Value of measuring serum FSH in addition to serum estradiol in a coasting programme to prevent severe OHSS

T. Al-Shawaf1,3, A. Zosmer1, A. Tozer1, C. Gillott1, A.M. Lower1 and J.G. Grudzinskas1,2

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


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Withholding gonadotrophins (coasting) can reduce the risk of severe ovarian hyperstimulation syndrome (OHSS) in patients having assisted reproduction therapy. This requires daily serum estradiol (E2) measurements, which occasionally have been seen to decline suddenly and sharply. METHODS: To increase the sensitivity of the coasting programme we measured serum FSH in parallel with E2 in patients at risk of developing OHSS. RESULTS: Out of a total of 1240 cycles, 106 were coasted and in 89 both serum E2 and FSH were measured at least twice during the coasting period. One case of late severe OHSS was encountered in the study group. The serum FSH declined by a rate of 24.3 ± 4.5% per day. Serum E2 level reached a `safe level' of <10 000 pmol/l when the serum FSH declined to 5 IU/l or less. CONCLUSION: The results from this study show that measuring serum E2 and FSH can assist in predicting the point at which serum E2 has declined to a level safe enough to administer the trigger HCG.

Key words: assisted reproduction/coasting/OHSS/serum estradiol/serum FSH


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Withholding gonadotrophin (coasting) in women undergoing assisted reproduction therapy who are at risk of developing severe ovarian hyperstimulation syndrome (OHSS) is effective in reducing the incidence of severe OHSS without compromising pregnancy rates (Ben-Nun et al., 1993Go; Sher et al., 1995Go; Benadiva et al., 1997Go; Fluker et al., 1999Go; Waldenström et al., 1999Go; Al-Shawaf et al., 2001Go). The coasting strategy reduces or entirely avoids the need to abandon the cycle or cryopreserve all embryos, which are the two methods typically used in this situation. The coasting strategy, whilst continuing to offer the chance of a pregnancy in the index cycle, reduces the cost of therapy and the distress that may be associated with abandoning a cycle and with the unknown outcome of the `freeze all embryos' strategy. By using ultrasound monitoring only, patients at risk of OHSS can be selected for serum estradiol (E2) measurements (Al-Shawaf et al., 2001Go) further reducing both the inconvenience to patients and costs.

Some authors (Lee et al., 1998Go; Egbase et al., 1999aGo,bGo,2000Go) 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., 1997Go; Fulker et al., 1999; Al-Shawaf et al., 2001Go). Moreover, if daily serum E2 measurements are not available further difficulties may arise (Egbase et al., 2000Go).

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., 1995Go). 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.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
This was a prospective observational study. The IVF ± ICSI stimulation was managed as previously reported (Al-Shawaf et al., 2001Go). In brief, the patients underwent long down-regulation with a gonadotrophin releasing hormone (GnRH) agonist, followed by gonadotrophin stimulation with the dose selected on the basis of age, previous response, early follicular phase serum FSH levels and body mass index (BMI). Gonadotrophins were administered subcutaneously and the gonadotrophin used was urinary or recombinant dependent upon the availability and cost. Follicular monitoring was performed by transvaginal ultrasound, normally starting on day 9 of gonadotrophin stimulation but in some selected cases, when a high follicular response was anticipated (polycystic ovarian syndrome, previous high response), it started on day 7 of stimulation.

Women undergoing IVF ± ICSI in our programme are monitored for risk of severe OHSS according to criteria published earlier (Al-Shawaf et al., 2001Go). 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 2–3 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., 1992Go).

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 75–13 200 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.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Between March 1998 and December 1999 a total of 1240 cycles of IVF ± ICSI was carried out, 106 cycles of which were coasted. The study group consisted of 89 coasted cycles (89 patients) in which at least two concomitant measurements of the serum E2 and FSH were available. The remaining 17 coasted patients had only one or non-sequential serum FSH measurements, hence they were not included in the study. The demographic characteristics of the patients in the study group are detailed in Table IGo. A total of 22 cycles (24.7%) were in patients with polycystic ovarian syndrome (PCOS) as a primary or secondary aetiology, the largest single aetiological group being male factor infertility and 33.7% needing ICSI (33.7%).


