH-apituitarydesensitizationsignificantly highergonadotrophinsamount are required (Horvarthet al., 1988) Directaction (?): GnRH-areceptors on the ovary (Latoucheet al., 1989: Janssenset al., 2000)

  12. the numberoffollicleswithgoodclinicalresults (Faberet al, 1998; Ubaldiet al, 1999) www.generaroma.it Cessation of GnRH-a administration the numberofoocytesretrieved the numberof daysofstimulation and dose ofgonadotrophins (Dirnfeldet al, 1999; Garcia-Velascoet al, 2000) Comparablepregnancyrates

  13. Sistematic review and meta-analysisClinical pregnancy rate www.generaroma.it Cessation of GnRH-a administration Kyrou, Fertil Steril 2009

  14. www.generaroma.it Management of poor responders • High dosesofgonadotrophins • Additionof GH • LutealGnRH-a and itscessation at menses • GnRH-aflare-up • GnRHantagonists • Naturalcycle • Novelproposals GnRH-aflare-up

  15. www.generaroma.it GnRH-agonist flare regimen Wasdesignedto take advantageof the release ofendogenousgonadotropinsinducedbyGnRH- agonistadministered in the earlyfollicularphase (Garcia 1990)suggestingbetterclinicaloutcome in poorresponders(Padilla 1996) Lower fertilization and pregnancy rates in normo- responders (Loumaye 1990; Ron-El 1990; San Roman 1992; Kondaveeti 1996; Anserini 1997; Cramer 1999) due to high incidence of corpus luteum rescue, higher serum LH, P and T in the early foll phase (San Roman 1992)

  16. www.generaroma.it GnRH-agonist flare vs long protocol • 26 prospectiverandomized • trials • The common OR forclinical • pregnancy per startedcycle • was 1.32(95% CI 1.10–1.57) • in favourof the long GnRH- • agonistprotocol(P<0,05) REVIEWER CONCLUSIONS: On the basis of clinical pregnancy rate per cycle started, this meta-analysis demonstrates the superiority of the long protocol over the short and ultashort protocols for GnRH-a use in IVF and GIFT cycles

  17. gonadotrophin dose, daysofstimulation, cancel- lation rate, abortion rate and pregnancyrates (Katayama 1988; Garcia 1990; Toth 1996; Padilla 1996) www.generaroma.it GnRH-agonist flare regimen 1/50 of the normal dose of GnRH-a was able to sti- mulate significant release of FSH while inhibiting premature LH surge (Scott & Navot 1994) Worseresults in “poorresponders” (Brzyski 1988; Gindoff 1990; Anserini 1997; Karande 1997) Pretreatment with OCs eliminate the possible rescue of a “pre-existing” CL and no increase of T, P and LH was reported (Schoolcraft 1997; Surrey 1998)

  18. Sistematic review and meta-analysis www.generaroma.it GnRH-agonist flare vs GnRH-antagonist RR (fixed)95%CI RR (fixed)95%CI Weight % n/N n/N STUDY Short Agonist Antagonist Akman 2001 4/24 4/24 De Placido 2006 5/67 4/66 Malmusi 2005 6/30 7/25 Schimdt 2005 13/24 11/24 Total (95% CI) 145 139 15.00 1.00 (0.28, 3.54) 15.11 1.23 (0.35, 4.39) 28.64 0.71 (0.28, 1.85) 41.25 1.18 (0.67, 2.09) 100.00 1.03 (0.66, 1.60) Test for overall effect: Z= 0.12 P=0.90 Cancelled cycles Sunkara, RBM Online 2007

  19. Sistematic review and meta-analysis www.generaroma.it GnRH-agonist flare vs GnRH-antagonist WMD (fixed)95%CI WMD (fixed)95%CI Weight % STUDY N MEAN (sd) N MEAN (sd) Antagonist Short Agonist Akman 2001 24 5.50 (2.00) 24 4.50 (1.80) De Placido 2006 67 6.54 (3.08) 66 6.79 (3.89) Malmusi 2005 30 3.50 (1.40) 25 2.50 (1.20) Schimdt 2005 24 9.00 (1.20) 24 8.90 (0.90) Total (95% CI) 145 139 13.36 1.00 (-0.8, 2.08) 10.87 -0.25 (-1.44, 0,94) 32.78 1.00 (0.31, 1.69) 42.99 0.10 (-0.50, 0.70) 100.00 0.48 (0.08, 0.87) Favours Short Oocyte retrieved Test for overall effect: Z= 2.38 P=0.02 Sunkara, RBM Online 2007

