Alternate day and daily administration of GnRH antagonist may prevent premature luteinization to a similar extent during FSH treatment

I.E. Messinis1,4, D. Loutradis3, E. Domali3, C.P. Kotsovassilis2, L. Papastergiopoulou1, A. Kallitsaris1, P. Drakakis3, K. Dafopoulos1 and S. Milingos3

1 Department of Obstetrics and Gynaecology, University of Thessalia, Larissa, 2 Clinical Chemistry Laboratory, General Hospital ‘G.Gennimatas’, Athens and 3 Department of Obstetrics and Gynaecology, University of Athens, Athens, Greece

4 To whom correspondence should be addressed. E-mail: messinis{at}med.uth.gr


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: This randomized controlled trial was designed to evaluate whether a GnRH antagonist given every other day could prevent premature luteinization in women undergoing IVF/ICSI treatment. METHODS: A total of 73 women receiving ovulation stimulation IVF cycles with recombinant FSH were allocated randomly on cycle day 7 to GnRH antagonist ganirelix in multiple doses (0.25 mg each), either daily (n = 37 women, group 1) or every other day (n = 36 women, group 2) until the day of HCG administration. RESULTS: Serum FSH, LH, estradiol and progesterone values showed similar trends in the two groups. During FSH stimulation, 13 (35%) of the women in group 1 had premature LH rises (≥10 IU/l) of which eight (22%) were after the start of antagonist administration. In group 2 there were 14 (39%) LH rises during FSH stimulation of which 10 (28%) were after the start of antagonist administration. Luteinization (serum progesterone >2 ng/ml) occurred in only one woman in each group overall (3%). A significantly smaller total dose of the antagonist was used in group 2 than in group 1 (P < 0.001). The study did not have power to evaluate differences in total dose of FSH, number of oocytes recovered and clinical pregnancy rate, all of which appeared similar in the two groups. CONCLUSIONS: Whether alternate day is as effective as daily administration of ganirelix in preventing premature luteinization should be addressed in a non-inferiority trial powered to evaluate live birth rate.

Key words: FSH/GnRH antagonist/LH/LH surge/luteinization


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
During the last decade, GnRH antagonists have been introduced into IVF programmes as the substitute for GnRH agonists (Frydman et al., 1991Go; Diedrich et al., 1994Go; Olivennes et al., 1994Go; Albano et al., 2000Go; Borm and Mannaerts, 2000Go; Fluker et al., 2001Go; European and Middle East Orgalutran Study Group, 2001Go). The antagonists act differently from the agonists via competitive binding to GnRH receptors, which results in a prompt decrease in circulating concentrations of pituitary gonadotrophins, particularly LH (Kenigsberg et al., 1984Go). When given during the follicular phase of the natural cycle, GnRH antagonists prevent the endogenous LH surge and interrupt a rise of LH (Fluker et al., 1991Go; Dubourdieu et al., 1994Go; Leroy et al., 1994Go). In IVF programmes, the antagonists are injected during the second half of the follicular phase of FSH-induced cycles either in a single dose of 3 mg or in small daily doses of 0.25 mg each (Diedrich et al., 2002Go). The two protocols seem to give comparable results (Olivennes et al., 1998Go; Albano et al., 2000Go), although a randomized study has not been performed. However, in studies that have compared antagonists with agonists, the pregnancy rate is lower with the antagonists (Albano et al., 2000Go; Borm and Mannaerts, 2000Go; