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 Should we use estrogens in luteal phase support?

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

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

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

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.

Luteal phase support In the luteal phase of an IVF cycle, serum E 2 and P often drop to low levels unless hormonal support is provided, resulting in reduced implantation and pregnancy rates Hutchinson-Williams, et al, 1989 This defect in the luteal phase is more pronounced in GnRH-agonist long protocols compared with short protocols and is present even after an early cessation of its administration Devreker, et al., 1996; Beckers, et al., 2000

Luteal phase support It is well accepted that luteal phase supplementation is crucial from the time of clearance of exogenous hCG given for final oocyte maturation until the appearance of endogenous hCG during the early phases of implantation Nyboe Andersen, et al., 2002 Supplementation of the luteal phase with P in IVF cycles is the most commonly used approach, whereas support with hCG is associated with an increased risk of OHSS Daya and Gunby, 2004 The benefit of additional luteal supplementation with E 2 is, however, controversial.The benefit of additional luteal supplementation with E 2 is, however, controversial.

Luteal phase support – E 2 The role of E 2 in the follicular phase of the menstrual cycle is well documented. E 2 is essential for endometrial priming, also responsible for proliferation of uterine surface epithelium, glands, stroma, and blood vessels. The role of E2 in the luteal phase, including the preparation of the endometrium for embryo implantation, remains unclear, and its depletion in the human luteal phase does not appear to adversely affect the morphological developmental capacity of the endometrium Younis, et al., 1994

Luteal phase support – E 2 The decline in late luteal E 2 in unsuccessful cycles raised speculations that peri-implantation endometrial development may be compromised Smitz, et al., 1988 Magnitude of the decline in serum E 2 concentrations, measured by the ratio of peak E 2 (on the day of hCG administration) to midluteal E 2 (10 days after hCG administration), was found to be predictive of IVF success. Peak E 2 _________________  5 Midluteal E 2 resulted in significantly lower implantation and ongoing pregnancy rates. Sharara and McClamrock, 1999

Progesterone vs. HCG Moderate-severe OHSS / ET Daya and Gunby, 2004 OR= 0.46 ( )

Progesterone + E vs. P LBR / ET Daya and Gunby, 2004 OR= 0.89 ( )

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

Progesterone + E vs. P CPR / ET Daya and Gunby, 2004 OR= 0.89 ( )

Gelbaya, et al., 2008, in press An electronic search was conducted targeting all reports published between January 1960 and March RCTs met the criteria for inclusion in the meta- analysis. Fertil Steril, 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 Gelbaya, et al., 2008, in press Luteal phase support – E 2

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 Gelbaya, et al., 2008, in press Luteal phase support – E 2

10 RCTs The sample size varied from 63 to 666 cycles A total of 2280 ET cycles E 2 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 Gelbaya, et al., 2008, in press Luteal phase support – E 2

E 2 was administered transdermally in two studies Gorkemli, et al., 2004 Serna, et al., 2008 and vaginally in one study Engmann, et al., 2005 (  2008) Gelbaya, et al., 2008, in press Luteal phase support – E 2

P was given vaginally in 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 E 2 and/or P varied between studies Gelbaya, et al., 2008, in press Luteal phase support – E 2

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 Gelbaya, et al., 2008, in press Luteal phase support – E 2

Three studies reported significantly improved outcomes after administration of combined E 2 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 Gelbaya, et al., 2008, in press Luteal phase support – E 2

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

Gelbaya, et al., 2008, in press

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

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

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

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

Gelbaya, et al., 2008, in press Luteal phase support – E 2

Gelbaya, et al., 2008, in press Luteal phase support – E 2

Gelbaya, et al., 2008, in press Luteal phase support – E 2

Gelbaya, et al., 2008, in press Luteal phase support – E 2

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

Although NO beneficial effect of E 2 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 E 2 supplementation in IVF and would also investigate the optimal regimen (dose and route) Luteal phase support – E 2 CONCLUSION

Thank you...

Progesterone + E vs. P Fatemi HM, et al., 2006