  20. Sistematic review and meta-analysisClinical pregnancy rate www.generaroma.it GnRH-agonist flare vs GnRH-antagonist Kyrou, Fertil Steril 2009

  21. www.generaroma.it GnRH-agonist flare vs GnRH-antagonist Prospective randomized trial Kahraman, Fertil Steril 2009

  22. www.generaroma.it GnRH-agonist flare vs GnRH-antagonist Prospective randomized trial Demirol & Gurgan, Fertil Steril 2009

  23. www.generaroma.it Management of poor responders • High dosesofgonadotrophins • Additionof GH • LutealGnRH-a and itscessation at menses • GnRH-aflare-up • GnRHantagonists • Naturalcycle • Novelproposals GnRHantagonists

  24. www.generaroma.it GnRH antagonists numberofoocytes(Marci 2005; D’Amato 2004) numberofoocytes(Cheung 2005; De Placido 2006) numberofoocytes(Akman 2001; Malmusi 2005) cancellation rate (Marci 2005; Schmidt 2005) can- cellation rate(Cheung 2005; Malmusi 2005; DePlacido 2006) pregnancy rate (Marci 2005; Cheung 2005; D’Amato) pregnancy rate (Akman 2001; Schmidt 2005) pregnancy rate(Malmusi 2005; Schoolcraft 2008)

  25. www.generaroma.it Management of poor responders The definitionusing the numberoffollicleswould appearmostacceptable Woman whofailsto produce anadequatenumber of mature follicles (generally <3 follicles <17mm) as a consequenceofwhich a suboptimalnumberof oocytes can beretrieved

  26. www.generaroma.it Management of poor responders The Cochrane Library Issue 3, 2007

  27. www.generaroma.it Cochranereview: inclusioncriteria Prospectiverandomizedcontrolledtrialswhere the poorresponsewasdefinedas <3 follicles >17mm in a previous treatment cyclewith a long protocol alone • Includedstudies: • Dirnfeldet al 1991 • Dirnfeldet al 1999 • Garcia-Velascoet al 2000 • Malmusiet al 2005 • Marci et al 2003 • Marci et al 2005 • Morgiaet al 2005

  28. www.generaroma.it Management of poor responders (Shanbhag 2007)

  29. www.generaroma.it Management of poor responders (Shanbhag 2007)

  30. www.generaroma.it Management of poor responders (Shanbhag 2007)

  31. www.generaroma.it Conclusions from the Cochrane review Thereisnotenoughevidencetoidentify the useofanyone particularinterventiontoimprove treatment outcomes A multicenter, doubleblinded, randomizedcontrolled trial in poorresponderswherethereis a cleardefinitionofpoor response in at leastoneprevious standard protocol and the poorresponseisdefinedstrictlyby the numberoffollicles recruited or the oocyteretrieved,iswarranted (Shanbhaget al, 2007)

  32. www.generaroma.it GnRH antagonist and poor responders The abilitytoassess the ovarianreserve in the cycle in which COH isplanned Decide whethertoinitiategonadotropinstailoring the ini- tiationofgonadotropinsto the cycle in which the proba- bilityof a favourableresponseisoptimal Gonadotropins can onlysupport the cohortoffollicles re- ceptivetostimulation and increasing the dose ofgonado- tropinscannotmanufacturefollicles de novo (Klinkertet al 2005)

  33. www.generaroma.it GnRH antagonist and poor responders In patientswith a meanfolliclecountof <5 follicles significantcycle-to-cyclevariability in antralfollicle countfrom -2 to +5 (Schefferet al 1999)to -3 to +7 (Bancsiet al 2004) A more fruitfultacticmaybe: US scan on day 2-3, ifthere are >3 potentially receptivefolliclesthen start gonadotropins. If there are <3 antralfollicles: a) await a cyclewith more antralfollicles b) natural IVF cycle

