1 Bahceci Women's Health Care Center and German Hospital at Istanbul, Istanbul, Turkey and 2 Department of Obstetrics and Gynecology, Ha'Emek Medical Center, Afula and the Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel
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Abstract |
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Key words: coasting/implantation rate/ovarian stimulation/pregnancy rate
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Introduction |
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Our retrospective analysis of assisted reproduction treatment cycles in which coasting was applied attempted to define the optimal duration for coasting in terms of conception rates.
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Materials and methods |
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A cycle was considered to have been treated by coasting when administration of gonadotrophins was withheld for at least 1 day prior to triggering of ovulation by HCG while GnRH agonist was continued. The treatment cycles were grouped by the duration of coasting in days. Coasting lasted 1 day in 39 cycles (18.8%), 2 days in 61 cycles (29.4%), 3 days in 49 cycles (23.6%) and 4 days in the remaining 58 cycles (28.5%).
Protocols
The ovulation induction protocol for ovarian stimulation began with pituitary desensitization by GnRH agonist (Lucrin; Abbott, France) in the mid-luteal phase of the preceding menstrual period. Administration of gonadotrophins at a dosage of 24 ampoules per day (Metrodin® HP, 75 IU; Serono, Aubonne, Switzerland or Humegon®, 75 IU; Organon, Oss, The Netherlands) was initiated when serum E2 concentrations fell below 50 pg/ml. The starting regimen was fixed for the first 4 days and thereafter the dose of gonadotrophins was adjusted according to the individual ovarian response. When at least two follicles reached 18 mm in diameter, HCG (Pregnyl®; Organon) 10 000 IU was administered i.m. Oocytes were retrieved 3238 h following HCG injection and subjected to ICSI. Embryos were transferred transcervically 3 days after oocyte retrieval under ultrasound guidance. Luteal phase was supported by either 100 mg/day progesterone in oil, i.m. or 100 mg/day micronized progesterone, orally.
Coasting was applied in cycles where E2 serum concentrations were >4000 pg/ml in the presence of at least 20 follicles, each >12 mm in diameter and at least 30% of them >15 mm. Daily measurements were taken until serum E2 concentrations dropped below 4000 pg/ml, on which day HCG 10 000 IU was administered. Clinical pregnancy was defined by the demonstration of a gestational sac on ultrasonography with concomitantly rising serum HCG concentrations.
Statistical analysis
Statistical analysis used 2 test, analysis of variance with Bonferoni post-hoc test and KruskallWallis rank sum test with Dunn post-hoc test as applicable. A P-value < 0.05 was considered significant.
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Results |
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The outcome of ovarian stimulation of cycles by days of coasting is shown in Table I. There was no difference between the groups in patients' age and E2 concentrations at the time of HCG administration. E2 concentrations on the day when gonadotrophins were withheld were different between the groups, showing an inverse relation to the duration of coasting. The mean number of gonadotrophin ampoules used was related to the duration of coasting, i.e. higher dosages were administered to patients who ended up coasting for
3 days compared with those coasting for 1 or 2 days. The mean number of oocytes retrieved in cycles with
4 days of coasting was significantly lower than in the cycles with 13 days of coasting. However, oocyte maturity, as reflected by metaphase II oocytes to total oocytes ratio in all patients, did not reveal any significant difference. Fertilization rates and cleavage of the derived zygotes were not different between the groups.
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Discussion |
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Tortoriello suggested that the coasting interval may affect outcome and should be studied in this regard (Tortoriello et al., 1998). Due to our relatively large patient population, we were able to define that coasting for >3 days did not have any adverse effect on oocyte quality and subsequent fertilization. It is therefore of significance that a coasting interval >3 days can affect embryo implantation. Since the threshold of E2 at which we administered HCG was uniform, we found no difference in E2 concentrations on the day of HCG administration among the various interval groups. It has been suggested that exposure to very high concentrations of E2 on the day of HCG administration may adversely affect the endometrium rather than oocyte quality (Simon et al., 1995
). On the other hand, Aboulghar showed that high E2 concentrations are associated with low oocyte quality (Aboulghar et al., 1997
). In our study we could not directly address this issue. However, in view of the following: (i) similar concentrations of E2 on the day of HCG administration; (ii) the lack of association between the different E2 concentrations and outcome (Table II
); and (iii) the comparable fertilization and cleavage rates among the various groups, it is likely that the interval of coasting mainly affected endometrial receptivity.
The data available about coasting in ovarian stimulation cycles are not abundant, and results from different studies do not fully agree in many aspects. Nevertheless, prevention of OHSS seems to succeed with this method. Several reports have detailed the interval of coasting, but did not analyse results accordingly. Sher et al. treated 17 patients with a mean coasting interval of 4.8 days, with 72% fertilization and 35.2% pregnancy (Sher et al., 1993). In a later report on 51 patients, a mean coasting interval of 6.1 days allowed 69% fertilization and 41% pregnancy (Sher et al., 1995
). Others (Benadiva et al., 1997
) compared 22 coasting cycles with a mean interval of 1.9 days with cycles with embryo transfer of cryopreserved embryos. They did not detect any significant difference in outcome between these groups. Dhont compared 120 coasting cycles with a mean interval of 1.9 days with regular control cycles and did not find any difference in fertilization and pregnancy rates (Dhont et al., 1998
). Tortoriello evaluated patients who underwent ovarian stimulation with coasting and grouped them by the pre-ovulatory serum E2 concentration at the time of HCG injection (Tortoriello et al., 1998
). They reported reduced implantation rates in those patients whose serum E2 concentration was >4000 pg/ml when they met the criteria for HCG injection. Interestingly, in their subset of patients with a mean interval of 2.6 coasting days they found a 19% implantation rate, while in those with 3.5 coasting days it was only 6.7%.
Our results, like those of Tortoriello and colleagues (Tortoriello et al. 1998), suggest that coasting for >3 days reduces the implantation and pregnancy rates, whilst oocyte quality does not appear to be affected. Although exact timing of the endometrial implantation window has not been clearly identified, it is likely that in order to obtain a successful outcome, the synchronization of endometrial phase to embryonic developmental phase should be achieved. It is possible that the receptivity of the endometrium is not merely hormonally-dependent, but also time-dependent.
In a retrospective judgement of the frequency of high E2 concentrations reached during the reported study period, we are now practising more cautious protocols with less daily gonadotrophins. A practical guideline from our results may be to consider cancellation of embryo transfer in patients who needed coasting for >3 days during their ovarian stimulation. This cancellation enables cryopreservation of good embryos, which in turn can be transferred to an ideally prepared endometrium in a subsequent frozenthawed cycle.
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Notes |
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Submitted on May 22, 2000; resubmitted on April 2, 2001
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References |
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accepted on October 2, 2001.