Re: Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin-induced natural cycle

4 03 2010

To the Editor:

We read with interest the paper by Fatemi et al. (1) on timing natural cycle (NC) frozen embryo transfer (FET). This randomized controlled trial compared timing NC-FET by spontaneous LH-P rise with hCG for triggering ovulation. The study was terminated early since an interim analysis found a significantly higher ongoing pregnancy rate in the spontaneous LH surge group.

The results of this study contrast markedly the results of our recent retrospective study (2). For us, of course, this is a reason for major concern since we have been using hCG triggering for timing NC-FET for several years with excellent results.

We therefore looked at differences in methodology between the studies. Our study, referred to as “small” by Fatemi et al. (1) was actually of almost identical size to the Belgian study. A total of 132 cycles were analyzed in our study, compared to 124 cycles in the study by Fatemi et al.

Our criteria for hCG administration were very strict, and patients were closely monitored. Those who demonstrated findings suggestive of impending ovulation were not eligible for hCG administration. In the study by Fatemi et al., patients in the hCG group had LH levels that were 3.7 times higher on the day of hCG administration compared to baseline levels and with a very wide standard of deviation. Without doubt, many of these patients were already ovulating when hCG was administered, a fact that could seriously compromise the accuracy of timing FET. Such patients should have been withdrawn from the study rather than receiving hCG.

Timing of thawing and transfer are not clearly described. It is stated that FET was performed 5 days after the LH rise or 5 days after hCG administration. Elsewhere it is stated that embryos were cultured overnight after thawing and FET was performed on the next morning. It therefore appears that embryos that were frozen on day 3 of cleavage, were thawed on day 2 of the natural cycle, and transferred one day later, when they are already at day 4 of preimplantation development. This could be another source for less than optimal synchronization, and explain the overall relatively low ongoing pregnancy rates in both arms of the study.

Embryo quality was significantly different between the groups. It is not stated which scoring system was used and whether scoring refers to the fresh or the post-thaw stage. Nevertheless, it is questionable whether both groups are at all comparable if a significant difference in such a major variable exists.

Fatemi el al. hypothesize that a detrimental effect of exogenous hCG on implantation exists. This is surprising since hCG has been widely used with great success for many years for triggering ovulation in both spontaneous and induced cycles. If, however, such a detrimental effect does at all exist, we hypothesize that it could be “corrected” by the administration of vaginal P for luteal support following NC-FET, as was done in our protocol, but not in the study by Fatemi et al. This could explain the discrepancy in the results between the studies.

Many of the practices in our field are not scientifically proven or evidence-based. Among these are the protocols for endometrial preparation for FET. In a recent large-scale survey (3), representing nearly 40,000 FET cycles worldwide, it was revealed that NC-FET is the preferred method for endometrial preparation in 45% of FET cycles. hCG is used for triggering ovulation in 24% of cycles, and is added after ovulation has occurred in another 37% of cycles. In 54% of cycles luteal support is being used. While it is difficult to draw any scientific conclusions from a survey, these results indicate that hCG administration is widely used, and therefore ART centers must be satisfied with the results.

Very recently, our findings were confirmed in a randomized prospective study (4), which we hope to publish soon. In our hands, it works beautifully: it simplifies the monitoring process without compromising live birth rates. We strongly hope that the negative findings on hCG administration by Fatemi et al. will call for further studies on this subject rather than to the abandonment of this elegant treatment modality.

Ariel Weissman, M.D.
Amir Ravhon, M.D.
Eran Horowitz, M.D.
David Levran, M.D.

IVF Unit
Wolfson Medical Center
Holon, Israel

References
1. Fatemi HM, Kyrou D, Bourgain C, Van den Abbeel E, Griesinger G, Devroey P. Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin-induced natural cycle. Fertil Steril, in press.

2. Weissman A, Levin D, Ravhon A, Horowitz E, Golan A, Levran D. What is the preferred method for timing natural cycle frozen-thawed embryo transfer? Reprod Biomed Online 2009;19:66-71.

3. http://www.ivf-worldwide.com/survey/survey-fet-results.html.

4. Weissman A, Horowitz E, Ravhon A, Steinfeld Z, Golan A, Levran D. Timing natural cycle frozen-thawed embryo transfer by HCG triggering: a randomized prospective trial In: 65th Annual Meeting of the American Society for Reproductive Medicine. Atlanta, GA, Fertil Steril 2009; 92 (Suppl):S24.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.03.003

The Authors Respond:

We are truly delighted that the publication of our paper (1) initiated a constructive debate with a recently published letter to the editor by Weissman. The focus of this debate is the hCG triggering for timing natural cycle-frozen embryo transfer (NC-FET). Our results demonstrated the superiority of the natural cycle as compared with the natural cycle controlled by hCG administration in FET cycles.

