1 IVI-Madrid, Madrid, 2 Instituto Valenciano de Infertilidad (IVI) and 3 Department of Paediatricis, Obstetrics and Gynaecology, Valencia University of Medicine, Valencia, Spain
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Abstract |
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Key words: coasting/oocyte donation/oocyte quality/ovarian hyperstimulation syndrome
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Introduction |
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Several risk factors have been described: young age, polycystic ovarian syndrome (PCOS), low body mass index (BMI), rapidly increasing and/or high serum estradiol (E2) level after ovarian stimulation, large number of follicles after ovarian stimulation and a large number of oocytes recovered after ovarian puncture (Whelan and Vlahos, 2000). None of them is completely reliable in predicting OHSS (Fluker et al., 1999
). Thus, several strategies have been developed for the prevention of this condition. Since there is no single strategy that totally avoids the possibility that the syndrome may still appear, most agree that cycle cancellation is the safer choice (Whelan and Vlahos, 2000
). Withholding gonadotrophins (coasting) has been described as an effective way of avoiding cycle cancellation, while decreasing the risk of severe OHSS (Sher et al., 1995
; Benadiva et al., 1997
; Lee et al., 1998
; Tortoriello et al., 1998
; Fluker et al., 1999
; Waldenstrom et al., 1999
; Al-Shawaf et al., 2001
).
When dealing with volunteer oocyte donors, who altruistically are willing to donate their oocytes, extreme measures must be taken to avoid OHSS. Oocyte donors are young women (Remohi et al., 1997), which means that their ovaries are larger and highly responsive to ovarian stimulation (Whelan and Vlahos, 2000
). Most of them are also lean (low BMI) and some may even have polycystic ovaries (PCO). So it is not uncommon to find oocyte donors with a high response to ovarian stimulation and a very high risk of developing OHSS. However, some authors consider that oocyte donors have a low risk of OHSS as they do not undergo embryo transfer, avoiding pregnancy and the second wave of HCG originated by trophoblast invasion (Sauer et al., 1996
; Sauer, 2001
). Nevertheless, OHSS may occur, and cycle cancellation seems to be the safer choice.
Similar pregnancy rates have been described in women undergoing coasting compared with women who did not, although not all authors agree. Pregnancy rate seems to be directly related to the duration of coasting (Al-Shawaf et al., 2001). Oocyte quality and/or the endometrial receptivity could be impaired during prolonged coasting (Waldenstrom et al., 1999
) although to the best of our knowledge this issue has not yet been addressed. The oocyte donation model provides the ideal clinical setting to study the outcome of oocytes from women undergoing coasting in recipients in whom the endometrial receptivity is not altered by the coasting procedure.
Thus, our main objectives were to describe: (i) oocyte donation cycle outcome in donors undergoing coasting; (ii) oocyte and embryo quality obtained from these cycles; and (iii) to determine the influence of coasting duration in cycle outcome.
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Materials and methods |
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Oocyte donors
All our donors volunteered altruistically, after being thoroughly informed, to donate their oocytes and fulfilled the criteria to be admitted in our oocyte donation programme, according to the current Spanish law for assisted reproduction (Peinado and Russell, 1990).
They all underwent a long protocol of down-regulation with a GnRH agonist (Decapeptyl®, 0.1 mg; Ipsen Pharma, Barcelona, Spain). A basal vaginal ultrasound was performed to ascertain ovarian quiescence on the first 3 days of menses, and then ovarian stimulation was started as previously described (Remohi et al., 1997). Briefly, they received recombinant FSH (Gonal-F®; Serono, Madrid, Spain) 300 UI/day for the first 3 days and then 150 IU/day, with individual dose adjustments as required, until more than six follicles >18 mm were found on vaginal ultrasound. HCG (Profasi®, 10 000 IU; Serono) was administered and ovarian puncture was performed 36 h afterwards. According to our institutional criteria as well as to the described series, if more than 20 follicles >18 mm and/or serum E2 level >4500 pg/ml were observed, donors were considered to have a high response to ovarian stimulation, which made them an extremely high risk population for the development of OHSS. Gonadotrophin administration was withheld and the GnRH agonist was maintained (coasting), until daily measurements of serum E2 levels showed that it decreased to <3500 pg/ml. HCG (10 000 IU) was then administered and ovarian puncture was performed 36 h afterwards.
Follow-up was performed by telephone contact, but donors were encouraged to contact us at any time if minimum symptoms of OHSS developed. OHSS was classified (Golan et al., 1989) as: mild when abdominal discomfort/distension appeared; as moderate when there also was sonographic evidence of ascites; and as severe when there was ascites plus changes in renal function, coagulation abnormalities, haemoconcentration and trouble breathing with or without hydrothorax. When OHSS appeared, treatment for each individual case was recorded.
