1 St Bartholomew's and The London NHS Trust, Reproductive Medicine Centre, 2nd Floor KGV Block, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE and 2 Department of Obstetrics and Gynaecology, St Bartholomew's and The Royal London School of Medicine and Dentistry, St Bartholomew's Hospital, London, UK
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Abstract |
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Key words: assisted reproduction/coasting/OHSS/serum estradiol/serum FSH
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Introduction |
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Some authors (Lee et al., 1998; Egbase et al., 1999a
,b
,2000
) have questioned the value of the coasting strategy to prevent severe OHSS mainly on the grounds of the variability of serum E2 levels used by different groups to initiate coasting and/or the E2 levels deemed to be `safe' for HCG `trigger' administration. Furthermore, there is concern about the consequences observed with the coasting strategy. A sharp drop in serum E2 levels is associated with a reduction in the number of oocytes and may lower the pregnancy rate (Benadiva et al., 1997
; Fulker et al., 1999; Al-Shawaf et al., 2001
). Moreover, if daily serum E2 measurements are not available further difficulties may arise (Egbase et al., 2000
).
Measuring serum FSH along with E2 and ultrasound has been suggested as particularly helpful in monitoring ovarian stimulation in high and low responders (Ben Rafael et al., 1995). In our IVF ± intracytoplasmic sperm injection (ICSI) programme, serum FSH was measured concurrently with serum E2 levels in patients at risk of developing severe OHSS. We prospectively studied the correlation between serum FSH and E2 levels in coasted patients at risk of developing severe OHSS to ascertain if FSH measurement could be of additional value to predict the optimal serum E2 level `safe' for administration of HCG.
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Materials and methods |
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Women undergoing IVF ± ICSI in our programme are monitored for risk of severe OHSS according to criteria published earlier (Al-Shawaf et al., 2001). In brief, during ultrasound monitoring serum E2 is measured in women with
20 follicles (>5 mm in mean diameter). If the leading follicles are
13 mm in mean diameter and serum E2 is between 3000 and 13 200 pmol/l the gonadotrophin dose is halved. If the serum E2 is >13 200 pmol/l, gonadotrophin injections are withheld provided the leading follicles are >15 mm in mean diameter. HCG is administered only if three or more follicles are
18 mm and serum E2 levels are <13 200 pmol/l (or <10 000 pmol/l in coasted patients). GnRH agonist was continued until the day of the HCG trigger injection. Serum FSH was measured whenever an E2 measurement was undertaken. In this study, only cycles in which at least two or more serum E2 and FSH measurements were analysed, were included. The decision when to administer the HCG was not influenced by knowledge of the FSH level.
Routine IVF ± ICSI laboratory procedures were used. A maximum of three embryos was transferred, patients having been advised to have only two embryos transferred. Vaginal progesterone pessaries were prescribed for luteal support. A urinary pregnancy test was performed 2 weeks following the embryo transfer, pregnant women being asked to have a transvaginal ultrasound scan 23 weeks later. A clinical pregnancy was defined by the presence of an intrauterine gestational sac with a fetal pole and a positive fetal heart beat. Patients were encouraged to contact the centre if they experienced symptoms of OHSS or required hospitalization elsewhere. The severity of OHSS was determined according to Navot's classification (Navot et al., 1992).
The serum E2 measurements were performed by a Bayer immuno-1 automated analyser (Bayer, Newbury, Bucks, UK) with a <5% coefficient of variation in the range 7513 200 pmol/l. The serum FSH was analysed using the same automated analyser and with a <5% coefficient of variation and inter- and intra-coefficient of variation of 1%.
Statistical analysis
Mean and standard deviation (SD) were used for presenting parametric data. Medians were used when it was considered that the data was not uniform. Since serum E2 was measured up to 13 200 pmol/l, the median value was used in the analysis. Linear regression analysis was used to demonstrate the correlation between serum FSH and E2.
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Results |
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Three patients were abandoned (Table III). One was for administrative reasons. The other two cases which were abandoned were due to a marked drop in the serum E2. In both cases, coasting was for 5 and 7 days respectively. The serum E2 level on days 2 and 3 before the final result was >13 200 pmol/l, the FSH levels were 4.5 IU/l and 7.4 IU/l. In both these cases, the serum E2 levels were 605 pmol/l and 705 pmol/l and the FSH was 2.7 IU/l and 2.6 IU/l on the day the decision to abandon was made. In a further three cycles, all embryos were frozen. One woman was an ovum donor. The second woman had symptoms of moderate OHSS on the day of embryo transfer. In this case, coasting was for 2 days but the serum E2 level on the day before HCG was >13 200 pmol/l and the FSH was 4.7 IU/l. No further increase in symptoms was noted and the patient was managed on an outpatient basis. She did not conceive following transfer of cryopreservedthawed embryos. In the third case, no embryo replacement was performed because the patient had developed severe OHSS in a previous cycle and was concerned that she may suffer severe OHSS again. This patient was asymptomatic at this time. The case of severe OHSS developed in a patient with twin pregnancy following the transfer of three embryos at the patient's request despite advice to transfer two embryos. The serum E2 and FSH 1 day before HCG were >13 200 pmol/l and 5.2 IU/l. She was admitted 10 days post-embryo transfer with symptoms of moderate/severe OHSS and remained hospitalized for 2 weeks. Symptoms resolved on medical management but she miscarried at 7 weeks.
