Critical analysis of Critical analysis of OC use in ovulation OC use in ovulation

inductioninduction

Prof.Dr.Erkan AlataşProf.Dr.Erkan Alataş

Pamukkale UniversityPamukkale UniversityFaculty of MedicineFaculty of Medicine

Department of Obstetrics and GynecologyDepartment of Obstetrics and Gynecology

ParadoxParadox

Treating subfertile patients with a medicine that Treating subfertile patients with a medicine that

is is mainly used to prevent conceptionmainly used to prevent conception

Oral Contraceptive Oral Contraceptive PillsPills

Developed in the 1950sDeveloped in the 1950s

Clinically used in the 1960sClinically used in the 1960s

Used for IVF in mid 1980sUsed for IVF in mid 1980s

IngredientsIngredients

Synthetic EstrogenSynthetic Estrogen (Desogestrel, Ethynl estradiol, Mestranol)(Desogestrel, Ethynl estradiol, Mestranol)

C-19 steroids with progestational activityC-19 steroids with progestational activity

Oral Contraceptives Oral Contraceptives PretreatmentPretreatment

Oral Ethynl Estradiol in the early follicular phaseOral Ethynl Estradiol in the early follicular phase

Suppression in gonadotropinsSuppression in gonadotropins

Lengthening of the follicular phaseLengthening of the follicular phase

Tsai CC,Yen SS, 1971Vaitukaitis JL et al, 1971

Programming Oocyte RetrievalProgramming Oocyte Retrieval

To Prevent the premature LH surge and luteinizationTo Prevent the premature LH surge and luteinization

To Turn oocyte retrieval from an emergency to an To Turn oocyte retrieval from an emergency to an elective operationelective operation

Randomized studies have showed the superiority of Randomized studies have showed the superiority of GnRH-aGnRH-a

OCs in Ovulation-Induction OCs in Ovulation-Induction ProgramsPrograms

AuthorsAuthors Study designStudy design SampleSample Experimental Experimental RegimenRegimen

Branigan et alBranigan et al Prospective,non-randomizationProspective,non-randomization 38 CC-resistant women38 CC-resistant women OC followed by repeat CCOC followed by repeat CC

19991999 ObservationalObservational 100mg for 5 days100mg for 5 days

Branigan et alBranigan et al Randomized,controlledRandomized,controlled 48 CC-resistant women 48 CC-resistant women OC followed by repeat CCOC followed by repeat CC

20032003 100mg for 5 days100mg for 5 days

Elkind-Hirsch et alElkind-Hirsch et al Prospective,non-randomization Prospective,non-randomization 20 PCOS women20 PCOS women OC in COS with r-FSH andOC in COS with r-FSH and

20032003 GnRH-agonist GnRH-agonist

Oral contraceptive Oral contraceptive followed by clomiphene followed by clomiphene

citratecitrate RCT, 48 CC resistant patients, OC+CC vs CC aloneRCT, 48 CC resistant patients, OC+CC vs CC alone

Significantly reduces 17 beta-estradiol, luteinizing Significantly reduces 17 beta-estradiol, luteinizing hormone, and androgen levels hormone, and androgen levels

İmproves ovulation and pregnancy rates İmproves ovulation and pregnancy rates

Branigan EF et al 2003

OCs in Ovulation-Induction OCs in Ovulation-Induction ProgramsPrograms

AuthorsAuthors Clinical ResultsClinical Results CommentsComments

Branigan et alBranigan et al ↑ ↑ Ovulation rateOvulation rate No randomizationNo randomization

19991999 ↑ ↑ Pregnancy ratePregnancy rate No statical analysisNo statical analysis

No control groupNo control group

Branigan et alBranigan et al ↑ ↑ Ovulation rate Ovulation rate Randomized,controlled designRandomized,controlled design

20032003 ↑ Cumulative↑ CumulativePregnancy ratePregnancy rate Adequate sample sizeAdequate sample size ↓ 17-↓ 17-ßß E2, LH, AndrogensE2, LH, Androgens

Elkind-Hirsch et alElkind-Hirsch et al ↑ ↑ Ovulation rate Ovulation rate No randomizationNo randomization

