Critical analysis of OC use in ovulation induction Prof.Dr.Erkan Alataş Pamukkale University Faculty of Medicine Department of Obstetrics and Gynecology

Paradox Treating subfertile patients with a medicine that is mainly used to prevent conception

Oral Contraceptive Pills Developed in the 1950s Developed in the 1950s Clinically used in the 1960s Clinically used in the 1960s Used for IVF in mid 1980s Used for IVF in mid 1980s

Ingredients Synthetic Estrogen Synthetic Estrogen (Desogestrel, Ethynl estradiol, Mestranol) (Desogestrel, Ethynl estradiol, Mestranol) C-19 steroids with progestational activity C-19 steroids with progestational activity

Oral Contraceptives Pretreatment Oral Ethynl Estradiol in the early follicular phase Oral Ethynl Estradiol in the early follicular phase Suppression in gonadotropins Suppression in gonadotropins Lengthening of the follicular phase Lengthening of the follicular phase Tsai CC,Yen SS, 1971 Vaitukaitis JL et al, 1971

Programming Oocyte Retrieval To Prevent the premature LH surge and luteinization To Prevent the premature LH surge and luteinization To Turn oocyte retrieval from an emergency to an elective operation To Turn oocyte retrieval from an emergency to an elective operation Randomized studies have showed the superiority of GnRH-a Randomized studies have showed the superiority of GnRH-a

OCs in Ovulation-Induction Programs AuthorsStudy designSampleExperimental Regimen Branigan et alProspective,non-randomization38 CC-resistant womenOC followed by repeat CC 1999Observational100mg for 5 days Branigan et alRandomized,controlled 48 CC-resistant womenOC followed by repeat CC mg for 5 days Elkind-Hirsch et al Prospective,non-randomization20 PCOS womenOC in COS with r-FSH and 2003GnRH-agonist

Oral contraceptive followed by clomiphene citrate RCT, 48 CC resistant patients, OC+CC vs CC alone RCT, 48 CC resistant patients, OC+CC vs CC alone Significantly reduces 17 beta-estradiol, luteinizing hormone, and androgen levels Significantly reduces 17 beta-estradiol, luteinizing hormone, and androgen levels İmproves ovulation and pregnancy rates İmproves ovulation and pregnancy rates Branigan EF et al 2003

OCs in Ovulation-Induction Programs AuthorsClinical ResultsComments Branigan et al↑ Ovulation rateNo randomization 1999↑ Pregnancy rateNo statical analysis No control group Branigan et al ↑ Ovulation rate Randomized,controlled design 2003↑ CumulativePregnancy rateAdequate sample size ↓ 17-ß E2, LH, Androgens Elkind-Hirsch et al ↑ Ovulation rate No randomization 2003↑ Pregnancy rate No control group ↑ Ongoing Pregnancy rateNo power analysis Preliminary data

Use of OCs in IVF programs GnRH-Agonist Reversibly supresses pituitary function Reversibly supresses pituitary function Avoids premature LH peak and luteinization Avoids premature LH peak and luteinization Causes functional ovarian cyst formation Causes functional ovarian cyst formation

OCs and GnRH-agonists in IVF Programs AuthorsStudy designSampleExperimental Regimen Damario et alRetrospective,,non-controlled73 high responder womenDual suppression with OC and 1997GnRH-a in IVF-ET cycles Biljan et al Retrospective,,non-controlled 31 infertile womenOC prior to GnRH-a in IVF cycles 1998 Biljan et al Randomized,controlled83 infertile women OC prior to GnRH-a in IVFcycles 1998

OCs and GnRH-agonists in IVF Programs AuthorsClinical ResultsComments Damario et al↑ Fertilization rateRetrospective analysis 1998↑ Clinical pregnancy rateNo control group ↑ Ongoing pregnancy rate Biljan et al↓ Functional ovarian cysts Retrospective analysis 1998 ↓ Time to pituitary supressionNo control group Small sample size Biljan et al ↓ Functional ovarian cysts Randomized controlled design 1998 ↓ Time to pituitary supression Adequate sample size ↓ Ampoules of gonadotropin requiredPower analysis ↓ Ampoules of gonadotropin requiredPower analysis ↑ Pregnancy rate ↑ Pregnancy rate