Oocyte recipients
There were 38 oocyte recipients who shared oocytes from the donors submitted to coasting and 37 from donors not undergoing coasting. They entered our oocyte donation programme due to advanced age (n = 14), at least two previous IVF cycles with low quality oocytes/embryos (n = 13), premature ovarian failure (n = 25), genetic or chromosomal disorders not suitable for preimplantation genetic diagnosis (n = 1), or low response to ovarian stimulation (n = 22). All oocyte recipients were under hormonal replacement therapy (HRT) as previously described (Remohi et al., 1995). Briefly, patients with ovarian function were desensitized with a depot preparation of a GnRH agonist, which was administered in the midluteal phase of the previous cycle. HRT was started on the first day of the cycle with increasing doses of estradiol valerate (Progynova®; Schering Spain, Madrid, Spain), which were given as follows: 2 mg/day from day 1 to day 8, followed by 4 mg/day from day 9 to day 11 and then 6 mg/day from day 12 and continued until the oocyte donation was performed or until the patient had vaginal spotting, in which case the cycle was cancelled. On the 15th or 16th day after the beginning of HRT, a vaginal ultrasound, to measure endometrial thickness and pattern, and a serum E2 level were measured and oocyte donation was scheduled. The duration of estrogen priming was variable as we have shown that it does not influence the results (Remohi et al, 1995
). Micronized progesterone (800 mg/day, intravaginal) (Progeffik; Effik Laboratories, Madrid, Spain) was started on the day of oocyte donation, and embryo transfer was performed according to each patient's individual programme on day 2 or 3. Serum ß-HCG was measured on the 12th day after embryo transfer and 20 days later pregnancy was confirmed by visualization of an embryo with heart beat, by means of a transvaginal ultrasound. Only clinical pregnancies were considered for the purpose of the study.
Embryo quality classification
On the second day of cleavage, all embryos were classified according to the number of blastomeres and cytoplasmic fragmentation (grade 1: 0% fragmentation; grade 2: 25%; grade 3: 2650%; grade 4: 5175%; grade 5: >75% of the embryo surface), as well as symmetry of blastomeres (grade 1: all blastomeres with similar size, grade 2: 75% of blastomeres symmetric, grade 3: <50% with similar size) (Conaghan et al., 1993
). The number of blastomeres with multiple nuclei was registered.
Hormonal measurements
Serum E2 was analysed using a commercially available microparticle enzyme immunoassay kit (Abbot Laboratories, Abbot Park, IL, USA). Inter- and intra-assay variability for E2 at a concentration of <40 pg/ml was 2.8 and 4.3% respectively.
Statistics
Data were expressed as mean ± SEM. Statistical calculations were performed using Sigma Stat for Windows, version 2.0 (Jandel Scientific Corporation, San Rafael, CA, USA). For comparisons, t-test, Fisher's or 2-test were used when appropriate. P < 0.05 was considered statistically significant.
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Results |
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Donors were further divided into two groups according to the length of coasting: group A included oocyte donors in whom coasting lasted for 4 days, and group B, those whose coasting lasted >4 days (coasting was not prolonged for >6 days in any donor). There were no differences between groups at the beginning of coasting (Table III
). Although it was not statistically significant, the total number of oocytes and metaphase II oocytes obtained in group A was considerably larger than in group B. Interestingly, the two donors whose serum E2 level dropped abruptly to <1000 pg/ml belonged to group B. There were no differences in the incidence of OHSS between groups.
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Discussion |
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High serum E2 levels have been shown to be detrimental to oocytes/embryos, as suggested by diminished implantation and pregnancy rates as well as embryo development rate (Simon et al., 1995; Valbuena et al., 2001
). All our donors had very high serum E2 levels when coasting was started. However, there are no data available on how this might affect the oocyte once serum E2 levels begin to decrease during coasting. Some authors report that prolonging coasting yields fewer and low quality oocytes (Waldenstrom et al., 1999
; Al-Shawaf et al., 2001
). Nevertheless, normal fertilization and cleavage rates have been reported even after 6 days of coasting (Sher et al., 1995
). Prolonging coasting for >4 days was necessary in seven of our 15 oocyte donors. Although there was a trend towards obtaining fewer (15 versus 24) oocytes, it did not reach a statistically significant difference.
