Levent M. SENTURK , M.D., Professor in Ob&Gyn Istanbul University Cerrahpasa School of Medicine Dept. of Ob&Gyn

1. Should we use estrogensin luteal phase support? Levent M. SENTURK, M.D.,Professor in Ob&Gyn Istanbul University Cerrahpasa School of Medicine Dept. of Ob&Gyn, Division of Reproductive Endocrinology, IVF Unit

2. Implantation • Implantation window is the most critical period of time in human reproduction. • Human embryo at blastocyst stage and endometrium in secretory phase come to contact with each other • Apposition • Attachment • Invasion

4. Luteal phase support • The estimated onset of placental steroidogenesis (the luteoplacental shift) occurs during the 5th gestational week, as calculated by the patients’ last menses. Scott et al., 1991 • Stimulated IVF cycles are associated with a defective luteal phase in almost all patients. Ubaldi et al., 1997; Macklon and Fauser, 2000; Kolibianakis et al., 2003

5. Luteal phase support ‘‘...although it can be shown statisticallythat aspiration of follicles may be associated with a decreasedluteal function in both oestrogen and progesterone steroidogenesis,we do not believe that this is of clinical significancein most patients...’’ ‘‘...once more,it should be emphasized that the average patient following invitro fertilization will not, in our experience, need supplementationof the luteal phase...’’ Georgeanna SeegarJones, 1982 (Norfolk IVF)

6. Luteal phase support • Use of GnRH agonist causes the suppression of pituitary LH secretion for as long as 10 days(2 to 3 wks) after the last dose of agonist. • Without this LH signal, the corpus luteum may be dysfunctional, and subsequent progesterone and estrogen secretion may be abnormal. • Without proper progesterone or estrogen stimulation, endometrial receptivity may be compromised, leading to decreased implantation and decreased pregnancy rates.

7. Luteal phase support • In the luteal phase of an IVF cycle, serum E2 and Poften drop to low levels unless hormonal support is provided,resulting in reduced implantation and pregnancy ratesHutchinson-Williams, et al, 1989 • This defect in the luteal phase is more pronounced inGnRH-agonist long protocols compared with shortprotocols and is present even after an early cessation of its administration Devreker, et al., 1996; Beckers, et al., 2000

8. Luteal phase support • It is well accepted that luteal phase supplementationis crucial from the time of clearance of exogenous hCGgiven for final oocyte maturation until the appearance of endogenoushCG during the early phases of implantationNyboe Andersen, et al., 2002 • Supplementation of the luteal phasewith P in IVF cycles isthe most commonly used approach, whereas support with hCGis associated with an increased risk of OHSS Daya and Gunby, 2004 • The benefit of additional luteal supplementationwith E2 is, however, controversial.

9. Luteal phase support – E2 • The role of E2 in the follicular phase of the menstrual cycle iswell documented. • E2 is essential for endometrial priming, also responsible for proliferation of uterine surface epithelium,glands, stroma, and blood vessels. • The role of E2 in theluteal phase, including the preparation of the endometrium forembryo implantation, remains unclear, and its depletion in thehuman luteal phase does not appear to adversely affect the morphologicaldevelopmental capacity of the endometriumYounis, et al., 1994

10. Luteal phase support – E2 • The decline in late luteal E2 in unsuccessful cycles raised speculations that peri-implantation endometrial development may be compromised Smitz, et al., 1988 • Magnitude of the decline in serum E2 concentrations, measured by the ratio of peak E2(on the day of hCG administration) to midluteal E2(10 days after hCG administration), was found to be predictive of IVF success. Peak E2 _________________  5 Midluteal E2 resulted in significantly lower implantation and ongoing pregnancy rates. Sharara and McClamrock, 1999

12. Progesterone vs. HCGModerate-severe OHSS / ET Daya and Gunby, 2004 OR= 0.46 (0.26-0.81)

13. Progesterone + E vs. PLBR / ET Daya and Gunby, 2004 OR= 0.89 (0.34-2.32)

14. Progesterone + E vs. P OPR / ET Daya and Gunby, 2004 OR= 0.89 (0.34-2.32)

15. Progesterone + E vs. PCPR / ET Daya and Gunby, 2004 OR= 0.89 (0.43-1.84)

17. Gelbaya, et al., 2008, in press Fertil Steril, 2008, in press • An electronic search was conducted targeting all reports published between January 1960 and March 2007 • 10 RCTs met the criteria for inclusion in the meta-analysis.

