A review on the luteal phase

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 “controlled” ovarian superovulation ? • 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 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 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 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 ?

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 )

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 Endometrial advancement Kolibianakis FS 2002

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

18. Histologicalregression 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 WHY ?

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

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

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

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

33. Steroid serum concentrations Tavaniotou Master Thesis Brussels 2000

34. Luteal phase supplementation is mandatory • hCG versus no treatment significantly better • Vaginal progesterone versus no treatment significantly better Pritts HR 17 2002

36. hCG versus prog IM + E2V (RCT) Smitz unpublished

37. Progesterone IM + E2V versus vaginal progesterone + E2V (RCT) Smitz HR 1992

38. Vaginal progesterone versus vaginal progesterone + E2V (RCT) Smitz HR 1993

39. Is luteal support necessary in GnRH antagonist cycles? Fixed dose of rec FSH 150 IU, daily antagonist by a follicle of 14mm By a follicle of 18mm patients were randomized to receive rec hCG, rec LH, GnRH agonist No luteal support When 40 patients had been included, the study was canceled prematurely because of observed premature luteal phase bleeding and extremely low pregnancy rates. Beckers et al 2004 JCEM

40. Support of corpus luteum function remains mandatory after ovarian stimulation for IVF with GnRH antagonist cotreatment. Is luteal support necessary in GnRH antagonist cycles? Beckers et al 2004 JCEM

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

42. GnRH agonist triggering Segal FS 1992

43. 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

44. Cycle outcome Odds ratio (95 % CI) 0.11 (0.02 – 0.52) P level = 0.005 Kolibianakis HR 2005

45. GnRH agonist triggering in a GnRH antagonist cycle KolibianakisHR 2005

46. Conclusions • Ovarian superovulation (IVF) destroys luteal phase function • Endocrinology • Endometrium behaviour • Luteal phase supplementation is mandatory • The degree of luteal steroid production is the key factor