Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Vrije Universiteit Medical Centre (VUMC), Amsterdam, The Netherlands
1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, VUMC, P.O.Box 7075, 1007 MB Amsterdam, The Netherlands. Email: cb.lambalk{at}vumc.nl
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Abstract |
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Key words: GnRH antagonist/IVF/implantation/LH/progesterone
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Introduction |
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The role of LH on implantation is still not fully elucidated. It has been established that severe suppression of LH using GnRH agonists is associated with impaired IVF outcome (Fleming et al., 1998; Howles, 2000
; Balasch et al., 2001
; Filicori, 2002
) and increased pregnancy loss (Westergaard et al., 2000
). A certain LH threshold needs to be achieved for adequate folliculogenesis and steroidogenesis, which is required to provide an appropriate milieu for successful fertilization and implantation (Hillier, 1994
; European Recombinant human LH Study Group, 1998
; Howles, 2000
; Filicori, 2002
; Shoham, 2002
). On the other hand, there are convincing data suggesting that elevated LH levels are associated with impaired fertilization and pregnancy rates and with higher miscarriage rates (Stanger and Yovich, 1985
; Howles et al., 1986
; Homburg et al., 1988
; Regan et al., 1990
; Chappel and Howles, 1991
; Shoham, 2002
; Tesarik and Mendoza, 2002
; Loumaye et al., 2003
), the so called ceiling effect (Hillier, 1994
). The optimal LH levels to provide an endocrine milieu which results in the highest number of clinical pregnancies in patients undergoing IVF, in protocols with FSH stimulation, are still a matter of debate and have rarely been studied in GnRH antagonist-treated cycles. One recent study demonstrated that exposure to high LH levels in the early follicular phase of GnRH antagonist-treated cycles is associated with a reduced chance of pregnancy (Kolibianakis et al., 2003a
). An additional randomized controlled trial in which 257 women were randomized to receive either 150 or 200 IU rFSH per day showed a trend towards higher pregnancy rates, despite lower number of oocytes retrieved, in the lower recombinant (r)FSH dose group in which higher LH levels were found (Out et al., 2004
). However, lower early follicular phase LH and estradiol levels after early administration of the GnRH antagonist, stimulation day 1 versus day 6 in 60 patients, did not alter the IVF outcome (Kolibianakis et al., 2003b
).
In a previous study we demonstrated that various endogenous LH levels can be induced by different doses of repeated GnRH antagonist injections in IVF/ICSI patients undergoing ovarian stimulation with rFSH (Huirne et al., 2004). The aim of the present study was to examine the effect of various LH concentrations, induced by different GnRH antagonist doses, on the outcome of IVF.
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Materials and methods |
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Study design
A phase II, single centre study, conducted in two phasesa double-blind phase with two parallel treatment groupswas followed by an open phase. In the double-blind phase, 60 patients were randomized to two different treatment groups (A: 2 mg/2 ml; B: 1 mg/ml). To improve patients' convenience, the 2 mg in group A was given as two injections of 1 mg/ml antide, one injection in the morning and one in the evening, since we expected that one injection with a volume of 2 ml would be too painful. Patients in group B received placebo in the morning and 1 mg/ml antide in the evening. Since none of the two groups turned out to be a failure group (i.e. with two or more LH surges) we decided to add an open phase in which three additional treatment groups with lower antide dosages were studied (0.5 mg/0.5 ml, 0.5 mg/ml, 0.25 mg/ml). The additional arms were added in a consecutive order and patients were enrolled in a chronological fashion. New evidence which became available after the start of this study suggested that the bioavailability of antide increases after dilution in larger volumes of glucose 5% (data on file: Serono International, Geneva). Therefore in two groups (0.5 and 0.25 mg/ml) antide was diluted in larger volumes of glucose 5% solution: 0.5 and 0.25 mg in 1 ml respectively. This means that in two arms, 0.5 mg antide was administered but in group C it was diluted in 1.0 ml glucose 5% solution and in group D it was diluted in 0.5 ml glucose 5% solution.
Each group was intended to contain 30 patients unless more than one LH surge occurred, which according to the protocol led to the discontinuation of that particular dose group and was considered to be a failure dose. More than one LH surge per 30 patients was considered to be unacceptable for clinical use in IVF patients. Additional observations were performed, to search for optimal GnRH antagonist and/or LH levels. We made scatter plots to see whether an optimal range could be found for clinical pregnancy.
