Human Reproduction, Vol. 17, No. 5, 1212-1216,
May 2002
© 2002 European Society of Human Reproduction and Embryology
‘Early coasting' in patients with polycystic ovarian syndrome is consistent with good clinical outcome
1 IVF Centre, Maternity Hospital, Kuwait and 2 Department of Obstetrics and Gynaecology, St Bartholomew's and The Royal London School of Medicine and Dentistry, Royal London Hospital, London E1 1BB, UK
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Abstract |
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BACKGROUND: Coasting can be an effective strategy for the prevention of severe ovarian hyperstimulation syndrome (OHSS) during ovarian stimulation. However, OHSS may still occur in cases of excessive follicular response (i.e. >10 follicles/ovary and serum estradiol (E2) concentration >3000 pg/ml). Furthermore, prolonged coasting may result in a reduction of the oocyte retrieval rate and embryo quality. This pilot study investigates the potential of withholding gonadotrophins at an earlier stage, with the intention of minimizing these risks. METHODS: Gonadotrophin injections were withheld for a fixed period of 3 days once the leading follicle was 15 mm, whilst continuing pituitary down-regulation in 102 obese patients with polycystic ovarian syndrome (PCOS) in whom there was evidence of excessive ovarian follicular response (>10 follicles per ovary and serum E2 >1500 but <3000 pg/ml). The events of ovarian stimulation, embryological and clinical outcomes were studied prospectively. RESULTS: The mean number of ampoules (75 IU per ampoule) of high purity (hp) FSH was 23.2. The mean serum E2 level on coasting day 1 was 1943.7 and 2169.2 pg/ml on the day of HCG administration. Normal fertilization and cleavage rates were obtained despite early withdrawal of hpFSH in the obese PCOS patients, being 73.9 and 87.7% respectively. The clinical pregnancy rate was 45.1%. There were no cases of severe OHSS. Four patients suffered pregnancy-associated late-onset moderate OHSS. CONCLUSIONS: This pilot study suggests that withholding gonadotrophins at an earlier stage in patients with excessive ovarian follicular response at anticipated risk of developing severe OHSS in the course of ovarian stimulation is consistent with good embryological and clinical outcome in IVF and ICSI treatment cycles.
Key words: clinical outcome/early coasting/embryology/PCOS
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Introduction |
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Severe ovarian hyperstimulation syndrome (OHSS) is probably the most serious complication of gonadotrophin administration, occurring in
0.5–2% of all ovarian stimulation treatment cycles (Forman et al., 1990
). Coasting, i.e. withholding gonadotrophins whilst continuing GnRH agonist administration for pituitary down-regulation, is being increasingly employed to prevent or minimize the incidence of severe OHSS. The reported efficacy has not been uniformly consistent, probably because of the differing criteria that have been used either to start or to conduct the strategy, the level of serum estradiol (E2) or the size of the leading follicle at onset of coasting varying from 3000 to 6000 pg/ml and from 16 to 18 mm respectively whilst the duration has ranged from 1 to 11 days (Sher et al., 1995; Benadiva et al., 1997; Lee et al., 1998; Tortoriello et al., 1998; Egbase et al., 1999a; Fluker et al., 1999; Waldenstrom et al., 1999; Al-Shawaf et al., 2001). Whilst coasting allows the serum E2 level to fall below 3000 pg/ml, the commonly used arbitrary serum E2 level when the risk of severe OHSS is considered to be lessened (Forman et al., 1990), it has become evident that the serum E2 level could initially rise for a variable number of days in many patients prior to its decline (Benadiva et al., 1997; Egbase et al., 1998a) suggesting that follicles that have reached critical sizes may have the potential to continue growth for a limited period. It is thus conceivable that if gonadotrophins were withheld earlier, i.e. prior to the leading follicle reaching >18 mm (criteria for administration of trigger dose of HCG), those follicles within a cohort of excessive multiple follicles in controlled ovarian stimulation treatment cycles, as may occur in PCOS patients, could continue growing to meet the HCG trigger criteria. This strategy would allow coasting to be started at serum E2 levels <3000 pg/ml rather than >3000 pg/ml as reported in most of the published data. This large pilot study was therefore designed to examine the efficacy of withholding gonadotrophins early when the leading follicle was 15 mm and there were >10 follicles per ovary with serum E2 level between 1500 and 3000 pg/ml for a fixed interval of 3 days in obese patients with polycystic ovarian syndrome (PCOS) in relation to the embryology and clinical outcome. |
Materials and methods |
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Patient population