In our series, embryo quality does not seem to be compromised by prolonged coasting. However, the observed decrease in implantation and pregnancy rates suggests a deleterious effect of prolonged coasting in oocyte/embryo quality that we are unable to determine by our current oocyte/embryo grading systems. A second control group, with patients at similar risk for the development of OHSS, in whom coasting was not performed but where another measure had been taken to prevent OHSS, would have been an even better study design. Unfortunately, we did not do this due to the high risk of severe OHSS. Recent experimental data rule out the possibility of a relationship to hyperstimulated ovaries, which may lead to a higher proportion of abnormality in ovulated oocytes with respect to their being at inappropriate meiotic stages (Tain et al., 2000). Oocyte donors with prolonged coasting showed high serum E2 levels for a longer period. We might speculate that their oocytes were exposed to the deleterious effect of high E2 levels (Valbuena et al., 2001
) for a longer period. This may partially explain the reduced implantation and pregnancy rates observed in this group of donors. Nevertheless, we cannot rule out that the lack of FSH administration during coasting and the reduced circulating FSH levels may affect the final stages of follicular growth and maturation.
It has been suggested that FSH induces the formation of LH receptors (Waldenstrom et al., 1999) and inhibits apoptosis in granulosa cells (Tortoriello et al., 1998
). When withholding gonadotrophins during coasting, small follicles undergo atresia, while the large follicles are capable of continuing their growth and maturation process since they possess the cellular machinery to withstand the depletion of FSH (Dhont et al., 1998
). However, if coasting is continued beyond a certain and still undetermined point, even the large follicles will undergo atresia, resulting in a small number of oocytes of low quality (Al-Shawaf et al., 2001
). During prolonged coasting there may be changes in the follicular milieu not only of E2 levels, but of other hormones too (androgens, E2:androgen ratio), which may affect the oocyte quality.
Endometrial receptivity could be impaired in patients undergoing coasting, as in most high responder IVF patients (Simón et al., 1995; Valbuena et al., 2001
). However, our model did not address this issue. In fact, oocyte recipients from both groups were comparable in terms of endometrial receptivity as evaluated by serum E2 levels, endometrial thickness, and patient age. Thus, the oocyte donation model is a useful tool to confirm that coasting does not compromise oocyte/embryo quality unless it is prolonged for >4 days, when both implantation and pregnancy rates drop significantly.
The reasons why coasting is effective in decreasing the risk of OHSS are still unknown. Initially coasting was proposed as an effective method of totally avoiding severe OHSS (Sher et al., 1993, 1995
), but severe OHSS may still appear in women undergoing coasting. Coasting has proven to be safe and effective in diminishing the risk of severe OHSS to 220% (Dhont et al., 1998
; Lee et al., 1998
; Tortoriello et al., 1998
; Egbase et al., 1999
; Fluker et al., 1999
; Waldenstrom et al., 1999
; Al-Shawaf et al., 2001
). A reduction of severe OHSS from 80% to a maximum of 20% (Lee et al., 1998
; Fluker et al., 1999
) is a remarkable achievement. However, a better understanding of the coasting procedure, as well as of OHSS pathogenesis, should reduce this risk even further. Coasting is also effective in decreasing the risk of OHSS in women with polycystic ovaries (Ohata et al., 2000
). In our oocyte donors, no case of severe OHSS was diagnosed, and all cases of mild/moderate OHSS were appropriately managed on ambulatory bases. As suggested by other authors (Dhont et al., 1998
; Waldenstrom et al., 1999
), the incidence of OHSS did not change with the duration of coasting, stressing the concept that multiple factors are involved in the pathogenesis of OHSS (Lee et al., 1998
).
Coasting is effective in decreasing the risk of severe OHSS only when serum E2 levels are allowed to fall to a safe level before HCG administration. In two of our donors, we obtained fewer than five oocytes after ovarian puncture and they both belonged to the prolonged coasting group (>4 days). These two donors had an abrupt decrease in serum E2 levels to values <1000 pg/ml. In such cases, cycle cancellation is advised as a very poor outcome is predictable (Al-Shawaf et al., 2001).
In conclusion, coasting is a safe and effective procedure for decreasing the risk of severe OHSS in voluntary, healthy young oocyte donors with high response to ovarian stimulation. Although it does not abolish completely the incidence of OHSS, it decreases its severity and makes ambulatory management possible. Coasting also reduces the number of cycles cancelled in this high risk population, allowing oocyte retrieval to proceed. As a whole, the outcome of oocyte donation from donors undergoing coasting is not impaired, as good implantation rate and pregnancy rate are achieved. However, if coasting in oocyte donors is prolonged for >4 days there is a significant decrease in implantation and pregnancy rates, probably due to a decrease in oocyte quality.
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Notes |
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References |
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Submitted on January 3, 2002; accepted on March 19, 2002.