Letter to the Editor |
Reply: Enhancement of embryo developmental potential by a single administration of GnRH agonist at the time of implantation
1 MAR&Gen, Molecular Assisted Reproduction and Genetics, Gracia 36, 18002 Granada, Spain and 2 ARCEFAR, 15 rue Faraday, 75017 Paris, France
3 To whom correspondence should be addressed. E-mail: cmendoza{at}ugr.es
Sir,
We have read with interest the letter by Hannam concerning our previously published paper on a beneficial effect of a single administration of a short-acting GnRH agonist to donor oocyte recipients 6 days after ICSI (Tesarik et al., 2004
). The letter by Hannam describes preliminary experience with the same protocol applied in ovarian stimulation cycles and suggests that the treatment with GnRH agonist in the luteal phase may increase the risk of ovarian hyperstimulation syndrome (OHSS). In this comment we should like to summarize the recent clinical data regarding this new indication for GnRH agonist.
In the aformentioned prospective randomized study (Tesarik et al., 2004) we used a design based on an oocyte-sharing oocyte-donation programme. This design was chosen to evaluate the potential direct effect of GnRH agonist on the implanting embryo while excluding parallel effects on the corpus luteum. In fact, this structure was absent in the oocyte recipients receiving the luteal-phase GnRH agonist treatment, either because of their spontaneous anovulatory status or as a sequela of previous pituitary down-regulation. Hence, ovulation was absent, and the luteal phase was maintained artificially by exogenous progesterone administration. Consequently, the risk of OHSS was non-existent.
However, extension of these findings to other clinical scenarios, including those involving controlled ovarian stimulation protocols, was a logical next step to be explored. Hannam reports cases of mild ovarian hyperstimulation syndrome (OHSS) after luteal GnRH agonist administration as well as one case of severe OHSS which was, however, completely resolved within 48 h. This latter observation was made in an at-risk patient.
The effects of GnRH agonist administered in the luteal phase remain a controversial issue. Early studies suggested that GnRH agonist treatment in the luteal phase (1 or 2 administrations of 500 µg buserelin) may act as a luteolytic agent for contraceptive purposes (Lemay et al., 1982, 1983), supposedly due to GnRH receptor desensitization in gonadotroph cells. In fact, this may be true for certain doses of GnRH agonist, although the hypothesis of a contraceptive action of GnRH agonists has never been definitely confirmed. On the other hand, recent data show that low doses of GnRH agonist (100 µg buserelin) have an opposite, stimulatory effect on the corpus luteum (Pirard et al., 2005). These observations are interesting with regard to the possible therapeutic value of GnRH agonists in the luteal phase of assisted reproduction cycles. However, no straightforward conclusion as to their contribution to, or prevention of, OHSS can be drawn from them.
To address the latter point, the effects of luteal phase GnRH agonist administration on the secretion of vascular endothelial growth factor (VEGF), the main player in the development of OHSS (McClure et al., 1994; Neulen et al., 1995; Krasnow et al., 1996), has to be examined. This kind of study has been performed in an animal (rat) model, showing that GnRH agonist administration during the luteal phase reduces the expression of VEGF and VEGF receptors, both at mRNA and protein levels, and decreases vascular permeability in the hyperstimulated ovaries (Kitajima et al., 2004).
Comparable evidence is not yet available for the human species. However, it has been shown that the continuation of GnRH agonist administration in GnRH agonist down-regulated IVF cycles prevents early OHSS in at-risk patients in whom embryo transfer is not performed and all embryos are cryopreserved (Endo et al., 2002). Based on this observation, we began administering a GnRH agonist (triptorelin, 0.1 mg daily) during 1 week following oocyte retrieval in all at-risk oocyte donors (peak serum estradiol concentration of >3000 pg/ml and/or >20 oocytes retrieved) 2 years ago. So far we have treated 76 at-risk donors in this way without any case of severe (requiring hospitalization) OHSS complication.
In the light of these observations, it has to be asked whether the OHSS cases mentioned by Hannam were of the early type (related to exogenous HCG administration) or of the late type (related to endogeneous HCG rise at the beginning of pregnancy). An increased risk of the early OHSS owing to the luteal GnRH agonist administration at the doses described in our study (Tesarik et al., 2004) is unlikely. The risk of the late OHSS, on the other hand, might be increased because of the direct effect of GnRH agonist on embryo developmental potential, thus leading to an increased incidence of pregnancies, in general, and of multiple pregnancies in particular (Tesarik et al., 2004). This effect of luteal GnRH agonist administration should be taken into account when taking the decision about the number of embryos to be transferred in each specific clinical condition.
References
Endo T, Honnma H, Hayashi T, Chida M, Yamazaki K, Kitajima Y et al (2002) Continuation of GnRH agonist administration for 1 week, after hCG injection, prevents ovarian hyperstimulation syndrome following elective cryopreservation of all pronucleate embryos. Hum Reprod 17,2548–2551.
Kitajima Y, Endo T, Manase K, Nishikawa A, Shibuya M and Kudo R (2004) Gonadotropin-releasing hormone agonist administration reduced vascular endothelial growth factor (VEGF), VEGF receptors, and vascular permeability of the ovaries of hyperstimulated rats. Fertil Steril 81(Suppl 1), 842–849.[CrossRef]
Krasnow JS, Berga SL, Guzick DS, Zeleznik AJ and Yeo KT (1996) Vascular permeability factor and vascular endothelial growth factor in ovarian hyperstimulation syndrome: a preliminary report. Fertil Steril 65,552–555.[Web of Science][Medline]
Lemay A, Faure N and Labrie F (1982) Sensitivity of pituitary and corpus luteum responses to single intranasal administration of buserelin in normal women. Fertil Steril 37,193–200.[Web of Science][Medline]
Lemay A, Faure N, Labrie F and Fazekas AT (1983) Gonadotrophin and corpus luteum responses to two successive intranasal doses of a luteinising hormone-releasing hormone agonist at different days after the mid-cycle luteinising hormone surge. Fertil Steril 39,661–687.[Web of Science][Medline]
McClure N, Healy DL, Rogers PA, Sullivan J, Beaton L, Haning RV Jr et al (1994) Vascular endothelial growth factor as capillary permeability agent in ovarian hyperstimulation syndrome. Lancet 344,235–236.[CrossRef][Web of Science][Medline]
Neulen J, Yan Z, Raczek S, Weindel K, Keck C, Weigh HA et al (1995) Human chorionic gonadotropin-dependent expression of vascular endothelial growth factor/vascular permeability factor in human granulosa cells: importance in ovarian hyperstimulation syndrome. J Clin Endocrinol Metab 80,1967–1971.[Abstract]
Pirard C, Donnez J and Loumaye E (2005) GnRH agonist as a novel luteal support: results of a randomized, parallel group, feasibility study using intranasal administration of buserelin. Hum Reprod, Epub May 12, 2005.
Tesarik J, Hazout A and Mendoza C (2004) Enhancement of embryo developmental potential by a single administration of GnRH agonist at the time of implantation. Hum Reprod 19,1176 – 1180
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