This prospective large pilot study was carried out at the IVF Centre, Maternity Hospital, Kuwait between January 1999 and December 2000. Approval for the study was granted by the institution's medical ethics committee. Signed informed consent was obtained from all the patients prior to recruitment into the study. One hundred and two consecutive obese patients whose body mass index (BMI) was >30 kg/m2 with PCOS (raised serum testosterone, early follicular phase serum LH/FSH ratio >2, classical ultrasound appearance of polycystic ovaries, hirsutism and oligomenorrhoea or amenorrhoea) who were undergoing ovarian stimulation for conventional IVF or ICSI for associated tubal disease or male factor infertility with an anticipated risk of severe OHSS in the index cycle were recruited. The criteria for anticipated risk to develop severe OHSS for the purpose of this study were defined as the presence of >10 follicles per ovary with a leading follicle of 15 mm and serum E2 level between 1500 and 3000 pg/ml. Of the 102 obese PCOS patients recruited with the above criteria in the course of ovarian stimulation in the index cycle, 17 of these had suffered severe OHSS (six early onset and 11 late onset) and cancellation of cycles had occurred in 14 patients because of the risk of severe OHSS in previous treatments cycles performed either at our IVF unit or elsewhere; in 22 patients, previous treatment cycles were not complicated with OHSS. The remaining 49 patients were undergoing their first treatment in the index cycle.
Ovarian stimulation
The details of the ovarian stimulation protocols have been previously reported (Egbase et al., 1996). Briefly, pituitary down-regulation was achieved and maintained using the long protocol luteal phase administration of GnRH agonist, the starting dose of high purity (hp)FSH (Metrodin HP; Serono, Geneva, Switzerland) being 150 IU per day for the first 7 days. Ovarian follicular response was monitored with ultrasound scan and serum E2 measurements, which were first performed on day 8 of ovarian stimulation and subsequently repeated every other day. The dose of gonadotrophin was increased by 75 IU if the size of the leading follicle had not increased by an average of 1 mm per day. Gonadotrophins were withheld for a fixed interval of 3 days in all of these patients whilst GnRH agonist was continued when the leading ovarian follicle was 15 mm and there were >10 follicles per ovary with the serum E2 level between 1500 and <3000 pg/ml. During this interval, ultrasound scans and serum measurements were performed daily. The trigger dose of HCG (10 000 IU i.m.) was administered on the third day of coasting. Transvaginal ultrasound-guided oocyte retrieval was performed 35–36 h after HCG administration. Prophylactic antibiotics (Metronidazole 1 g and Cefatriaxone, 2 g i.v.) were administered during oocyte retrieval (Egbase et al., 1999c).
Embryology and embryo transfer
Conventional IVF or ICSI was performed according to the cause of infertility and a maximum of three embryos were transferred 2 days after oocyte retrieval. The luteal phase support comprised vaginal progesterone 200 mg three times daily (Cyclogest; Shire, Andover, UK). All patients were seen 5 days after embryo transfer to determine if there was early clinical or ultrasound evidence of OHSS. OHSS was classified as mild, moderate or severe according to criteria described previously (Schenker and Weinstein, 1978; Navot et al., 1992). Clinical pregnancy was diagnosed by transvaginal ultrasound if a regular gestation sac with embryonic heart activity was seen 4–5 weeks after embryo transfer.
Serum E2measurements
Serum E2 was assayed using a commercial kit (Boehringer Mannheim Immunodiagnostics, Mannheim, Germany), the dynamic range of which was 16–1800 pg/ml. Serum E2 concentrations above this range were measured in dilution. The within- and between-assay coefficients of variation were 4.5 and 5.8% respectively.
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Results |
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The treatment characteristics, embryology events and clinical outcome are summarized in Table I
. Seventy-eight patients had ICSI for male factor infertility while 24 had IVF for tubal factors. The mean (± SD) duration of ovarian stimulation was 10.8 ± 1.9 days and total dosage of hpFSH (75 IU/ampoule) was 23.2 ± 7.1 ampoules. The oocyte retrieval rate per follicle punctured was 65.5% and the fertilization and cleavage rates were 73.9 and 87.7%. The mean (± SD) serum E2 level on coasting day 1 was 1943.7 ± 693.4 pg/ml, rising to 2526.4 ± 1063.2 pg/ml on day 2 before falling to 2169.2 ± 975.8 pg/ml on the third day when a trigger dose of HCG was administered. All patients in the study had embryo transfer (mean number of embryos per patient being 2.4 ± 0.2) and the clinical pregnancy rate per cycle 45.1% (46/102). Four patients suffered late-onset pregnancy-associated moderate OHSS.
