Coasting resulting in a sharp decline in serum estradiol does not compromise implantation

25 01 2010

To the Editor:

We read the retrospective analysis of Abdalla and Nicopoullos (1) with great interest. We agree with the results, especially regarding the effects of estradiol drop (E2d). As was previously mentioned in the early studies, no strict, evidence-based criteria were established regarding the initial estradiol level (E2i) to start coasting that would not compromise oocyte/embryo quality or implantation capacity of the embryos. Moreover, there is not a safety threshold of E2d that determines whether to cancel or continue the IVF cycle (2-5).

A short period of coasting (50% E2d does not seem to interfere with endometrial receptivity and/or implantation (2). Recently in a report of two cases, we demonstrated that even more dramatic E2d (>76%) during coasting did not compromise implantation in GnRH agonist (GnRHa) cycles (6). Abdalla and Nicopoullos clearly noted that neither E2i nor E2d has a negative effect on implantation (IR), miscarriage (MR) or live birth rates (LBR), except extremely low (20,000 pmol/L) serum E2 levels at hCG triggering (E2hCG) (1). Unfortunately, the authors did not separately analyze the data according to the protocol used: GnRHa or GnRH antagonist (GnRHant). It remains unclear whether sharper decrease in serum E2 occurs in GnRHant cycles due to potential direct effect of GnRHant.

Literature is also lacking concerning the definitive impact of coasting in GnRHant cycle, which is usually associated with a lower incidence of OHSS compared to GnRHa cycles. In a small study, Bahceci et al. (3) reported favorable outcomes in high-responder patients undergoing COS with GnRHant; however in that study E2d was not severe, with a mean E2hCG level of 4320±1953pg/mL. Conversely, Farhi et al. (4) showed that targeted serum E2 concentrations were obtained within short coasting periods (<2 days) in antagonist cycles, which is associated with a higher E2d. Furthermore, in GnRHant cycles, despite similar OHSS incidence and pregnancy rates, they observed a significant decrease in the number of oocytes harvested even in short coasting periods compared to GnRHa cycles. Aboulghar et al. (5) reported that in GnRHa cycles, co-treatment with GnRHant was superior to coasting with respect to duration of coasting and the number of oocytes retrieved and high quality embryos produced. Abdalla and Nicopoullos defined that extremely low and high serum E2 levels (20.000pmol/L) on hCG day were found to be related to decreased implantation and pregnancy rates, despite unaffected retrieved oocyte number (1). However, they also found extremely low serum E2 levels on hCG day reduced fertilization rates (1). Therefore, the effects of serum E2 drop rate and serum E2 levels on hCG day remain controversial. Surprisingly, we achieved an unexpected triplet pregnancy despite >10 times E2d (9299 declined to 798 pg/ml) subsequent to 4-day coasting, wherein 3 grade A embryos transferred (unpublished data).

In conclusion, we believe that a favorable clinical outcome can be expected despite dramatic E2d obtained during coasting periods, even in GnRHant cycles. However it remains unclear whether there is a serum E2 safety threshold during coasting, below which a pregnancy is unexpected in GnRHa or GnRHant cycles.

Cem Somer Atabekoğlu, M.D.a,b
Batuhan Özmen, M.D.a,b
Suheyla Isbacar, Ph.D.b
R. Aytac, M.D.a,b
Murat Sönmezer, M.D a,b

aAnkara University School of Medicine
Department of Obstetrics and Gynecology
bAnkara University
Center for Research on Human Reproduction
Ankara, Turkey

References
1. Abdalla H, Nicopoullos JD. The effect of duration of coasting and estradiol drop on the outcome of assisted reproduction: 13 years of experience in 1,068 coasted cycles to prevent ovarian hyperstimulation. Fertil Steril. 2009;Nov 23[Epub ahead of print]

2. Ulug U, Ben-Shlomo I, Bahceci M. Predictors of success during the coasting period in high-responder patients undergoing controlled ovarian stimulation for assisted conception. Fertil Steril 2004;82:338–42.

3. Bahceci M, Ulug U, Tosun S, et al. Impact of coasting in patients undergoing controlled ovarian stimulation with the gonadotropin-releasing hormone antagonist cetrorelix. Fertil Steril. 2006;85(5):1523-5.