Masking
Treatment packs for the double-blind phase of the study were prepared according to the randomization list by Serono International (Geneva, Switzerland). Patient packs, containing antide/placebo or antide/antide vials, were labelled with unique study identification numbers, provided by Serono International (Geneva, Switzerland), placebo vials contained a sterile isotonic aqueous solution. When eligible, patients were enrolled into the study by one of the two responsible trained researchers and received a unique study number in a chronological order at the start of the first stimulation day. The code was not known to the executors of the study. Assignment to group A or B was therefore double-blind, assignment to group C, D or E depending on the chronological entry of the study.
Treatment protocol
On day 2 or 3 of a spontaneous menstruation, rFSH (Gonal-F®; Serono, Switzerland) was given as a single daily s.c. injection. The starting dose varied between 150 and 300 IU, depending on previous ovarian response, but was fixed for the first 5 days. After this period, depending on ovarian response as assessed by daily ultrasound, the rFSH dose could be adjusted. All antide, placebo and rFSH injections from stimulation day 6 (S6) onwards were given subcutaneously, by a trained research professional. From stimulation day 6 onward, up to and including the day of rhCG (rhCG; Ovitrelle®; Serono) administration, daily antide was started. rhCG was administered as soon as one follicle was 18 mm and three follicles were
16 mm. Thirty-six hours after rhCG administration, oocyte retrieval was performed transvaginally and ultrasound-guided. The oocyte retrieval was followed by IVF with or without ICSI; a maximum of three embryos was replaced 23 days thereafter. Luteal support (200 mg progesterone vaginally, three times daily) was started 1 day after oocyte retrieval until the third week of pregnancy or a negative pregnancy test.
Assessments
One to three months before randomization, serum samples were taken to assess hormone levels (FSH, LH, estradiol, progesterone and prolactin), taken on cycle day 2 or 3. On stimulation day 1 (S1), before any study drug was administered, a blood sample was taken to perform a pregnancy test and to assess FSH, LH, estradiol (E2) and progesterone levels and a transvaginal ultrasound was performed to measure follicular activity, endometrium thickness and to exclude the presence of cysts. During antide administration, three samples per day were taken (in the morning before any injection, in the evening prior to Gonal-F or antide injection, and 2084 min later), to assess serum levels (FSH, LH, E2, progesterone and antide). The potential variation in timing of the evening post-injection blood sampling was intended to allow pharmacokinetic and pharmcodynamic modelling (data not shown). The mean sample time was 34.6 (SD 3.9) min after antide injection (range of the mean per patient varied from 30 to 53 min). Transvaginal ultrasound was performed daily to assess follicular development and endometrium thickness. On the day of embryo transfer, serum samples were taken to measure the antide level, and 711 days after oocyte retrieval to measure the levels of progesterone and antide. Finally, 2325 days after oocyte retrieval, serum hCG levels were measured. If positive, a vaginal ultrasound was performed 35 and 42 days following rhCG administration, to record the number of fetal sacs and fetal heart activity. Ultrasound was repeated at a gestational age of 12 weeks.
Serum assessment
Blood samples were processed to serum immediately after collection and stored at 20°C. Routine haematology, biochemistry and urine assessment were performed by the local laboratory (The Central Laboratory of the VUMC) using commercially available immunometric assays. LH and FSH levels before inclusion, in morning samples, were assessed by the local laboratory using immunometric assay kits (Amerlite; Amersham, UK). Patients were excluded for high LH and FSH values on cycle day 3, respectively >8 and >10 IU/l, using immunometric assay kits (Amerlite). Half-way through the study we were forced to change the assay, since Amerlite assays were no longer available. We decided to use Delphia (Finland) assays. During the transition period of the assays, we assessed LH levels using both assays in 89 patients. Excellent correlation was observed between the two assays for the measurement of LH (r=0.981) and FSH (r=0.996) A regression analysis revealed that the coefficient of LH was 1.24 using Delphia compared with Amerlite, thus the LH threshold level of 8 IU/l assessed by Amerlite was equivalent to 9.9 IU/l if assessed by Delphia assay. In addition, the coefficient of FSH was 1.28, thus the FSH threshold level of 10 IU/l assessed by Amerlite was equivalent to 12.8 IU/l if assessed by Delphia assay.