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Table I. Characteristics of the study group (n = 89)
 
Cycle characteristics are summarized in Table IIGo. A total of 61 (68.5%) cycles were coasted without a prior period of decreasing the dose of gonadotrophins. In 28 (31%) cycles, the gonadotrophin dose was halved before coasting started. The mean duration of gonadotrophin stimulation was 10.5 ± 1.9 days. The mean number of oocytes collected was 13.1 ± 6.3.The number of metaphase II (MII) oocytes in the ICSI patients was 259 out of a total of 335 (77.5%). The number of MII oocytes in the IVF patients was unknown, as oocytes were not stripped. The fertilization rate for the injected oocytes was 52.5%. The mean cycle day coasting commenced was 11.6 ± 2.2 days. The mean number of days the patients were coasted was 3.6 ± 1.5 days (range 2–9). In eight (9%) cycles coasting was continued for more than 5 days. Table IIIGo describes the treatment outcome. There were two patients with early-onset moderate and one with late onset severe OHSS. The pregnancy rate and the live birth rate were comparable with the overall rates in our centre during the period of study.


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Table II. Cycle characteristics in 89 women who underwent coasting
 

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Table III. Treatment outcome in 89 women who underwent coasting
 
The median levels for serum E2 were used for analysis because quantitative levels of serum E2 above 13 200 pmol/l were not available. Figure 1Go shows the median values of serum FSH and E2 in relation to the number of days prior to HCG administration. The FSH curve shows that with E2 levels >13 200 and coasting implemented, the FSH declined gradually. Median E2 levels declined to <10 000 pmol/l (defined in our protocol as safe for HCG administration) the day after the median FSH level was 5.0 IU/l. Figure 2Go shows the decline of the serum FSH for each patient studied. The mean rate of decline was noted to be 24.3 ± 4.5% per day (Figures 1 and 2GoGo). There was a correlation coefficient of –0.29; P < 0.001, between the serum E2 and the serum FSH levels (Figure 3Go).



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Figure 1. Changes in median serum estradiol (E2) and FSH from day of coasting.

 


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Figure 2. The rate of decline in serum FSH levels in relation to commencement of coasting.

 


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Figure 3. Correlation between the level of E2 and the level of FSH on the day of HCG administration.

 
There was one case (1.1%) from whom no oocytes were retrieved. This patient was coasted for 2 days. The serum FSH on the day before HCG was administered was 3.5 IU/l and the E2 was 7743 pmol/l. Another patient had one oocyte retrieved, which failed to fertilize. In this case, the dose of gonadotrophin was halved for 2 days then withheld for 3 days, the serum E2 level, one day before the HCG, was 4144 pmol/l and the FSH was 6.1 IU/l. Another patient had two oocytes retrieved of which one fertilized and was transferred. She conceived and delivered at term. The serum E2 on HCG day was 1742 pmol/l and the FSH was 3.4 IU/l and her gonadotrophin dose had been decreased for 2 days and was followed by coasting for 3 days. Serum E2 on the day coasting started was >13 200 pmol/l and her FSH was 9.3 IU/l.

Three patients were abandoned (Table IIIGo). 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 cryopreserved–thawed 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.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The risk of severe OHSS in patients undergoing IVF who develop a large number of follicles during controlled ovarian stimulation has been estimated at 30–80% (Blankstein et al., 1987Go; Asch et al., 1991Go; Enskog et al., 1999Go). Furthermore, in coasted patients with a large number of follicles, albeit using a different serum E2 criteria from ours for when to coast, 40% developed severe OHSS (Egbase et al., 2000Go). Our modified coasting strategy (Al-Shawaf et al., 2001Go), based on ultrasound to identify patients at risk, reduced the risk of severe OHSS to 1% in these high risk patients without reducing pregnancy rate or resorting to freezing all embryos. Although the majority of patients progressed to oocyte retrieval, a few had to be abandoned because of a sharp fall in serum E2 levels, whilst in others a steep decline in E2 levels was accompanied by a markedly reduced number of oocytes retrieved (Benadiva et al., 1997Go; Fulker et al., 1999; Al-Shawaf et al., 2001Go). In this observational prospective study we investigated the possible benefit of FSH measurement concomitant with E2 level to optimize the timing of the HCG trigger injection.

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, 1978Go; Van Weissenbruch et al., 1993Go). 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., 1988Go).

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., 1970Go), 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 4–5 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., 1994Go; Matikainen et al., 1994Go).

Benadiva reported that the serum FSH declined significantly during the coasting period but the level remained adequate to sustain follicular development (Benadiva et al., 1997Go). 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., 2000Go). 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., 1993Go; le Cotonnec et al., 1994Go; Matikainen et al., 1994Go) but the ovarian response and sensitivity present a large inter-patient variability (Ben-Raphael et al., 1986; Porchet et al., 1994Go). 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., 1988Go). 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., 1986Go; 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., 1986Go).

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.


    Notes
 
3 To whom correspondence should be addressed. E-mail: talhayas{at}aol.com Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on August 7, 2001; resubmitted on November 7, 2001; accepted on January 16, 2002.