4. Farhi J, Ben-Haroush A, Lande Y, et al. In vitro fertilization cycle outcome after coasting in gonadotropin-releasing hormone (GnRH) agonist versus GnRH antagonist protocols. Fertil Steril. 2009;91:377-82.

5. Aboulghar MA, Mansour RT, Amin YM, et al. A prospective randomized study comparing coasting with GnRH antagonist administration in patients at risk for severe OHSS. RBMonline2007;5(3):271-9.

6. Atabekoglu C, Sonmezer M, Ozkavukcu S, Isbacar S. Unexpected pregnancy despite extremely decreased oestradiol levels during ovarian stimulation. Fertil Steril. 2008;90:2003.e5-9.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.01.061

The Authors Respond:

We read with great interest the letter by Atabekoğlu et al. (1) and thank them for their interest in our research. We will address their comments in turn.

They comment on the lack of an evidence base for the estradiol threshold for commencement of coasting that would not compromise oocyte/embryo quality or implantation capacity of the embryos and the lack of evidence on which a safe estradiol threshold is chosen for continuation or cancellation of a cycle. Although we concur with the lack of a good evidence base, as we discuss (2), we would emphasize that the choice of estradiol threshold for both the commencement of coasting and decision to proceed with hCG trigger should be based solely on patient safety and the minimization of ovarian hyperstimulation risk. Thereafter, our data should allow us to reassure couples that the coasting duration and estradiol drop has not jeopardized outcome.

On two occasions Atabekoğlu et al. suggest that we found decreased implantation and pregnancy outcome at trigger estradiol levels of 20.000 pmol/L. Statistical analysis was not directly performed on these groups due to limited number. However, analysis of the subgroups used demonstrated no significant difference in pregnancy or implantation in cycles with estradiol at trigger of 15,000 pmol/l (2).

Atabekoğlu et al. continue by discussing the potential effect of cycle protocol on the extent of both estradiol drop and cycle outcome following coasting. It is worth noting that only 34 of the 1068 coasted cycles identified used a GnRH-antagonist protocol. Even taking into account only cycles since the GnRH-antagonist protocol became a widely used option, the proportion of coasted cycles that followed GnRH-antagonist was significantly lower than the proportion of antagonist use in all cycles over the same time period. This is in keeping with the well documented protective effect on OHSS risk of GnRH-antagonist protocols (3), but may also be as a consequence of the preferential use of such protocols in potential poor responders in whom the inherent OHSS risk is low. Further analysis within the constraints of the limited sample number demonstrated that the mean duration of coasting (2.7 vs. 3.3 days) and estradiol drop (8300 vs 9770 pmol/l) were not significantly different by protocol and furthermore the number of oocytes retrieved (16.0 vs. 16.4) and 2PN embryos (9.0 vs 9.3) achieved were similar. A clinical pregnancy and livebirth rate of 45.5% and 31.0% was achieved in the coasted antagonist cycles.

Although the data on coasted GnRH-antagonist cycles does remain limited and Atabekoğlu et al. discuss comparisons between coasting and such protocols, we would continue to recommend both as options, potentially in combination, as part of our armamentarium in reducing OHSS risk.

James D.M. Nicopoullos, M.D.
Hossam Abdalla, M.D.
Lister Fertility Clinic
Lister Hospital
London, United Kingdom

References
1. Atabekoğlu CS, Ozmen B, Isbacar S, Aytac R, Sonmezer M. Coasting resulting in a sharp decline in serum oestradiol does not compromise implantation. Fertil Steril 2010; In Press

2. Abdalla H, Nicopoullos JD. The effect of duration of coasting and estradiol drop on the outcome of assisted reproduction: 13 years of experience in 1,068 coasted cycles to prevent ovarian hyperstimulation. Fertil Steril. 2009;Nov 23[Epub ahead of print]

3. Al-Inany HG, Abou-Setta AM, Aboulghar M. Gonadotrophin-releasing hormone antagonists for assisted conception: a Cochrane review. Reprod Biomed Online 2007; 14: 640-9.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.01.060

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