1. A review on the luteal phase P Devroey MD PhD Centre for Reproductive Medicine Dutch-speaking Brussels Free University Brussels - Belgium

2. Learning objectives Is the luteal phase defective after ovulation induction in anovulatory women ? Is the luteal phase defective after ovulation induction in anovulatory women ? Is the luteal phase defective after “controlled” ovarian superovulation ? Is the luteal phase defective after “controlled” ovarian superovulation ? If yes, which is the mechanism behind ? If yes, which is the mechanism behind ?

3. Controlled ovarian superovulation for IVF Are the luteal phase LH concentrations normal after controlled ovarian stimulation with gonadotrophins alone ? Are the luteal phase LH concentrations normal after controlled ovarian stimulation with gonadotrophins alone ? Are the luteal phase LH concentrations normal after controlled ovarian stimulation with the combination of GnRH agonists and gonadotrophins ? Are the luteal phase LH concentrations normal after controlled ovarian stimulation with the combination of GnRH agonists and gonadotrophins ?

4. Controlled ovarian superovulation for IVF (continued) Are the luteal phase LH concentrations normal after controlled ovarian stimulation with the combination of GnRH antagonists and gonadotrophins ? Are the luteal phase LH concentrations normal after controlled ovarian stimulation with the combination of GnRH antagonists and gonadotrophins ? Are the luteal phase LH concentrations normal after controlled ovarian stimulation with the combination of clomiphene citrate and gonadotrophins ? Are the luteal phase LH concentrations normal after controlled ovarian stimulation with the combination of clomiphene citrate and gonadotrophins ?

5. Endometrium Is there any influence on endometrial histology after the administration of gonadotrophins before injection of human chorionic gonadotrophins (hCG) ? Is there any influence on endometrial histology after the administration of gonadotrophins before injection of human chorionic gonadotrophins (hCG) ? Is there any influence on endometrial histology in GnRH agonist/antagonist - gonadotrophin stimulated cycles 36 hours after injection of hCG ? Is there any influence on endometrial histology in GnRH agonist/antagonist - gonadotrophin stimulated cycles 36 hours after injection of hCG ?

6. Luteal phase supplementation or substitution Is luteal phase supplementation mandatory in GnRH - agonist / antagonist - gonadotrophin stimulated cycles ? Is luteal phase supplementation mandatory in GnRH - agonist / antagonist - gonadotrophin stimulated cycles ?

7. Is there any influence on endometrial histology during the follicular phase in gonadotrophin stimulated cycles before the injection of hCG ? YES or NO

8. Is there any influence on endometrial histology during the follicular phase in gonadotrophin stimulated cycles before the injection of hCG ? YES or NO Answer : Yes 100 % secretory advancement in preovulatory endometria ( pre - hCG ) during ovarian stimulation ( Marchini FS 1991 ) ( Marchini FS 1991 )

9. Is there any influence on endometrial histology in agonist / gonadotrophin stimulated cycles 36 hours after hCG administration ? YES or NO

10. Is there any influence on endometrial histology in agonist / gonadotrophin stimulated cycles 36 hours after hCG administration ? YES or NO Answer : Yes 100 % ( n = 40 patients ) 2 - 5 days advancement ( Ubaldi FS 1997 )

11. Is there any influence on endometrial histology in antagonist / gonadotrophin stimulated cycles ? YES or NO

12. Is there any influence on endometrial histology in antagonist / gonadotrophin stimulated cycles ? YES or NO Answer : Yes 100 % ( n = 55 patients ) 2 - 4 days advancement ( Kolibianakis FS 2002 )

13. Endometrial biopsy on the day of ovulation, natural cycle No secretory features

14. Endometrial biopsy on the day of oocyte retrieval, GnRH agonist and gonadotrophin stimulation cycle Clear secretory features

15. Is there any relation between endometrial advancement and ongoing pregnancy rates ? YES or NO

16. Is there any relation between endometrial advancement and ongoing pregnancy rates ? YES or NO Answer : Yes ≤ 3 days > 3 days P hMG / agonist 10 / 32 0 / 7 recFSH / antagonist 8 / 49 8 / 49 0 / 6 TOTAL 18 / 81 0 / 13 < 0.05 Endometrial advancement Kolibianakis FS 2002

17. Endometrial advancement persists in the midluteal phase YES or NO

18. Histological regression of endometrium from oocyte retrieval to the midluteal phase Kolibianakis, Bourgain, Platteau, Albano, Van Steirteghem, Devroey F S 80 2003

19. Describe the LH concentration during the luteal phase ( post hCG ) in agonist gonadotrophin stimulated cycles LOW or HIGH

20. Describe the LH concentration during the luteal phase ( post hCG ) in agonist gonadotrophin stimulated cycles LOW or HIGH Answer : Low Smitz HR 1988

21. Are the LH concentrations during the luteal phase ( post hCG ) in agonist - gonadotrophin stimulated cycles similar to the LH concentrations in the follicular phase ? YES or NO

22. Are the LH concentrations during the luteal phase ( post hCG ) in agonist - gonadotrophin stimulated cycles similar to the LH concentrations in the follicular phase ? Answer : No Demoulin FS 1991 Before hCG 1.5 mIU / ml 12 hours after hCG 0.5 mIU / ml 96 hours after hCG 0.2 mIU / ml P < 0.0001 WHY ?