  34. www.generaroma.it Management of poor responders • High dosesofgonadotrophins • Additionof GH • LutealGnRH-a and itscessation at menses • GnRH-aflare-up • GnRHantagonists • Naturalcycle • Novelproposals Naturalcycle

  35. www.generaroma.it Natural cycle in poor responders AuthorStudy design PatientsCycles Preg. rates/ET Lindheim 1997 prospectivewith 30 35 33,4% historicalcontrol Bassil 1999 prospectivewith 11 16 18,6% historicalcontrol Feldman 2001 prospectivewith 22 44 20,1% historicalcontrol Morgia 2004 prospective 59 114 14,9% Elizur 2005 retrospective 52 14,3% Ubaldi 2007 retrospective 533 962 18,1% Schimberni 2009 retrospective 294 500 17,1%

  36. www.generaroma.it Natural vs stimulated cycles Natural cycles COH mini-flare P Cycles 114 101 Age (mean+SD) 38,9+3,4 39,1+4,1 - Cycles with ET (%) 41,2 68,3 ns No. embryos/ET 1,0 1,8+0,4 ns Preg.rate/cycle 6,1 6,9 ns Preg.rate/ET 14,9 10,1 ns Implantation rate 14,9 5,5 0,05 Morgia, FertilSteril 2004 Modified natural cycles FSH+GnRH-ant Long GnRH-a Cycles 52 200 288 No. oocytes 1,4 2,3 2,5 <0,05 Preg.rate/ET 14,3 10,2 10,6 ns Implantation rate10,06,7 7,4 ns Elizur, J Assist Reprod Genet 2005

  37. 962 consecutive “natural” cycles of any patient’s age and high basal FSH serum level • Follicle >14 mm GnRH-antagonist 0,25 mm sc every 24 hours+75-150 IU gonadotropins hCG administration Overall results Started cycles 962 Patients 533 Cycle/patient (mean+SD) 1,8 Age (mean+SD) 39,0+3,9 Basal FSH (mIU/mL) (mean+SD) 14,6+5,6 www.generaroma.it Natural cycles with minimal stimulation Ubaldi et al., RBM Online 2007

  38. www.generaroma.it Natural cycles with minimal stimulation Overall results Cancelled cycles prior to oocyte retrieval (%) 129/962 (13,4) Cycles with no egg retrieved (%) 147/833 (17,6) Cycles with egg retrieved (%) 686/962 (71,3) 2PN Fertilization rate (%) 557/679 (82,0) N. of ET/started cycles (%) 524/962 (54,4) Ubaldi et al., RBM Online 2007

  39. www.generaroma.it Natural cycles with minimal stimulation Overall results N. of ET/started cycles (%) 524/962 (54,4) Pregnancy rate/ cycle (%) 95/962 (9,9) Pregnancy rate/ patient (%) 95/533 (17,8) Pregnancy rate/ OPU (%) 95/833 (11,4) Pregnacy rate/ ET (%) 95/524 (18,1) Implantation rate (%) 97/547 (17,7) Ubaldi et al., RBM Online 2007

  40. www.generaroma.it Management of poor responders • High dosesofgonadotrophins • Additionof GH • LutealGnRH-a and itscessation at menses • GnRH-aflare-up • GnRHantagonists • Naturalcycle • Novelproposals Novelproposals

  41. www.generaroma.it DHEA pre-treatment (0,25 mgx3) Barad and Gleicher, 2006 Pre-DHEA Post-DHEA Patients 25 25 Weeks of DHEA - 17,6 Cancellation % 32 4,3 p=0,02 N. Oocytes retrieved 3,4 4,4 p<0,05 Fertilization rate % 39 67 p<0,001 Transferred embryos 1,4 2,4 p=0,005 How DHEA mighteffecttheseoutcomeimprovements? Substratefor Testosterone and Androstenedione production which acttogetherwith FSH tostimulatefolldifferentiation(Hillier 1985), topromotefoll. recruitment and toincrease IGF-1(Vendola 1999)