20032003 ↑ ↑ Pregnancy rate Pregnancy rate No control groupNo control group

↑ ↑ Ongoing Ongoing Pregnancy ratePregnancy rate No power analysisNo power analysis

Preliminary dataPreliminary data

Use of OCs in IVF programsUse of OCs in IVF programsGnRH-AgonistGnRH-Agonist

Reversibly supresses pituitary functionReversibly supresses pituitary function

Avoids premature LH peak and luteinizationAvoids premature LH peak and luteinization

Causes functional ovarian cyst formationCauses functional ovarian cyst formation

OCs and GnRH-agonists in IVF OCs and GnRH-agonists in IVF ProgramsPrograms

AuthorsAuthors Study designStudy design SampleSample Experimental RegimenExperimental Regimen

Damario et alDamario et al Retrospective,,non-controlledRetrospective,,non-controlled 73 high responder women73 high responder women Dual suppression with OC and Dual suppression with OC and

19971997 GnRH-a in IVF-ET cyclesGnRH-a in IVF-ET cycles

Biljan et alBiljan et al Retrospective,,non-controlled Retrospective,,non-controlled 31 infertile women 31 infertile women OC prior to GnRH-a in IVF OC prior to GnRH-a in IVF cyclescycles

19981998

Biljan et al Biljan et al Randomized,controlledRandomized,controlled 83 infertile women 83 infertile women OC prior to GnRH-a in IVFcyclesOC prior to GnRH-a in IVFcycles

19981998

OCs and GnRH-agonists in IVF OCs and GnRH-agonists in IVF ProgramsPrograms

AuthorsAuthors Clinical ResultsClinical Results CommentsComments

Damario et alDamario et al ↑ ↑ Fertilization rateFertilization rate Retrospective analysisRetrospective analysis

19981998 ↑ Clinical p↑ Clinical pregnancy rateregnancy rate No control groupNo control group

↑ ↑ Ongoing pOngoing pregnancy rate regnancy rate

Biljan et alBiljan et al ↓ ↓ Functional ovarian cystsFunctional ovarian cysts Retrospective analysisRetrospective analysis

19981998 ↓ Time to pituitary supression↓ Time to pituitary supression No control groupNo control group

Small sample sizeSmall sample size

Biljan et alBiljan et al ↓ ↓ Functional ovarian cysts Functional ovarian cysts Randomized controlled Randomized controlled designdesign

19981998 ↓ Time to pituitary supression↓ Time to pituitary supression Adequate sample sizeAdequate sample size

↓ ↓ Ampoules of gonadotropin requiredAmpoules of gonadotropin required Power analysisPower analysis

↑ ↑ PPregnancy rateregnancy rate

OCs and GnRH-a CombinationOCs and GnRH-a Combination

Normalize Normalize LH / FSH ratio and reduce LH / FSH ratio and reduce ovarian androgen concentrations ovarian androgen concentrations

Improved the IVF outcome Improved the IVF outcome

Reduce miscarriage rate in the following Reduce miscarriage rate in the following pregnancy pregnancy

Damario MA et al, 1997Suikkarı AM et al, 2001Clifford K et al, 1996

The use of OCs prior to controlled ovarian The use of OCs prior to controlled ovarian hyperstimulation (COH) allows for convenient hyperstimulation (COH) allows for convenient cycle scheduling aswell as for ovulation cycle scheduling aswell as for ovulation suppression so that subsequent GnRH-a suppression so that subsequent GnRH-a treatment cannot stimulate residual corpus treatment cannot stimulate residual corpus luteum function.luteum function.

OCs also can reduce the incidence of OCs also can reduce the incidence of functional ovarian cyst formation, shorten the functional ovarian cyst formation, shorten the time required to achieve pituitary suppression time required to achieve pituitary suppression and decrease gonadotropin requirements . and decrease gonadotropin requirements .

Biljan MM et al 1998Barmat LI et al 2006

OCs plus GnRH-a protocolsOCs plus GnRH-a protocols

Since so many positive reports have been Since so many positive reports have been published concerning OCs in IVF published concerning OCs in IVF treatment,combined use of OCs and treatment,combined use of OCs and GnRH-a down regulation has become a GnRH-a down regulation has become a standard protocol in IVF therapy today.standard protocol in IVF therapy today.