23. Is the luteal phase LH concentration ( post hCG ) in antagonist - gonadotrophin cycles normal or decreased ?

24. Answer : decreased Is the luteal phase LH concentration ( post hCG ) in antagonist - gonadotrophin cycles normal or decreased ?

25. Are the luteal phase concentrations ( post hCG ) similar in gonadotrophin alone versus antagonist gonadotrophin stimulated cycles ? YES or NO

26. Are the luteal phase concentrations ( post hCG ) similar in gonadotrophin alone versus antagonist gonadotrophin stimulated cycles ? YES or NO Answer : Yes Tavaniotou HR 2001 Tavaniotou HR 2001

27. Luteinizing hormone serum concentrations in Clomid gonadotrophin antagonist or gonadotrophin antagonist cycles Tavaniotou F S 77 2002

28. Is the luteal phase length normal after gonadotrophin stimulation in non IVF ? YES or NO

29. Is the luteal phase length normal after gonadotrophin stimulation in non IVF ? YES or NO Answer : No Olson FS 1983 Cycles78 Normal length 60 Shortened 18 ( 23 % )

30. Statement : GnRH antagonist can be safely administered in gonadotrophin stimulated IUI cycles without luteal phase supplementation Ragni HR 2001 Ragni HR 2001

31. Is the statement in contradiction with the lecture ? YES or NO

32. Is the statement in contradiction with the lecture ? YES or NO Answer : No Ragni HR 2001 Stimulation FSH + antagonist FSH alone Mean no of follicles 2.7 2.7 3.2 3.2 FSH units 10801054 E2 ( ng/ml ) ( pre hCG) 500 500 900 900 LH ( U / L ) ( day 4 post hCG ) 1.8 1.8 2.5 2.5

33. Steroid serum concentrations Natural Stimulated cycles Patients (n) 25 4 Progesterone (  g/L) 8.5 8.5 50.5 50.5 E 2 (ng/L) 92.0549.5 Tavaniotou Master Thesis Brussels 2000

34. Is GnRH agonist triggering an option ? PubMed 01.03.2011 n : 83 publications PubMed 01.03.2011 n : 83 publications Gonadotrophin-releasing hormone agonist triggering : the way to eliminate ovarian hyperstimulation syndrome - a 20 years experience Gonadotrophin-releasing hormone agonist triggering : the way to eliminate ovarian hyperstimulation syndrome - a 20 years experience Kol Sem Reprod Med 2010

35. GnRH agonist triggering GnRH-ahCG n : 84 n : 95 Age (years) 3334 Eggs (mean) 5.9 5.9 5.2 5.2 Embryos transferred 2.5 2.5 2.3 2.3 Pregnancy rates 20 % 19 % Segal FS 1992

36. Reflexion It is possible that down regulation of pituitary receptors and reduced LH support for the corpus luteum may occur even after a single administration of GnRH agonist Segal FS 1992

37. Cycle outcome Brussels AgonisthCG Stimulation (in patients) 1824 OPU (n) 1824 ET (n) 1520 Ongoing pregnancy rate / started cycle 1/18 (5.6 %) 1/18 (5.6 %) 10/24 (41.7 %) Odds ratio (95 % CI) 0.11 (0.02 – 0.52) P level = 0.005 Kolibianakis HR 2005

38. Triggering GnRH agonist 0.2 mg Triptorelin hCG 10 000 Vaginal progesterone ++ Estradiol valerate ++ Discontinuation-- Pregnancy rate 5.6 % 41.7 % Kolibianakis HR 2005 GnRH agonist triggering in a GnRH antagonist cycle

39. GnRH agonist triggering in GnRH antagonist cycles in OHSS risk AIM : avoiding OHSS AIM : avoiding OHSS Patients (n : 12) Patients (n : 12) > 25 follicles > 25 follicles GnRH agonist triggering and 1 500 hCG 35 hours later GnRH agonist triggering and 1 500 hCG 35 hours later COC (n : 20) COC (n : 20) Ongoing pregnancies 50 % (6/12) Ongoing pregnancies 50 % (6/12) No OHSS No OHSS Humaidan RBMO 2009

40. GnRH agonist triggering in GnRH antagonist cycles (RCT) GnRH agonist + 1 500 hCG hCG 10 000 Patients (n) 152150 Transfer rate (%) 86 86 92 92 Delivery rate / patient 36 / 152 (24 %) 36 / 152 (24 %) 47 / 150 (31 %) 47 / 150 (31 %) Humaidan FS 2010

41. Oocyte donors (GnRHa donors) TriggeringGnRHahCGP Subjects (n) 50 50 Age (y) 25 25 rFSH dose (U) 2 300 Eggs retrieved (mean) 17 17 19 19 OHSS rate 0 / 50 0 / 50 8 / 50 8 / 500.03 Melo RBMO 2009

42. Conclusions 1.Ovarian superovulation (IVF) destroys luteal phase function EndocrinologyEndocrinology Endometrium behaviourEndometrium behaviour 2.Luteal phase supplementation is mandatory 3.The degree of luteal steroid production is the key factor