Human Reproduction, Vol. 15, No. 2, 493-495,
February 2000
© 2000 European Society of Human Reproduction and Embryology
Letters to the Editor |
A comparison of three GnRH analogues in an IVF programme
IVF Unit, Department of Obstetrics and Gynecology, Kaplan Medical Center, Rehovot Hadassah-Hebrew University School of Medicine, Jerusalem, Israel
Dear Sir,
We read with interest the paper by Dada et al. (1999) on the comparison of three different gonadotrophin-releasing hormone (GnRH) analogues for pituitary desensitization prior to ovarian stimulation for in-vitro fertilization (IVF). The authors have found that with intranasal nafarelin and depot leuprorelin pituitary desensitization and ovarian suppression are obtained significantly earlier as compared with s.c. buserelin administration. The three preparations were found comparable in every other aspect of ovarian response to stimulation and cycle outcome.
In its conventional packaging, nafarelin (Synarel) is metered to give 200 µg per puff. Due to its long half-life and high potency relative to native GnRH, nafarelin can usually be administered twice daily. We are unaware of the dosage and formulation of nafarelin used in the study by Tada et al. i.e. 100 µg three times daily.
Significant differences in ovarian suppression were found based on the criteria selected by the authors for pituitary desensitization. The requirements for desensitization included endometrial thickness <3 mm and serum oestradiol concentrations <130 pmol/l. The authors provide us with no explanation for the reasons which made them select these specific values.
Criteria for pituitary desensitization have not been uniformly established. The optimum level for serum oestradiol concentrations before commencing ovarian stimulation has not been defined and may vary greatly between clinics. It is generally accepted that satisfactory pituitary suppression has been achieved when oestradiol concentrations are in the post-menopausal range, in the absence of follicular activity. Furthermore, the need for a state of `medical hypophysectomy' with complete ovarian quiescence before gonadotrophin stimulation has been challenged by several investigators. Calhaz-Jorge et al. (1995) have shown that when the oestradiol concentration was <367 pmol/l at the end of pituitary desensitization phase, the degree of pituitary suppression had no effect on either the ovarian response to stimulation or the pregnancy and live birth rates. Similarly, Dantas et al. (1994) and Senoz et al. (1995) did not find any difference in treatment outcome when ovarian suppression at the start of the stimulation phase was less profound. A commonly used cut-off value for serum oestradiol concentrations is 200 pmol/l. This value is based on the findings of Jenkins et al. (1992) who found that 200 pmol/l was the 95th percentile established for 727 IVF cycles without apparent functional ovarian cysts. Using the same criterion, we have recently shown that an endometrial thickness (6 mm had a positive predictive value of 95.9% for pituitary desensitization; Barash et al., 1998). Furthermore, in the presence of a functional ovarian cyst mean endometrial thickness was found to be 9.6 ± 2.0 mm (Weissman et al., 1998
), far above the 3 mm cut-off value used in the present study. A close look at Figure 1a of the present study reveals that if a cut-off value of 200 pmol/l had been selected, the degree of ovarian suppression would have been found similar for all three preparations. Thus, the significant differences in the degree of pituitary desensitization on days 6 and 15 of treatment with the three GnRH analogue preparations are of questionable clinical value, and should not be used to guide the caring physicians in selecting and prescribing GnRH analogue preparations.
It is noteworthy that in a recent publication by the same group of authors (Salha et al., 1998) different criteria for pituitary desensitization were used. In the later paper pituitary desensitization was confirmed when there were no ovarian follicles >5 mm in diameter and the endometrial thickness was <5mm. Thus, an explanation for the selection of specific criteria of pituitary desensitization for the present study is awaited with interest.
References
Barash, A., Weissman, A., Manor, M. et al. (1998) Prospective evaluation of endometrial thickness as a predictor of pituitary down-regulation following GnRH-a administration in an IVF program. Fertil. Steril., 69, 496–499.[Web of Science][Medline]
Calhaz-Jorge, C., Leal, F., Cordiero, I. et al. (1995) Pituitary down-regulation in IVF cycles: is it necessary to use strict criteria? J. Assist. Reprod. Genet., 12, 615–619.[Web of Science][Medline]
Dada, T., Salha., O, Baillie, H.S. and Sharma, V. (1999) A comparison of three gonadotrophin-releasing hormone analogues in an in-vitro fertilization programme: a prospective randomized study. Hum. Reprod., 14, 288–293.
Dantas, Z.N., Vicino, M., Balmaceda, J.P. et al. (1994) Comparison between nafarelin and leuprolide acetate for in vitro fertilization: preliminary clinical study. Fertil. Steril., 61, 705–708.[Web of Science][Medline]
Jenkins, J.M., Davies, D.W., Abthony, F.W. et al. (1992) The detrimental influence of functional ovarian cysts during in-vitro fertilization cycles. Hum. Reprod., 7, 776–780.
Salha, O., Nughent, D., Tada, T. et al. (1998) The relationship between follicular fluid aspirate volume and oocyte maturity in in-vitro fertilization cycles. Hum. Reprod., 13, 1901–1906.
Senoz, S., Gulekli, B., Turhan, N.O. et al. (1995) Do the suppression criteria in GnRH-a cycles predict in vitro fertilization outcome? Gynecol. Endocrinol., 9, 91–96.[Web of Science][Medline]
Weissman, A., Barash, A., Manor, M. et al. (1998) Acute changes in endometrial thickness after aspiration of functional ovarian cysts. Fertil. Steril., 69, 1142–1144.[Web of Science][Medline]
Assisted Conception Unit, St James University Hospital, Beckett Street, Leeds LS9 7TF, UK
Dear Sir,
We agree with most of Dr Weissman's and Dr Barash's comments. The purpose of this study was to compare the rate and duration of suppression, achieved with depot leuprorelin in comparison with the other two preparations that we had used as a routine, for several years previously in our programme. We have used nafarelin (Synarel) in the dose of one puff, three times daily (200 µg per puff), since it was first marketed for use in endometriosis and at which time, its effectiveness in an in-vitro fertilization (IVF) programme was not established. We used a slightly higher dose than that routinely prescribed for endometriosis, in order to ensure that a high degree of pituitary suppression was achieved quickly and subsequently was maintained to abolish any premature luteinizing hormone (LH) surge. We have achieved good results consistently over the previous several years with this regime and therefore, wished to compare the depot preparation to our conventionally used treatments without changing it, using our protocols, rather than the dose proposed for endometriosis.
In our programme, we only perform biophysical assessment of pituitary desensitization by confirming inactive ovaries and an endometrial thickness of 
5 mm, a minimum of 2 weeks after stating the analogue. We agree with Barash and Weissman that this biophysical assessment is quite adequate and absolute concentrations of oestrogens prior to starting gonadotrophins will have no impact on the outcome, provided the two biophysical criteria mentioned above have been met. Other programmes, however, perform biochemical assessments.
All patients received weekly biophysical and biochemical assessments for the purpose of this study, but all patients after 3 weeks, were stimulated if ultrasound criteria for down-regulation were met, as per our routine practice. The analyses of the endocrine data is, therefore, retrospective and did not influence the management of these patients. The purpose here was again, to compare the depot leuprorelin with our conventional protocol of using nafarelin and buserelin, prior to starting gonadotrophin therapy.
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