  42. www.generaroma.it DHEA pre-treatment AuthorsStudy design Results Sonmezer 2009 Case reports 2 pregnancies in poorresponders Gleicher 2009 RetrospectiveReducedabortion rate Mamas 2009 ReviewBetteroocyte production and pregnancy Karp 2009 Case reportGeneralizedseizureafter DHEA intake Mamas 2009 Case reportsPregnancy in POF patients Barad 2007 Case-controlSignificantlyincreasedpregnancyrates Barad 2006 Case-controlBetterovarianfunction

  43. www.generaroma.it Transdermal testosterone pre-treatment (2,5 mg) Prospective with hystorical control No Testost. Testosterone Patients 25 25 Total FSH units (IU) 4005 3570 p<0,05 E2 on the day HCG (pg/mL) 392 1396 p<0,05 Follicles >10 mm 1,6 8,5 p<0,05 Oocytes retrieved 5,8 Embryos transferred 3,5 Implantation rate % 16 Clinical pregnancy/ET % 30 Balasch et al, Hum Reprod, 2006

  44. www.generaroma.it Transdermal testosterone pre-treatment (2,5 mg) Prospective Randomized Trial No Testost. Testosterone Patients 31 31 ns Total FSH units (IU) 3950 3154 p<0,01 E2 on the day HCG (pg/mL) 1427 1171 ns Follicles >18 mm 3,1 4 ns Oocytes retrieved 4,3 5,1 ns Embryos transferred 1,5 1,7 ns Implantation rate % 18 16 ns Clinical pregnancy/ET % 22 24 ns Fabregues et al, Hum Reprod, 2009

  45. www.generaroma.it Transdermal testosterone pre-treatment (gel 1 g) Prospctive randomized Placebo Testosterone Patients 25 24 Total FSH units (IU) 4068 3659 ns E2 on the day HCG (pg/mL) 907 948 ns Follicles >17 mm 3,2 2,4 ns Oocytes retrieved 5 5,3 ns Embryos transferred 1,8 2,2 ns Implantation rate % 9 15 ns Massin et al, Hum Reprod, 2006

  46. www.generaroma.it “Novel” approaches Ultrashort GnRH-agonist/GnRH-antagonistprotocol: GnRH agonist GnRH antagonist hCG Gonadotropins Day 1 3 14mm 18mm numberoffollicles, oocytes and embryos(Orvieto 2008) Lutealestradiol(patch/tablet)/GnRHantagonist: GnRH antagonist hCG E2(0.1 mg) patch E2(2 mg)tablet Gonadotropins 7-10 days after LH surge Day 3 8 14mm 18mm ovarianresponse and labresultswith LE (Frattarelli 2008, Hill 2009) Similarlab and clinicalresultswithmini-flare(Weitzman 2009)

  47. “Novel” approaches GnRH antagonist Letrozole 2,5 mg Gonadotropins www.generaroma.it AI: ovarianresponse, clinicalpregnancy rate (Mitwally 2002 Garcia 2005)implantation rate (Garcia 2005) GnRH-antagonist/letrozole protocol hCG Day 3 8 14mm 18mm • Betterresultswithmini-flare • Betterlabbutcomparableclinicalresults (AI) • Reductioncancellation rate and costs (Schoolcraft, 2008) (Yarali, 2009) (Ozmen, 2009)

  48. www.generaroma.it Management of poor responders Oocytedonation

  49. www.generaroma.it Conclusions The lackof a uniformdefinitionofpoorrespondersmakes itdifficultto compare treatment outcomes and develop and assessprotocolsforprevention and management Thereisnotenoughevidencetoidentify the useofanyone particularinterventiontoimprove treatment outcomes A multicenter, doubleblinded, randomizedcontrolled trial in poorresponderswherethereis a cleardefinitionofpoor responseiswarranted Natural IVF cycleswith minimal stimualtion can beconsi- deredan easy and cost-effectiveapproach. A verydetailed counsellingismandatory

  50. www.generaroma.it CLINICA VALLE GIULIA, Rome SALUS, ASIMEDICAL, Marostica (VI) GENERA, Umbertide (PG) Gynaecology: Filippo Ubaldi Elena Baroni Silvia Colamaria Fabio Sapienza Maddalena Giuliani Matteo Buccheri Massimo Salvatori Embriology: Laura Rienzi Stefania Romano Roberta Maggiulli Laura Albricci Antonio Capalbo Benedetta Iussig Nicoletta Barnocchi

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