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Discussion |
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Comparative studies of clinical and biological characteristics indicate that among OHSS patients, polycystic ovary (PCO)-like conditions (i.e. hyperandrogenism, anovulation, LH/FSH ratio >2) are more frequent (Delvigne et al., 1993
). Patients with PCOS compared with controls usually have significantly higher serum E2 levels on the day of HCG administration, develop more follicles and produce more oocytes (MacDougall et al., 1993). Thus, it is important to diagnose PCOS before ovarian stimulation is initiated as these patients are more likely to develop severe OHSS (Dale et al., 1991; Buyalos and Lee, 1996). Although the chronic low-dose gonadotrophin protocol compared with conventional regimen has been shown to reduce the incidence of severe OHSS in PCOS patients (Homburg et al., 1995; Balasch et al., 1996; Edwards et al., 1996; ESHRE Capri Workshop, 1997), there seems to be a subset of obese (BMI >30 kg/m2) PCOS patients in our practice that respond to low threshold doses of gonadotrophins in an 'all or nothing' manner, the effect always being excessive when there is an ovarian response (Egbase et al., 1999a). When excessive multiple follicular response is encountered in GnRH agonist down-regulated treatment cycles, none of the strategies currently employed seems to completely avert severe OHSS except cancellation of the treatment cycle. We have confirmed in prospective randomized, controlled trials that follicular aspiration either before or after HCG administration does not prevent severe OHSS (Egbase et al., 1997; 1999a). Numerous studies have also demonstrated the apparent ineffectiveness of human albumin administered around the time of oocyte retrieval to prevent severe OHSS in all cases (Chen et al., 1997; Ndukwe et al., 1997). Likewise, cryopreservation of all resulting embryos when there is serious risk of severe OHSS at best prevents pregnancy-associated late onset of OHSS but not the early onset of the condition that is precipitated with the trigger HCG dose (Lyons et al., 1994; Queenan et al., 1997). Bilateral or unilateral ovarian diathermy performed prior to gonadotrophin stimulation in the index cycle (Rimington et al., 1997; Egbase et al., 1998b) mutes the ovarian response but probably at the cost of substantial ovarian tissue damage. Although the results from coasting have been encouraging (Sher et al., 1995; Benadiva et al., 1997; Fluker et al., 1999; Waldenstrom et al., 1999; Al-Shawaf et al., 2001), this strategy does not completely prevent severe OHSS (Lee et al., 1998; Tortoriello et al., 1998; Egbase et al., 1999a) if gonadotrophins are withheld in the presence of >10 follicles per ovary and serum E2 >3000 pg/ml. Moreover, excessively high serum E2 levels prolong the duration of coasting typically for more than 3 or 4 days to allow the serum E2 levels to fall below 3000 pg/ml reducing the oocyte retrieval rate per follicle punctured (Egbase et al., 1999a) and also adversely affecting the quality of oocytes and embryos (Tortoriello et al., 1998; Waldenstrom et al., 1999). This study therefore examined the embryology and clinical outcome in obese PCOS patients when gonadotrophins were withheld early at leading follicle of 15 mm in the presence of excessive ovarian follicular response (>10 follicles per ovary) and serum E2 between 1500 and <3000 pg/ml. Gonadotrophins were withheld for a fixed period of 3 days in the light of the possible negative impact of prolonged coasting (Tortoriello et al., 1998; Egbase et al., 1999a; Waldenstrom et al., 1999), and our previous finding that serum E2 levels would rise on days 1 and 2 of coasting before starting to fall by the third day in the majority of patients (Egbase et al., 1998a) was presumably a function of the serum terminal half life of exogenous hpFSH being 43–47 h (Duijkers et al., 1997). There are no previous reports describing embryology events (fertilization and cleavage rates) and clinical pregnancies from oocytes retrieved from follicles amongst a cohort of excessive multiple follicles that have achieved growth in vivo to meet the trigger criteria for HCG administration (follicular size >18 mm) after gonadotrophins have been withheld early in ovarian stimulation. The novelty of this strategy and clinical concerns about the possibility of apoptosis or atresia of the granulosa cells leading to poor outcome, were fully reviewed by the institution ethics committee (Egbase et al., 1999b) and with the patients prior to obtaining informed consent and recruitment into the study. In a limited preliminary study to test the hypothesis in patients with similar criteria but in whom the serum E2 was <1500 pg/ml, the serum E2 level fell consistently (without a rise on the first and second days) and the oocytes