Critical analysis of OC use in ovulation induction

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

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

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

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

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

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

7. OCs in Ovulation-Induction Programs Authors Study design Sample Experimental Regimen Branigan et al Prospective,non-randomization 38 CC-resistant women OC followed by repeat CC 1999 Observational 100mg for 5 days Branigan et al Randomized,controlled 48 CC-resistant women OC followed by repeat CC 2003 100mg for 5 days Elkind-Hirsch et al Prospective,non-randomization 20 PCOS women OC in COS with r-FSH and 2003 GnRH-agonist

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

9. OCs in Ovulation-Induction Programs Authors Clinical Results Comments Branigan et al ↑ Ovulation rate No randomization 1999 ↑ Pregnancy rate No statical analysis No control group Branigan et al ↑ Ovulation rate Randomized,controlled design 2003 ↑ CumulativePregnancy rate Adequate sample size ↓ 17-ßE2, LH, Androgens Elkind-Hirsch et al ↑ Ovulation rate No randomization 2003 ↑ Pregnancy rate No control group ↑ Ongoing Pregnancy rate No power analysis Preliminary data

10. Use of OCs in IVF programsGnRH-Agonist • Reversibly supresses pituitary function • Avoids premature LH peak and luteinization • Causes functional ovarian cyst formation

11. OCs and GnRH-agonists in IVF Programs Authors Study design Sample Experimental Regimen Damario et al Retrospective,,non-controlled 73 high responder women Dual suppression with OC and 1997 GnRH-a in IVF-ET cycles Biljan et al Retrospective,,non-controlled 31 infertile women OC prior to GnRH-a in IVF cycles 1998 Biljan et al Randomized,controlled 83 infertile women OC prior to GnRH-a in IVFcycles 1998

12. OCs and GnRH-agonists in IVF Programs Authors Clinical Results Comments Damario et al ↑ Fertilization rate Retrospective analysis 1998 ↑ Clinical pregnancy rate No control group ↑ Ongoing pregnancy rate Biljan et al ↓ Functional ovarian cysts Retrospective analysis 1998 ↓ Time to pituitary supression No 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 required Power analysis ↑ Pregnancy rate

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

14. 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 . Biljan MM et al 1998 Barmat LI et al 2006

15. 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.

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

17. Monophasic vs Triphasic OCPs

18. Monophasic vs Triphasic OCPs

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

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

21. OCs and GnRH-antagonists in IVF Programs Authors Study design Sample Experimental Regimen Fischl et al Randomized,controlled 150 infertile women OC pretreatment in 2001 GnRH-antagonist downloaded IVF- ET cycles Copperman et al Retrospective,,non-controlled 1343 infertile women OC pretreatment in 2003 GnRH-antagonist downloaded IVF- ET cycles Barmat et al Randomized,controlled 80 infertile women OC pretreatment in 2005 GnRH-a or GnRH-antagonist IVF-ET cycles Huirne et al Randomized,controlled 182 infertile women Cetrorelix with OC pretreatment vs 2006 buserelin Rombauts et al Randomized,controlled 351 infertile women OC pretreatment in 2006 GnRH-antagonist with non- scheduled in GnRH-antagonist or long GnRH-a IVF-ET cycles Kolibianakis et al Randomized,controlled 425 infertile women OC pretreatment in fixed doseof r-2006 FSH and GnRH-antagonist

22. OCs and GnRH-antagonists in IVF Programs Authors Clinical Results Comments Fischl et al No difference in any reproductive outcome Randomized controlled design 2001 Adequate sample size Power analysis Copperman et al No difference in normal responders Retrospective data 2003 ↑ Clinical pregnancy rate No control group ↓ Cancellation rate in poor responders Barmat et al No difference in any reproductive outcome Randomized controlled design 2005 Inadequate sample size No power analysis

23. OCs and GnRH-antagonists in IVF Programs Authors Clinical Results Comments Huirne et al Lower gonadotropins,thinner endometrium Randomized controlled design 2006 More oocytes, More FSH required Rombauts et al ↓ Basal serum E2 levels Randomized 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

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

25. IVF Outcome Huirne JA et al, 2006

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

27. Cycle Cancellation Rates Rombauts L et al, 2006

28. Rombauts L et al, 2006

29. Rombauts L et al, 2006

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

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

32. Summary statistics of efficacy parameters Kolibianakis EM et al, 2006

33. Pregnancy Outcome Kolibianakis EM et al, 2006

34. OCP Pretreatment in Antagonist Cycles • Monophasic pills,14 days, 504 patients • Longer duration of stimulation in OCP group • İncreased gonadotropin requirement • No difference in PR (OCP 20.4% vs non-OCP 23.6%) • İncreased pregnancy loss in OCP group (36.4% vs 21.6%) Kolibianakis et al,2006

35. Pregnancy Outcome • Retrospective, case-control study • GnRH antagonist protocol with/without OC pretreatment • Age <36 • n=944 (OCP group) vs n=595 (non-OCP group) Bellver J et al, 2007

36. Pregnancy Outcome • Similar early pregnancy loss rates • 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 Bellver J et al, 2007

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

38. Conclusions-1 • 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 • No significant difference in ongoing pregnancy rates between patients who received OCP pretreatment and those who did not is currently present

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

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

43. 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. Branigan EF et al 2003

44. Hormonal Profiles Damario MA et al, 1997

45. Damario

46. OCP pretreatment in Analog Cycles Retrospective study, 105 cycles • Decreased LH levels • Reduced DHEAS concentrations • Blunted gonadotropin flare response • Improved pregnancy rates (39.2% vs 7.4%) Damario MA et al, 1997

47. Decreased incidence of cyst≥14mm(0 vs 52.9%) Shorter duration of GnRH-a administration until downregulation Fewer days of ovarian stimulation Decreased requirement for gonadotrophins( 10 vs 14 ampoules) Similar PR ( 37.2% vs 33.3%) OCP in Ovarian Stimulation for IVF with GnRH-agonist Biljan MM, 1998

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

49. Huirne JA et al, 2006