Similar endometrial development in oocyte donors treated with either high- or standard-dose GnRH antagonist compared to treatment with a GnRH agonist or in natural cycles

C.Simon 1 2 J.Obery 0 J.Bellver 1 C.Vidal 1 E.Bosch 1 J.A.Horcajadas 2 C.Murphy 3 S.Adams 3 A.Riesewijk 4 B.Mannaerts 0 A.Pellicer 1 2 0 Clinical Development Department 1 Instituto Valenciano de Infertilidad (IVI) , Valencia , Spain 2 Instituto Valenciano de Infertilidad Foundation (FIVI)-University of Valencia 3 Departments of Anatomy and Histology and The Institute of Wildlife Research, University of Sydney , Sydney , Australia 4 Department of Pharmacology, NV Organon , Oss , The Netherlands BACKGROUND: This descriptive study evaluates the impact on endometrial development of standard and high doses of a GnRH antagonist in stimulated cycles compared with GnRH agonist and natural cycles. METHODS: Thirty-one oocyte donors were treated with a combination of rFSH and 0.25 mg/day ganirelix (standard dose), 2 mg/day ganirelix (high dose) or 0.6 mg/day buserelin (long protocol). Vaginal progesterone (200 mg/day) was administered in the luteal phase. Endometrial biopsies were performed 2 and 7 days after HCG administration. Additional biopsies were carried out in a subset of 12 subjects, 2 and 7 days following the LH peak of their previous natural cycle. Biopsies were evaluated histologically and by scanning electron microscopy. Gene expression profiles were also studied. RESULTS: At HCG +2, all the parameters studied were similar in all the groups and comparable to those observed in the natural cycle. At HCG +7, endometrial dating, steroid receptors and the presence of pinopodes were comparable in both GnRH antagonist groups and in the natural cycle. In buserelin group, endometrial dating and pinopode expression suggested an arrested endometrial development. For window of implantation genes, expression patterns were closer to those in the natural cycle following standard- or high-dose ganirelix than after buserelin administration. CONCLUSION: No relevant alteration was observed in the endometrial development in the early and midluteal phases in women undergoing controlled ovarian stimulation for oocyte donation following daily treatment with a standard- or high-dose GnRH antagonist. In addition, the endometrial development after GnRH antagonist mimics the natural endometrium more closely than after GnRH agonist. Introduction The GnRH antagonists ganirelix and cetrorelix are now widely used for the prevention of a premature LH surge in women undergoing controlled ovarian stimulation (COS) for assisted reproduction techniques. During the initial studies it became evident that a comparable number of good quality embryos could be obtained if COS is combined with a short GnRH antagonist treatment instead of the traditional long protocol of GnRH agonist (Out and Mannaerts, 2002). However, a Cochrane review of the initial five randomized studies indicated a trend towards slightly lower implantation and pregnancy rates for the GnRH antagonist treatment group compared to those in the GnRH agonist group (Al-Inany and Aboulghar, 2002). Various theories have been put forth to explain the results but consensus has not yet been reached. The dose-finding study (Devroey et al., 1998), investigating the effects of six different dosages of ganirelix, showed a dose-dependent decrease in implantation, with a complete absence of pregnancies at doses >1 mg/day, whereas no impact on the number of oocytes and good quality embryos was seen with higher doses. Follow-up of the frozen embryos obtained in this dose-finding study revealed that ongoing pregnancies were subsequently achieved in 11 patients, of which six were treated with a high ganirelix dose of 1.0 or 2.0 mg (Kol et al., 1999). These data indicate that high GnRH antagonist dosages do not affect the potential of embryos to establish pregnancy and consequently suggest that the lower implantation and pregnancy rates in cycles in which the GnRH antagonist is started at fixed doses, on day 6 of stimulation, may originate from differences in endometrial receptivity. Therefore, the present descriptive study was designed to evaluate the effect of both low- (0.25 mg) and high-dose (2.0 mg) GnRH antagonist as well as a GnRH agonist treatment on the endometrial development in women undergoing COS for oocyte donation. For a subset of patients, endometrial development in a previous natural cycle was studied as a reference. Parameters used in this study as markers of endometrial receptivity were evaluation of endometrial thickness and pattern by ultrasound and endometrial biopsy assessments in terms of endometrial dating, estrogen and progesterone receptor expression and surface structure (pinopodes). In addition, gene expression profiles were investigated. Materials and methods Subjects All subjects were selected and treated at the Instituto Valenciano de Infertilidad in Valencia, Spain. A total of 42 healthy women were screened and randomly assigned to one of three treatment groups (i.e. 14 subjects per treatment group) by means of a computer-generated randomization list. Eligible subjects were healthy women (age 1835 years, body mass index 1829 kg/m2) who had a regular menstrual cycle (range 2435 days) and were undergoing COS for oocyte donation. Women with any endocrine abnormality or abnormal early follicular gonadotrophin values were not eligible. Of the 42 subjects randomized, 31 subjects were considered evaluable (12 in the standard-dose ganirelix group, nine in the high-dose ganirelix group, and 10 in the buserelin group). Three patients did not start treatment for personal reasons; one stopped treatment prematurely because an exclusion criterion was violated; one stopped because of reasons unrelated to treatment outcome; four patients discontinued because of protocol violations; and one was not evaluable because only one endometrial biopsy was performed. For evaluation of the natural cycle, data on a subgroup of 12 subjects were available. Of these 12 patients, five were enrolled in the standard-dose ganirelix group, four in the high-dose ganirelix group, and three in the buserelin group in the subsequent cycle. Study design This open-label, randomized, single-centre study was designed to evaluate the effect of two dose regimens of GnRH antagonist (standard dose and high dose) on the endometrial receptivity in women undergoing COS for oocyte donation; a long protocol of a GnRH agonist was used as a reference treatment. Ganirelix treatment (Orgalutran; NV Organon, The Netherlands) was started on day 6 of recombinant FSH (rFSH) treatment and continued until and including the day of HCG administration. The ganirelix doses (0.25 or 2 mg) were administered s.c. in the thigh, once daily in the morning. The buserelin (Suprecur; Hoechst, Germany) protocol started on day 2124 of the preceding cycle. Buserelin was administered intranasally at a daily initial dosage of 0.6 mg/day (0.15 mg dosage, four times per day) until and including the day of HCG administration. If pituitary down-regulation was not achieved after 2 weeks (i.e. serum estr (...truncated)