For definitive analyses of all hormone and antide levels, as presented in this report, all serum samples (taken three times daily) were assessed retrospectively by LCG Bioscience Services Ltd. E2 was measured using Sorin Radioimmunoassay, progesterone using DPC Coat-a-Count radioimmunoassay solid phase coated tube separation, FSH and LH using Serono MAIAclone IRMA. The lower limit of quantification for LH was 1 IU/l. For the retrospective analyses, we defined an LH surge as LH > 12.4 IU/l and progesterone >2 ng/ml in one or more samples, taking all samples (three times daily) into account from S6 until hCG administration day, equivalent to the threshold levels using the Delphia assays. The retrospective centralized analysis of serum antide levels was performed by Woods Assay (radioimmunoassay); all samples were analysed in triplicate; 1 mg/l was the limit of quantification.
Outcome measures
Drug requirements, stimulation results, IVF outcome and its relationship to serum hormone and antide levels.
Statistical analyses
Treatment groups were compared depending on the nature of the variables, i.e. analysis of variance (ANOVA) or analysis of covariance (ANCOVA), 2-test, Fisher's exact test or non-parametric ranking methods such as KruskalWallis and MannWhitney U-tests. Results are reported as mean ± SD. Correlations were calculated according to Pearson's correlation coefficient. P<0.05 was considered to be statistically significant. Analyses were performed on all subjects who were randomized or received Gonal-F (all patients who were included in the study) unless otherwise reported. The number of patients included in A, B, C, D and E were 30, 30, 31, 23 and 30 respectively. An overall doseresponse test for linear trend with the treatment groups was performed on all efficacy data. For continuous normally distributed data, a linear contrast of the treatment groups was tested in a one-way ANOVA; for ordinal (ordered categorical) data, a JonckheereTerpstra test and for binary data a CochranArmitage test were used.
This pilot study was not powered to calculate pregnancy rates, but group size was based on clinically relevant arguments. More than one LH surge per 30 patients was considered to be unacceptable for clinical use in IVF patients. Therfore the number of patients was intended to be 30 per group unless more than one LH surge occurred. This study employs patients included in a previous dose-finding study in which IVF outcome and hormones were examined (Huirne et al., 2004).
Total exposure to antide and hormone levels was expressed as area under the curves (AUC) during antagonist administration [i.e. from stimulation day 6 (S6) to hCG administration day]. For this calculation, the sum of the mean daily levels (= sum of three samples per day/3) of all days during antide treatment was taken. To calculate the induced change in serum levels in comparison to the basal level on S6 (the time-point at which the antagonist was started), AUC was calculated after subtraction of the basal level on S6 of all samples, defined as AUCS6 (see Figure 1).
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Results |
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Discussion |
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In previous studies it was demonstrated that different endogenous LH levels can be induced by different GnRH antagonist dosages (Duijkers et al., 1998; Ganirelix dose-finding Study Group, 1998
; Oberye et al., 1999
; Huirne et al., 2004
). Thus, different GnRH antagonist dosages can be used as an instrument to induce deliberately different LH levels. To test our hypothesis that the induced differences in LH levels may be responsible for the observed optimal GnRH antagonist range rather than the antagonist level itself, we analysed in detail the relationship between LH levels, LH AUC levels and pregnancy rates. In line with the LH window postulated by others (Hillier, 1994
; Shoham, 2002
), we found an optimal area in LH AUC for the occurrence of a clinical pregnancy. No pregnancies were observed when the total LH AUC (calculated out of three samples taken per day) was >22.3 or <4.47 IU/l. The absolute LH levels taken on a single sample day, either day 7, 8 or hCG day, did not show any clear relationship with pregnancy rate. These findings are in line with an earlier report (Balasch et al., 2001
). Apparently, the parameter LH AUC associates more strongly with pregnancy rates than the absolute LH level taken in one single sample. Possibly, the AUC during the entire antagonist treatment period is a better representative of LH exposure. The association between LH AUC levels and pregnancy rates became clearer when the changes in LH levels (expressed as LH AUC, adjusted for the baseline LH levels) were taken into account. Apparently, too large changeseither increases or decreases in LH levels during the antagonist administration periodrather than absolute AUC levels, are associated with a decreased chance of clinical pregnancy. These findings were independent of baseline characteristics and other parameters of IVF outcome (see Table III). The occurrence of a pregnancy is effected by many factors and variables other than LH and progesterone. The only significant covariant to clinical pregnancy in a univariate analyses was change in LH levels (P=0.006).