retrieved were of poor quality. Thus the lower limit for the serum E2 was set at >1500 pg/ml in this study population. It had been suggested (Cahill et al., 1998) that follicular diameter of 15 mm was probably the critical follicular size prerequisite for LH surge in spontaneous ovulatory cycles. In-vivo follicular maturation after early withdrawal of gonadotrophins yielded oocytes with normal fertilization and cleavage rates of 73.9 and 87.5% consistent with normal embryo development when gonadotrophins are administered until the leading follicular size is >18 mm as is practised in routine ovarian stimulation for IVF and ICSI–embryo transfer. The mean serum E2 level on the first day of coasting (coasting day 1) was 1943.7 pg/ml. This contrasts with the excessively high serum E2 level (>3000 pg/ml) used to start coasting in the previously published data (Sher et al., 1995; Benadiva et al., 1997; Tortoriello et al., 1998; Lee et al., 1998; Egbase et al., 1999a; Fluker et al., 1999; Waldenstrom et al., 1999). The mean serum E2 level rose to 2526.4 pg/ml on coasting day 2 before falling to 2169.2 pg/ml on the third day in all but seven patients in whom the serum E2 levels rose consistently during the 3 days of coasting. In all of these seven patients, however, the E2 levels were <3000 pg/ml on the third day of coasting. Ultrasound performed daily during the period of coasting revealed continued follicular growth despite withholding gonadotrophins and the leading follicle was 
18 mm by the third day of coasting. Despite withholding gonadotrophins, follicles that reached a critical size within the cohort of excessive multiple follicles in these obese PCOS patients continued to grow with the leading follicle 18 mm on the third day of coasting, thus allowing the administration of the trigger dose of HCG. The oocytes retrieved had normal fertilization and cleavage rates yielding embryos that resulted in acceptable clinical pregnancy rate (45.1%) consistent with good outcome in routine IVF/ICSI–ET treatment. Although PCOS has been reported to adversely affect the quality and fertilization rates of oocytes (Aboulghar et al., 1997), the presence of this confounding variable did not adversely affect the fertilization and cleavage rates in the study group even when gonadotrophins were withheld early. Serum progesterone was not measured as it has not been shown to have any apparent relevance to the incidence of severe OHSS or clinical outcome when gonadotrophins are withheld whilst continuing GnRH agonist pituitary down-regulation (Benadiva et al., 1997; Egbase et al., 1998a, 1999a). The treatment cycles progressed to embryo transfer in all the patients and there were no cases of severe OHSS. Four patients (all had had severe OHSS in previous ovarian stimulation treatment cycles) suffered late-onset moderate OHSS associated with singleton pregnancy (two patients) and twin pregnancy (two patients). None of these patients needed admission to the intensive care unit or drainage of ascitic fluid. Withholding gonadotrophins at serum E2 levels >3000 pg/ml to prevent severe OHSS may be too late as the physiological mediators of OHSS [probably vascular endothelial growth factor (Agrawal et al., 1999a)] would have been induced already and this possibly may be the explanation for the many cases of severe OHSS that have been reported even after the serum E2 levels were allowed to fall <3000 pg/ml (Lee et al., 1998; Tortoriello et al., 1998; Egbase, 1999). In-vitro oocyte maturation with or without limited gonadotrophin ovarian stimulation in PCOS patients is another strategy currently being explored for the prevention of severe OHSS (Kodama et al., 1996; Chian et al., 1999; Jaroudi et al., 1999). The strategy of withholding gonadotrophins early is akin to the practice of limited gonadotrophin ovarian stimulation.
The results of our large pilot study have encouraged us to start a prospective randomized trial to compare the embryology and clinical outcome in in-vitro oocyte maturation and in-vivo follicular maturation after limited ovarian stimulation in obese PCOS patients. In addition, the apparent benefits in the prevention of severe OHSS when gonadotropins are withheld early at leading follicle of 15 mm and serum E2 levels >1500 rather than >3000 pg/ml with the leading follicle 18 mm would need to be validated in prospective, randomized controlled trials in patients matched with similar high risk factors for severe OHSS.
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3 To whom correspondence should be addressed. E-mail: n.m.rosen{at}qmul.ac.uk
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References |
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Submitted on December 21, 2000; resubmitted on July 20, 2001; accepted on December 12, 2001.
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