OCs and GnRH-a Combination Normalize LH / FSH ratio and reduce ovarian androgen concentrations Normalize LH / FSH ratio and reduce ovarian androgen concentrations Improved the IVF outcome Improved the IVF outcome Reduce miscarriage rate in the following pregnancy Reduce miscarriage rate in the following pregnancy Damario MA et al, 1997 Suikkarı AM et al, 2001 Clifford K et al, 1996

The use of OCs prior to controlled ovarian hyperstimulation (COH) allows for convenient cycle scheduling aswell as for ovulation suppression so that subsequent GnRH-a treatment cannot stimulate residual corpus luteum function. The use of OCs prior to controlled ovarian hyperstimulation (COH) allows for convenient cycle scheduling aswell as for ovulation suppression so that subsequent GnRH-a treatment cannot stimulate residual corpus luteum function. OCs also can reduce the incidence of functional ovarian cyst formation, shorten the time required to achieve pituitary suppression and decrease gonadotropin requirements. OCs also can reduce the incidence of functional ovarian cyst formation, shorten the time required to achieve pituitary suppression and decrease gonadotropin requirements. Biljan MM et al 1998 Barmat LI et al 2006

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

Optimal Type of Pill Retrospective design Retrospective design Monophasic vs Triphasic pill Monophasic vs Triphasic pill No difference in Clinical Pregnancy Rates No difference in Clinical Pregnancy Rates (50% vs 55.2%) Chung MT et al, 2006

Monophasic vs Triphasic OCPs

Triphasic OCs Higher quality embryos Higher quality embryos Although nonsignificant Although nonsignificant Higher Implantation rate Higher Implantation rate Higher pregnancy rate Higher pregnancy rate Chung MT et al, 2006

OCP Pretreatment in Antagonist Cycles Initation of ovarian stimulation depends on the beginning of menstruation Initation of ovarian stimulation depends on the beginning of menstruation Difficulty in cycle programming Difficulty in cycle programming Uncertain effect on pregnancy rates?? Uncertain effect on pregnancy rates??

OCs and GnRH-antagonists in IVF Programs AuthorsStudy designSampleExperimental Regimen Fischl et alRandomized,controlled150 infertile womenOC pretreatment in 2001GnRH-antagonist downloaded IVF- ET cycles Copperman et alRetrospective,,non-controlled 1343 infertile women OC pretreatment in 2003GnRH-antagonist downloaded IVF- ET cycles Barmat et al Randomized,controlled80 infertile women OC pretreatment in 2005GnRH-a or GnRH-antagonist IVF-ET cycles Huirne et alRandomized,controlled182 infertile womenCetrorelix with OC pretreatment vs 2006 buserelin Rombauts et al Randomized,controlled351 infertile women OC pretreatment in 2006GnRH-antagonist with non- scheduled in GnRH-antagonist or long GnRH-a IVF-ET cycles Kolibianakis et al Randomized,controlled425 infertile women OC pretreatment in fixed doseof r-2006 FSH and GnRH-antagonist

OCs and GnRH-antagonists in IVF Programs AuthorsClinical ResultsComments Fischl et alNo difference in any reproductive outcomeRandomized controlled design 2001Adequate sample size Power analysis Copperman et alNo difference in normal respondersRetrospective data 2003↑ Clinical pregnancy rateNo control group ↓ Cancellation rate in poor responders Barmat et al No difference in any reproductive outcomeRandomized controlled design 2005Inadequate sample size No power analysis

OCs and GnRH-antagonists in IVF Programs AuthorsClinical ResultsComments Huirne et al Lower gonadotropins,thinner endometriumRandomized controlled design 2006More oocytes, More FSH required Rombauts et al ↓ Basal serum E2 levelsRandomized controlled design 2006↓ cancelled cycles Adequate sample size ↑ Duration of r-FSH stimulation Power analysis ↑ Total r-FSH required ↓ premature LH peak ↓ ovarian response ↓ implantation rates Kolibianakis et al ↑ Duration of r-FSH stimulation Randomized controlled design 2006↑ Total r-FSH required Adequate sample size ↑ Early pregnancy rate Power analysis

Cetrorelix in an OC pretreatment cycle compared with Buserelin Huirne JA et al, 2006

IVF Outcome Huirne JA et al, 2006

Impact of OCP pretreatment on follicular growth and hormone profiles Rombauts L et al, 2006