Dr. Weissman emphasized his concern, since the results of our prospective randomized trial contrasted markedly the results of his retrospective study (2).

It should be stressed that a theory generated from a retrospective study must be confirmed in a subsequent properly designed prospective study. In scientific literature, numerous theories are presented constantly. The fact that the vast majority of these theories are not subsequently challenged cannot be interpreted as evidence of their own validity.

Dr. Weissman commented on the LH values on the day of hCG administration. His concern was that “without doubt”, many of the patients were already ovulating when hCG was administered. Moreover, he stressed his concern regarding the embryo scoring system, timing of thaw/transfer and an asynchrony between embryo and endometrium.

In our study, embryo quality was judged based on developmental stage, blastomere size and fragmentation and referred to scoring before freezing. Day 3 embryos were thawed 4 days after the LH surge/ hCG administration, cultured overnight to evaluate resumption of mitosis and transferred 5 days after LH surge (hCG), if further cleaved.

As mentioned in the paper (1), LH rise occurred in 36.5 % of the control group. Despite the LH rise, hCG was administered, since they were assigned to the control group. The LH rise in those patients did occur without Progesterone rise and therefore, one cannot define it as the time of “ovulation.”

Moreover, speaking of asynchrony between embryo and endometrium, the embryos were replaced at the start of the presumed implantation window in both patient groups. It is suggested that in a natural cycle the endometrium is receptive during 5 days (3). Therefore, asynchrony, if present, is unlikely to be involved in the different pregnancy rates observed in the hCG treated group.

Furthermore, Weissman hypothesizes that the “detrimental effect” of hCG should be corrected by the administration of progesterone for luteal support.

It would be a major error to compare the luteal phase of a natural cycle with the luteal phase of a stimulated cycle. The primary cause of the luteal phase defect in stimulated IVF cycles is related to the supra-physiological levels of steroids secreted by a high number of corpora, which directly inhibit the LH release via negative feedback actions at the hypothalamic-pituary axis level (4).

It was also suggested that the hCG administered for the final oocyte maturation could potentially cause a luteal phase defect by suppressing the LH production via a short-loop feedback mechanism (5). However, the administration of hCG did not downregulate the LH secretion in the luteal phase of unstimulated cycles (6).

Hence, progesterone supplementation has no effect on ongoing pregnancy rate in hCG induced NC-FET (7).

The possible detrimental effect of hCG on the endometrium is not related to a luteal phase defect which could simply be corrected by the administration of progesterone, as proposed by Weissman.

In our paper (1) it was clearly stated that there is an urged need for further well-designed trials.

In the context of such studies, the questions raised in this debate might be worth examining. Until, such evidence is available and the various hypotheses are properly tested, we choose not to succumb to speculations.

Human Mousavi Fatemi, M.D., PhD.
Dimitra Kyrou, M.D.
Claire Bourgain M.D., PhD.
Etienne Van den Abbeel, Ph.D.
Georg Griesinger, M.D., PhD.
Paul Devroey M.D., Ph.D.
Centre for Reproductive Medicine
Dutch-Speaking Free University Brussels
Brussels, Belgium

References
1. Fatemi HM, Kyrou D, Bourgain C, Van den Abbeel E, Griesinger G, Devroey P. Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin-induced natural cycle. Fertil Steril, in press.

2. Weissman A, Levin D, Ravhon A, Horowitz E, Golan A, Levran D. What is the preferred method for timing natural cycle frozen-thawed embryo transfer? Reprod Biomed Online 2009;19:66-71.

3. Lessey BA.; The role of the endometrium during embryo implantation.
Hum Reprod. 2000 Dec;15 Suppl 6:39-50. Review.

4. Fatemi HM, Popovic-Todorovic B, Papanikolaou E, Donoso P, Devroey P. An update of luteal phase support in stimulated IVF cycles. Hum Reprod Update. 2007 Nov-Dec;13(6):581-90. Epub 2007 Jul 11. Review.

5. Miyake,A., Aono,T., Kinugasa,T. Tanizawa O and Kurachi K, Suppression of serum levels of luteinizing hormone by short- and long-loop negative feedback in ovariectomized women. J.Endocrinol.1979, 80, 353-356.

6. Tavaniotou,A. and Devroey,P. Effect of human chorionic gonadotropin on luteal luteinizing hormone concentrations in natural cycles. Fertil.Steril. 2003, 80, 654-655.

7. Kyrou D, Fatemi H, Popovic-Todorovic B, VandenAbbeel E, Camus M and Devroey P. Vaginal progesterone supplementation has no effect on ongoing pregnancy rate in hCG induced natural frozen-thawed embryo transfer cycle. Eur J Obstet Gynecol Reprod Biol. In press.

Published online in Fertility and Sterility doi:10.1016/j.fertnstert.2010.03.004

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