Optimal Type of PillOptimal Type of Pill

Retrospective designRetrospective design

Monophasic vs Triphasic pillMonophasic vs Triphasic pill

No difference in Clinical Pregnancy RatesNo difference in Clinical Pregnancy Rates

(50% vs 55.2%)(50% vs 55.2%)Chung MT et al, 2006

Monophasic vs Triphasic OCPsMonophasic vs Triphasic OCPs

Monophasic vs Triphasic OCPsMonophasic vs Triphasic OCPs

Triphasic OCsTriphasic OCs

Higher quality embryosHigher quality embryos

Although nonsignificantAlthough nonsignificant Higher Implantation rateHigher Implantation rate Higher pregnancy rateHigher pregnancy rate

Chung MT et al, 2006

OCP Pretreatment in Antagonist OCP Pretreatment in Antagonist CyclesCycles

Initation of ovarian stimulation depends Initation of ovarian stimulation depends on the beginning of menstruationon the beginning of menstruation

Difficulty in cycle programmingDifficulty in cycle programming

Uncertain effect on pregnancy rates??Uncertain effect on pregnancy rates??

OCs and GnRH-antagonists OCs and GnRH-antagonists in IVF Programsin IVF Programs

AuthorsAuthors Study designStudy design SampleSample Experimental RegimenExperimental RegimenFischl et alFischl et al Randomized,controlledRandomized,controlled 150 infertile women150 infertile women OC pretreatment in OC pretreatment in 20012001 GnRH-antagonist GnRH-antagonist

downloaded IVF-downloaded IVF- ET cyclesET cycles

Copperman et alCopperman et al Retrospective,,non-controlled Retrospective,,non-controlled 1343 infertile women 1343 infertile women OC pretreatment in OC pretreatment in 20032003 GnRH-antagonist GnRH-antagonist

downloaded IVF-downloaded IVF- ET cyclesET cycles

Barmat et al Barmat et al Randomized,controlledRandomized,controlled 80 infertile women 80 infertile women OC pretreatment in OC pretreatment in 20052005 GnRH-a or GnRH-GnRH-a or GnRH-

antagonist antagonist IVF-ET cyclesIVF-ET cycles

Huirne et alHuirne et al Randomized,controlledRandomized,controlled 182 infertile women182 infertile women Cetrorelix with OC pretreatment vsCetrorelix with OC pretreatment vs20062006 buserelinbuserelin

Rombauts et al Rombauts et al Randomized,controlled Randomized,controlled 351 infertile women 351 infertile women OC pretreatment in OC pretreatment in 20062006 GnRH-antagonist with GnRH-antagonist with

non-non- scheduled in GnRH-scheduled in GnRH-antagonist or antagonist or long GnRH-a IVF-ET long GnRH-a IVF-ET cyclescycles

Kolibianakis et al Kolibianakis et al Randomized,controlled Randomized,controlled 425 infertile women 425 infertile women OC pretreatment in OC pretreatment in fixed doseof r-2006fixed doseof r-2006 FSH and GnRH-FSH and GnRH-antagonistantagonist

OCs and GnRH-antagonists in OCs and GnRH-antagonists in IVF ProgramsIVF Programs

AuthorsAuthors Clinical ResultsClinical Results CommentsComments

Fischl et alFischl et al No difference in any reproductive outcomeNo difference in any reproductive outcome Randomized controlled designRandomized controlled design20012001 Adequate sample size Adequate sample size

Power analysisPower analysis

Copperman et alCopperman et al No difference in normal respondersNo difference in normal responders Retrospective data Retrospective data 20032003 ↑ Clinical p↑ Clinical pregnancy rateregnancy rate No control groupNo control group

↓ Cancellation rate in poor responders↓ Cancellation rate in poor responders

Barmat et al Barmat et al No difference in any reproductive outcomeNo difference in any reproductive outcome Randomized controlled designRandomized controlled design20052005 Inadequate sample size Inadequate sample size