Cycle Cancellation Rates Rombauts L et al, 2006

OCP Pretreatment in Antagonist Cycles Monophasic pills,14-28 days, 110 patients Monophasic pills,14-28 days, 110 patients Increased duration of stimulation Increased duration of stimulation Increased requirement of FSH Increased 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 20.9% ) Similar pregnancy rates (OCP -16.2% vs non-OCP 20.9% ) Rombauts L et al, 2006

Effect of OCP pretreatment and GnRH Antagonist protocols on ongoing pregnancy rates Kolibianakis et al, 2006

Summary statistics of efficacy parameters Kolibianakis EM et al, 2006

Pregnancy Outcome Kolibianakis EM et al, 2006

OCP Pretreatment in Antagonist Cycles Monophasic pills,14 days, 504 patients Monophasic pills,14 days, 504 patients Longer duration of stimulation in OCP group Longer 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 21.6%) İncreased pregnancy loss in OCP group (36.4% vs 21.6%) Kolibianakis et al,2006

Pregnancy Outcome Retrospective, case-control study Retrospective, case-control study GnRH antagonist protocol with/without OC pretreatment GnRH antagonist protocol with/without OC pretreatment Age <36 Age <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 Outcome Similar early pregnancy loss rates Similar 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 pretreatment as a risk factor for miscarriage in patients stimulated with GnRH antagonist protocols There is not sufficient evidence to confirm OCP pretreatment as a risk factor for miscarriage in patients stimulated with GnRH antagonist protocols Bellver J et al, 2007

Altered Endometrial Receptivity OC administration is related to Reduced implantation rate Reduced implantation rate Increased miscarriage rate Increased miscarriage rate Lower endometrial thickness Lower endometrial thickness Rombauts et al 2006, Kolibianakis et al 2006

Conclusions-1 Pretreatment with OCs seems to be an effective and cheap alternative in CC-resistant patients Pretreatment with OCs seems to be an effective and cheap alternative in CC-resistant patients OCs are useful for scheduling IVF cycles in GnRH- antagonist and agonist protocols OCs are useful for scheduling IVF cycles in GnRH- antagonist and agonist protocols No significant difference in ongoing pregnancy rates between patients who received OCP pretreatment and those who did not is currently present No significant difference in ongoing pregnancy rates between patients who received OCP pretreatment and those who did not is currently present

Conclusions-2 More data are needed to define The exact timing between the suspension of OCs and start of ovarian stimulation The exact timing between the suspension of OCs and start of ovarian stimulation The type of OCs The type of OCs The duration of OCs treatment The duration of OCs treatment

Critical analysis of OC use in ovulation induction Prof.Dr.Erkan Alataş Pamukkale University Faculty of Medicine Department of Obstetrics and Gynecology

Suppression of the ovary with oral contraceptives results in excellent rates of ovulation and pregnancy in patients who previously were resistant to clomiphene citrate. Suppression of the ovary with oral contraceptives results in excellent rates of ovulation and pregnancy in patients who previously were resistant to clomiphene citrate. The decreases in ovarian androgens, luteinizing hormone, and 17 beta-estradiol may be responsible for the improved response. The decreases in ovarian androgens, luteinizing hormone, and 17 beta-estradiol may be responsible for the improved response. Branigan EF et al 2003

Hormonal Profiles Damario MA et al, 1997

Damario

OCP pretreatment in Analog Cycles Retrospective study, 105 cycles Decreased LH levels Decreased LH levels Reduced DHEAS concentrations Reduced 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 IVF with GnRH-agonist Decreased incidence of cyst≥14mm(0 vs 52.9%) Decreased incidence of cyst≥14mm(0 vs 52.9%) Shorter duration of GnRH-a administration until downregulation Shorter duration of GnRH-a administration until downregulation Fewer days of ovarian stimulation Fewer days of ovarian stimulation Decreased requirement for gonadotrophins( 10 vs 14 ampoules) Decreased requirement for gonadotrophins( 10 vs 14 ampoules) Similar PR ( 37.2% vs 33.3%) Similar PR ( 37.2% vs 33.3%) Biljan MM, 1998

OC pretreatment induces A deep pituitary supression lower serum LH levels before and during stimulation A deep pituitary supression lower serum LH levels before and during stimulation Direct follicular supression Direct follicular supression Kolibianakis et al, 2006

Huirne JA et al, 2006