Comment on the debate article: Embryo implantation: the Rubicon for GnRH antagonists

K. Diedrich1, R. Frydman2, P. Devroey3, R. Felberbaum1, A.V. Schally4, T. Reissmann5,7 and J. Engel6

1 Clinic for Obstetrics and Gynecology, Medical University of Lübeck, Germany, 2 Hospital Antoine-Beclere, Clamart Cedex, France, 3 Centre for Reproductive Medicine, Dutch-speaking Free University of Brussels, Belgium, 4 Endocrine, Polypeptide and Cancer Institute, VA Medical Center and Tulane University, New Orleans, USA, 5 Experimental Endocrinology, Corporate Research ASTA Medica AG, Frankfurt and 6 ASTA Medica AG, Frankfurt, Germany

Dear Sir,

The above article in the debate section (Hernandez, 2000Go) addressed the important question of the use of antagonists of gonadotrophin releasing hormone (GnRH)/luteinizing hormone-releasing hormone (LHRH) for IVF–embryo transfer, but we do not consider the viewpoints expressed to be correct. Although the title implied a scientific assessment of this approach, the article failed to provide an accurate picture of the scientific and clinical issues involved. The statements by the author that LHRH antagonists applied for the control of LH-secretion during ovarian stimulation for IVF have a negative impact on pregnancy rates are not substantiated within the article, are inaccurate and cannot be allowed to pass unchallenged.

It is correctly noted in the introduction that in the studies performed with LHRH antagonists compared with treatment with LHRH agonists no differences were found with respect to the number of oocytes, fertilization rate and embryo quality. Nevertheless, in the following sections the author speculates about possible negative effects of LHRH antagonists at the level of the granulosa cell, the oocyte or embryo development. These conjectures are based on in-vitro findings, especially those obtained in cancer cells. The author implies that inhibitory effects of cetrorelix (Asta Medica, Frankfurt, Germany) on growth factors like epidermal growth factor, (EGF), insulin-like growth factor (IGF)-I and IGF-II and their receptors obtained in extremely high (micromolar) concentrations, would also occur with the doses of antagonist used for LH control in IVF–embryo transfer. However the latter doses are in the lower nanomolar range. In-vitro tests revealed that this low plasma concentration of cetrorelix does not interfere with EGF-stimulated human granulosa cell proliferation (Yano et al., 1997Go).

The citation of the alleged work of one of us (A.V.S.) on inhibitory effects of GnRH (LHRH) antagonists on IGF in the debate article is inaccurate and inappropriate. Thus the author is citing purported effects of antagonists of LHRH, also called GnRH, while he is referring to an article on antagonists of growth hormone-releasing hormone (GHRH), reported by Schally and Varga in 1999. It is clear that he confused the name and the effect of GnRH (LHRH) antagonists with GHRH antagonists. The full reference to the article was omitted from the bibliography of the article.

The effects of high concentrations of LHRH antagonists on growth factors or the signal transduction pathways in endometrial or ovarian cancer cells have been reported to be the same as those attributed to LHRH agonists (Emons et al., 1998Go). Further more, Ortmann and Weiss have demonstrated that the granulosa-lutein cells recovered from IVF-patients treated with an LHRH agonist or cetrorelix do not differ in their oestradiol and progesterone response to gonadotrophin stimulation (Ortmann et al., 1998Go). So far, there is no indication that LHRH antagonists may interfere directly with the cell cycle of granulosa cells in concentrations as low as those found in patients undergoing assisted reproduction.

We agree with the author's view that the final parameter of success for any medication used in IVF is the pregnancy rate. It has already been reported in 1994 and 1995, that excellent pregnancy rates >35% per embryo transfer were obtained even after dual doses of cetrorelix using 5 or 3 mg respectively, administered 48 h or 72 h apart if the ovulation was not triggered in the meantime (Olivennes et al., 1994Go, 1995Go). These data clearly demonstrate a successful implantation after cetrorelix. Again, as the author himself stated in the introduction, no significant differences from the results with agonists were seen in all phase III studies performed with cetrorelix. Thus, at this time we cannot deduce from these data a lower pregnancy rate after cetrorelix. On the contrary, subsequent trials performed in different centres world-wide showed excellent pregnancy rates and since the pregnancy rates with the use of frozen-thawed embryos are the same for antagonists and agonists, there does not appear to be any harmful effect of either type of compound on the early embryo (Hamm, 1999Go; Kol et al., 1999Go; Al-Hasani et al., 2000Go). Thus, many favourable characteristics of LHRH antagonists such as cetrorelix in IVF–embryo transfer and controlled ovarian stimulation have already been established and studies in progress should define others.

Finally, this may not be important but for the reason of historical correctness, we would like to mention that Caesar was cited wrongly. The correct citation is `veni, vidi, vici'.

Notes

7 To whom correspondence should be addressed Back

References

Al-Hasani, S., Nikolettos, N., Felberbaum, R. et al. (2000) Comparison of cryopreservation outcome with human pronuclear oocytes obtained by the LHRH antagonist Cetrotide and LHRH agonists. Hum. Reprod., 15 (Abstract Bk 1), O-087

Emons, G., Muller, V., Ortmann, O. and Schulz, K.D. (1998) Effects of LHRH-analogues on mitogenic signal transduction in cancer cells. J. Steroid. Biochem. Mol. Biol., 65, 199–206[ISI][Medline]

Hamm, W. (1999) Cetrorelix multidose protocol: results of the largest multinational study with an antagonist in ART. Middle East Fertility Society J., 4, 24–25

Hernandez, E.R. (2000) Embryo implantation: the Rubicon for GnRH antagonists. Hum. Reprod., 15, 1211–1216[Abstract/Free Full Text]

Kol, S., Lightman, A., Hillensjo, T. et al. (1999) High doses of gonadotrophin-releasing hormone antagonist in in-vitro fertilization cycles do not adversely affect the outcome of subsequent freeze-thaw cycles. Hum. Reprod., 14, 2242–2244[Abstract/Free Full Text]

Olivennes, F., Fanchin, R., Bouchard P. et al. (1994) The single or dual administration of the gonadotropin-releasing hormone antagonist Cetrorelix in an in vitro fertilization-embryo transfer program. Fertil. Steril., 62, 468–476[ISI][Medline]

Olivennes F, Fanchin R, Bouchard P. et al. (1995) Scheduled administration of a gonadotrophin-releasing hormone antagonist (Cetrorelix) on day 8 of in-vitro fertilization cycles: a pilot study. Hum. Reprod., 10, 1382–1386[Abstract]

Ortmann, O., Felberbaum, R., Eick, F. et al. (1998) The GnRH antagonist cetrorelix does not affect steroidogenesis of human granulosa lutein cells. Exp. Clin. Endocrinol. Diabetes, 106, abs. S1[ISI][Medline]

Schally, A.V. and Varga, J.L. (1999) Antagonistic analogs of Growth Hormone Releasing Hormone: New potential antitumor agents. Trends Endocrinol. Metabol., 10, 383–391[ISI][Medline]

Yano, T., Yano, N., Matsumi, H. et al. (1997) Effect of luteinizing hormone releasing hormone analogs on the rat ovarian follicle development. Horm. Res., 48, 35–41[ISI][Medline]