Thus changes in the endocrine milieu seem to be important for the IVF outcome in terms of clinical pregnancy. Figure 6 gives our interpretation of these results. The physiological basis for the association of the increased change in LH levels and lower pregnancy rates is not clear. It may interfere with the correct sequence of maturational changes and right synchronization between nuclear and cytoplasmic maturation (Mattioli and Barboni, 2000; Luborsky et al., 2002
) but it may also cause advanced endometrium maturation (Kolibianakis et al., 2002
, 2003c
).
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LH is required to produce progesterone by luteinizing the granulosa cells and estradiol by producing androstendione as a substrate for estradiol. In a previous study we demonstrated that LH levels in GnRH antagonist cycles were related to progesterone and estradiol (Huirne et al., 2004). In an attempt to obtain information on the individual association of these parameters with clinical pregnancy, we performed scatter plots of these parameters with changes in LH levels and studied the occurrence of clinical pregnancy. Similar to the observed window for changes in LH, changes in progesterone levels also seemed to be closely related to the occurrence of clinical pregnancy. Absolute progesterone levels on hCG day were not correlated with clinical pregnancy. This is consistent with the findings of others (Urman et al., 1999
). However, in an observational study, progesterone levels >1.2 ng/ml on the day of hCG as a parameter of premature luteinization were associated with lower pregnancy and implantation rates (Bosch et al., 2003
).
Absolute progesterone levels are related to the total amount of luteinized granulosa cells, thus total number of follicles may be a confounder for the absolute progesterone levels on the day of hCG. Therefore we corrected the absolute progesterone levels on the day of hCG for the total number of follicles (progesterone/follicle), as a parameter for premature luteinization. This parameter showed a clear ceiling effect for the occurrence of clinical pregnancy. No pregnancy occurred in our study when the progesterone levels/follicle on the day of hCG exceeded a certain threshold (0.26 ng/ml/follicle).
Since LH and progesterone were closely correlated in the current study, we could not discriminate which of the two should be held responsible for the observed differences in pregnancy rates. No association was found for changes in estradiol levels nor for the absolute estradiol levels on the day of hCG administration with or without correction for the total number of mature follicles on that day. Similar results were found in other studies using GnRH antagonists (Ganirelix dose-finding Study Group, 1998). Altogether it seems to be that changes in LH and/or progesterone levels play a specific key role in the occurrence of clinical pregnancy rates in GnRH antagonist-treated IVF patients. Apparently a certain stability of these hormones associates with clinical pregnancy. These findings are in agreement with the observed lower pregnancy rates in the group with higher LH levels, in which hCG was administered 2 days later than a control group in GnRH antagonist-treated patients (Kolibianakis et al., 2003d
). We speculate that our findings may have implications particularly for specific patient groups which are sensitive for high fluctuations in LH levels. For example, in patients with extreme low or high body mass indexes, the minimum effective dose may result in respectively too strong or insufficient suppression of LH levels. In addition, patients with high baseline LH levels (polycystic ovarian syndrome or patients with diminished ovarian reserve) may be more prone to larger changes (decreases) in LH levels. Based on our results, it is expected that depending on the level of LH and progesterone suppression during antagonist suppression, some patients will benefit from adjustment of the GnRH antagonist dose or addition of LH. These findings are in line with a study, using GnRH agonists, demonstrating that addition of LH was beneficial for patients who had a very low endogenous LH level and detrimental for those with high endogenous LH levels (Loumaye et al., 2003
). The possibility of improving pregnancy rates in GnRH antagonist-treated cycles by adaptation of the GnRH antagonist dose or the addition of LH where the LH levels are inappropriate, or using a treatment regimen resulting in stable LH levels, should be studied in a prospective manner.
In conclusion, this is the first study demonstrating that the dynamics of LH and progesterone play a critical role in implantation when GnRH antagonist is used. No pregnancies occurred when the LH and progesterone changed too much (either increase or decrease) during GnRH antagonist administration due to insufficient or too high dosages of the GnRH antagonist. Moreover, a clear ceiling effect of high (absolute) progesterone levels per follicle could be observed. Further studies are required to investigate whether pregnancy rates can be improved by changing the treatment strategies, which result in stable and appropriate LH levels during the IVF cycle.
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Acknowledgements |
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References |
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Submitted on February 5, 2004; resubmitted on July 21, 2004; accepted on October 15, 2004.
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