18. Luteal phase support – E2 Gelbaya, et al., 2008, in press GnRH-a, long protocol • Smitz, et al., 1993 • Lewin, et al., 1994 • Farhi, et al., 2000 • Tay, et al., 2003 • Gorkemli, et al., 2004 • Lukaszuk, et al., 2005 GnRH antagonist • Fatemi, et al., 2006

19. Luteal phase support – E2 Gelbaya, et al., 2008, in press GnRH-a, short protocol • Farhi, et al., 2000 GnRH-a or GnRH antagonist • Engmann, et al., 2005 • Pouly, et al., 2005 • Serna, et al., 2008

20. Luteal phase support – E2 Gelbaya, et al., 2008, in press • 10 RCTs • The sample size varied from 63 to 666 cycles • A total of 2280 ET cycles • E2 was administered orally in 7 studies • Smitz, et al., 1993 • Lewin, et al., 1994 • Farhi, et al., 2000 • Tay, et al., 2003 • Lukaszuk, et al., 2005 • Pouly, et al., 2005 • Fatemi, et al., 2006

21. Luteal phase support – E2 Gelbaya, et al., 2008, in press • E2 was administered transdermally in two studies • Gorkemli, et al., 2004 • Serna, et al., 2008 • and vaginally in one study • Engmann, et al., 2005 ( 2008)

22. Luteal phase support – E2 Gelbaya, et al., 2008, in press • P was given vaginallyin the majority of the studies, • by IM injection in two trials • Lewin, et al., 1994 • Engmann, et al., 2005 (2008) • both vaginal and IM route • Farhi, et al., 2000 • by vaginal or oral route • Pouly, et al., 2005 • The duration of treatment and the doses of E2 and/or P varied between studies

23. Luteal phase support – E2 Gelbaya, et al., 2008, in press • All studies that were included in the meta-analysis showed no difference between groups regarding the population characteristics such as • age, • cause and duration of infertility, • total dose of gonadotropins, • number of embryos transferred

24. Luteal phase support – E2 Gelbaya, et al., 2008, in press • Three studies reported significantly improved outcomes after administration of combined E2 and P, including higher • PR per ET, • PR per cycle, • CP and OP rates per ET, • and implantation rate • The remaining trials showed nonsignificant differences between the compared arms for all outcome measures

25. Gelbaya, et al., 2008, in press Smitz, et al., 1993 Lewin, et al., 1994 Farhi, et al., 2000 Tay, et al., 2003 Gorkemli, et al., 2004 Lukaszuk, et al., 2005

26. Gelbaya, et al., 2008, in press

27. Luteal phase support – E2 Lukaszuk, et al., 2005

28. Luteal phase support – E2 Lukaszuk, et al., 2005

29. Luteal phase support – E2 Lukaszuk, et al., 2005

30. Gelbaya, et al., 2008, in press Engmann, et al., 2005 Pouly, et al., 2005 Serna, et al., 2008 Fatemi, et al., 2006

31. Luteal phase support – E2 Gelbaya, et al., 2008, in press

32. Luteal phase support – E2 Gelbaya, et al., 2008, in press

33. Luteal phase support – E2 Gelbaya, et al., 2008, in press

34. Luteal phase support – E2 Gelbaya, et al., 2008, in press

35. Luteal phase support – E2 Engmann, et al., 2008 n=54 n=57 n=84 n=82 • long GnRH agonist suppression / GnRH antagonist / • microdose GnRH agonist protocol • Vaginal estrace 2mgx2/d

36. Luteal phase support – E2 CONCLUSION • Although NO beneficial effect of E2 supplementation in the luteal phase of IVF cycles was shown, the up-to-date evidence remains rather scarce. • A large, well-designed, multicenter RCT that would further clarify • the role of luteal E2 supplementation in IVF and • would also investigate the optimal regimen (dose and route)

38. Thank you...