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Discussion |
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FSH is the most important regulator of follicular development (Ben Raphael et al., 1995). The effect of FSH at the follicular level is dependent on plasma concentration. This is influenced not only by the dose administered but also by the endogenous FSH secretion, metabolic clearance rate and volume distribution. Follicular sensitivity (threshold) to FSH is another factor that can influence ovarian response. These individual factors vary from woman to woman. The ovary probably responds in spontaneous cycles and gonadotrophin therapy cycles to a certain gonadotrophin threshold level (Brown, 1978; Van Weissenbruch et al., 1993
). Reducing the initial gonadotrophin dose in high responders reduces the serum FSH significantly, without significantly affecting the serum E2 levels or the number of follicles (Benadiva et al., 1988
).
Our results with the coasting strategy in patients at risk of developing severe OHSS show that the trend for the serum FSH is a steady and gradual decline once gonadotrophins are withheld. Serum E2 levels remained elevated to levels >13 200 pmol/l until the serum FSH fell below 5.0 IU/l. The following day, if coasting continues, the serum E2 will decline to the `safe' value of <10 000 pmol/l, permitting HCG to be administered. The percentage decline in serum FSH of about 25% per day overall can further assist in determining the probable day of administering the HCG. This strategy does not ensure oocyte retrieval in all cases, as in the one case described here. As we were unable to obtain daily E2 measurements over the weekend and the FSH level approached 5 IU/l, as the serum E2 level sharply dropped, we decided to abandon two cycles. If the FSH rate of decline (25 % per day) was applied in these cases a prediction for the HCG day could have been made.
The disappearance rate of FSH from the circulation in women who are post-menopausal or have had hypophysectomy has two components (Yen et al., 1970), an initial fast component and a slower component. There is a similar clearance rate noted after i.v. gonadotrophin administration, but it is different after i.m. administration (Diczfalusy et al., 1988). In the latter situation, a rise was first noted, probably reflecting a depot effect at the injection site. This was followed by a decline that was almost four-fold longer than that seen after the i.v. route, taking 45 days for the FSH level to return to pre-treatment levels. The gonadotrophins were administered subcutaneously in this study. A 25% decline per day was noticed, corresponding to the decline in absorption and increased clearance of FSH. A limitation in our study is the use of different gonadotrophins for stimulation. The FSH level was found to be higher after the administration of highly-purified urinary FSH than after recombinant FSH, reflecting differences in immunoreactivity, but no significant difference was evident in bioactivity (le Cotonnec et al., 1994
; Matikainen et al., 1994
).
Benadiva reported that the serum FSH declined significantly during the coasting period but the level remained adequate to sustain follicular development (Benadiva et al., 1997). Their study differed from ours in that the coasting period was short (1.9 ± 0.9 days) and they had access to measuring serum E2 levels at high dilution. This is another limitation of our study as exact E2 levels were not available at levels >13 200 pmol/l. It is arguable that measuring only serum E2 can eliminate the need to measure serum FSH, but this requires daily measurement, making the programme more stressful for couples and costly and inconvenient with travelling and time off work. Furthermore, clinics have to provide weekend assessment, adding further to the cost. The daily trend in serum E2 decline in 15 patients during coasting was estimated to be 40%, and the rates of serum E2 fall was not predictive of the development of moderate or severe OHSS (Egbase et al., 2000
). The coasting strategy in that study differed from ours in that coasting started when the E2 was >20 000 pmol/l and leading follicle mean diameter was 18 mm, a late onset coasting strategy that is perhaps not as effective in reducing OHSS. It is arguable that measuring both E2 and FSH may provide a more sensitive method of determining when to decrease/withhold the gonadotrophin injection in those at risk of severe OHSS.
In this study, patients received their gonadotrophin injections subcutaneously. We did not examine the time between the gonadotrophin administration and that of the blood test and the gonadotrophin injection time was not standard between patients. This would not have an effect on the FSH levels. After 4 days of subcutaneous or i.m. administration, the serum FSH level will reach a steady state between patients (Shoham et al., 1993; le Cotonnec et al., 1994
; Matikainen et al., 1994
) but the ovarian response and sensitivity present a large inter-patient variability (Ben-Raphael et al., 1986; Porchet et al., 1994
). In high responders, levels of up to 5 IU/l of FSH with high E2 levels have been noticed but despite changes in doses of gonadotrophins, the serum E2 pattern and number of follicles did not vary (Benadiva et al., 1988
). This explains why high responders always require careful assessment despite reducing the gonadotrophin dose. The FSH threshold of the granulosa cells is probably similar in normally cycling women, but it may differ in situations such as PCOS, pre-treatment with GnRH agonist, BMI and perimenopause (Chong et al., 1986
; Van Weissenbruch et al., 1990). This explains why the FSH threshold between patients is so variable, possibly due to varying threshold sensitivity levels and BMI (Chong et al., 1986
).
In conclusion, we found that measuring serum FSH and E2 is useful in monitoring those at risk of severe OHSS. A decline in serum FSH to 5 IU/l can help to predict the decline in serum E2 to a `safe' level of <10000pmol/l within 24 h. This threshold value, together with a 25% daily decline of FSH levels, can be combined to predict the safe timing of HCG trigger. This will limit the number of visits and also limit the number of cancellations due to a sudden drop in serum E2 levels.
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Notes |
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References |
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Submitted on August 7, 2001; resubmitted on November 7, 2001; accepted on January 16, 2002.