No power analysisNo power analysis

OCs and GnRH-antagonists in OCs and GnRH-antagonists in IVF ProgramsIVF Programs

AuthorsAuthors Clinical ResultsClinical Results CommentsComments

Huirne et al Huirne et al Lower gonadotropins,thinner endometrium Lower gonadotropins,thinner endometrium Randomized controlled designRandomized controlled design20062006 More oocytes, More oocytes, More FSH requiredMore FSH required

Rombauts et al Rombauts et al ↓ Basal serum E2 levels↓ Basal serum E2 levels Randomized controlled designRandomized controlled design20062006 ↓ cancelled cycles↓ cancelled cycles Adequate sample size Adequate sample size

↑ Duration of r-FSH stimulation↑ Duration of r-FSH stimulation Power analysisPower analysis↑ ↑ Total r-FSH requiredTotal r-FSH required ↓ ↓ premature LH peakpremature LH peak↓ ↓ ovarian responseovarian response↓ ↓ implantation ratesimplantation rates

Kolibianakis et al Kolibianakis et al ↑ Duration of r-FSH stimulation↑ Duration of r-FSH stimulation Randomized controlled Randomized controlled designdesign

20062006 ↑ Total r-FSH required↑ Total r-FSH required Adequate sample size Adequate sample size ↑ ↑ Early pregnancy rateEarly pregnancy rate Power analysis Power analysis

Cetrorelix in an OC pretreatment Cetrorelix in an OC pretreatment cycle compared with Buserelincycle compared with Buserelin

Huirne JA et al, 2006

IVF OutcomeIVF Outcome

Huirne JA et al, 2006

Impact of OCP pretreatment on Impact of OCP pretreatment on follicular growth and hormone follicular growth and hormone

profilesprofiles

Rombauts L et al, 2006

Cycle Cancellation RatesCycle Cancellation Rates

Rombauts L et al, 2006

Rombauts L et al, 2006

Rombauts L et al, 2006

OCP Pretreatment in Antagonist OCP Pretreatment in Antagonist CyclesCycles

Monophasic pills,14-28 days, 110 patientsMonophasic pills,14-28 days, 110 patients

Increased duration of stimulation Increased duration of stimulation

Increased requirement of FSHIncreased requirement of FSH

Increased incidence of LH rise (in non-OCP group)Increased incidence of LH rise (in non-OCP group)

Similar pregnancy rates (OCP -16.2% vs non-OCP Similar pregnancy rates (OCP -16.2% vs non-OCP 20.9% )20.9% )

Rombauts L et al, 2006

Effect of OCP pretreatment and GnRH Effect of OCP pretreatment and GnRH Antagonist protocols on ongoing Antagonist protocols on ongoing

pregnancy ratespregnancy rates

Kolibianakis et al, 2006

Summary statistics of efficacy Summary statistics of efficacy parametersparameters

Kolibianakis EM et al, 2006

Pregnancy OutcomePregnancy Outcome

Kolibianakis EM et al, 2006

OCP Pretreatment in Antagonist OCP Pretreatment in Antagonist CyclesCycles

Monophasic pills,14 days, 504 patientsMonophasic pills,14 days, 504 patients

Longer duration of stimulation in OCP groupLonger duration of stimulation in OCP group

İncreased gonadotropin requirement İncreased gonadotropin requirement

No difference in PR (OCP 20.4% vs non-OCP 23.6%) No difference in PR (OCP 20.4% vs non-OCP 23.6%)

İncreased pregnancy loss in OCP group (36.4% vs İncreased pregnancy loss in OCP group (36.4% vs 21.6%)21.6%)

Kolibianakis et al,2006

Pregnancy OutcomePregnancy Outcome

Retrospective, case-control studyRetrospective, case-control study

GnRH antagonist protocol with/without OC GnRH antagonist protocol with/without OC pretreatmentpretreatment

Age <36Age <36

n=944 (OCP group) vs n=595 (non-OCP group)n=944 (OCP group) vs n=595 (non-OCP group)

Bellver J et al, 2007

Pregnancy OutcomePregnancy Outcome

Similar early pregnancy loss ratesSimilar early pregnancy loss rates

23% (OCP group) vs 19.2% (non-OCP group)23% (OCP group) vs 19.2% (non-OCP group)

There is not sufficient evidence to confirm OCP There is not sufficient evidence to confirm OCP pretreatment as a risk factor for miscarriage in pretreatment as a risk factor for miscarriage in patients stimulated with GnRH antagonist patients stimulated with GnRH antagonist protocols protocols

Bellver J et al, 2007

Altered Endometrial ReceptivityAltered Endometrial Receptivity

OC administration is related toOC administration is related to

Reduced implantation rateReduced implantation rate

Increased miscarriage rateIncreased miscarriage rate

Lower endometrial thicknessLower endometrial thicknessRombauts et al 2006, Kolibianakis et al 2006

Conclusions-1Conclusions-1

Pretreatment with OCs seems to be an effective and Pretreatment with OCs seems to be an effective and cheap alternative in CC-resistant patientscheap alternative in CC-resistant patients

OCs are useful for scheduling IVF cycles in GnRH-OCs are useful for scheduling IVF cycles in GnRH-antagonist and agonist protocolsantagonist and agonist protocols

No significant difference in ongoing pregnancy rates No significant difference in ongoing pregnancy rates between patients who received OCP pretreatment and between patients who received OCP pretreatment and those who did not is currently presentthose who did not is currently present

Conclusions-2Conclusions-2

More data are needed to defineMore data are needed to define

The exact timing between the suspension of The exact timing between the suspension of OCs and start of ovarian stimulationOCs and start of ovarian stimulation

The type of OCsThe type of OCs

The duration of OCs treatmentThe duration of OCs treatment

Critical analysis of Critical analysis of OC use in ovulation OC use in ovulation

inductioninduction

Prof.Dr.Erkan AlataşProf.Dr.Erkan Alataş

Pamukkale UniversityPamukkale UniversityFaculty of MedicineFaculty of Medicine

Department of Obstetrics and GynecologyDepartment of Obstetrics and Gynecology

Suppression of the ovary with oral Suppression of the ovary with oral contraceptives results in excellent rates of contraceptives results in excellent rates of ovulation and pregnancy in patients who ovulation and pregnancy in patients who previously were resistant to clomiphene previously were resistant to clomiphene citrate. citrate.

The decreases in ovarian androgens, The decreases in ovarian androgens, luteinizing hormone, and 17 beta-estradiol luteinizing hormone, and 17 beta-estradiol may be responsible for the improved may be responsible for the improved response. response.

Branigan EF et al 2003

Hormonal ProfilesHormonal Profiles

Damario MA et al, 1997

DamarioDamario

OCP pretreatment in Analog OCP pretreatment in Analog CyclesCycles

Retrospective study, 105 cyclesRetrospective study, 105 cycles

Decreased LH levelsDecreased LH levels

Reduced DHEAS concentrationsReduced DHEAS concentrations

Blunted gonadotropin flare response Blunted gonadotropin flare response

Improved pregnancy rates (39.2% vs 7.4%)Improved pregnancy rates (39.2% vs 7.4%)

Damario MA et al, 1997

OCP in Ovarian Stimulation for OCP in Ovarian Stimulation for IVF with GnRH-agonistIVF with GnRH-agonist

Decreased incidence of cystDecreased incidence of cyst≥14mm(0 vs 52.9%)≥14mm(0 vs 52.9%)

Shorter duration of GnRH-a administration until Shorter duration of GnRH-a administration until downregulationdownregulation

Fewer days of ovarian stimulationFewer days of ovarian stimulation

Decreased requirement for gonadotrophins( 10 vs 14 Decreased requirement for gonadotrophins( 10 vs 14 ampoules)ampoules)

Similar PR ( 37.2% vs 33.3%)Similar PR ( 37.2% vs 33.3%) Biljan MM, 1998

OC pretreatment inducesOC pretreatment induces

A deep pituitary supression lower serum LH A deep pituitary supression lower serum LH levels before and during stimulationlevels before and during stimulation

Direct follicular supressionDirect follicular supression

Kolibianakis et al, 2006

Huirne JA et al, 2006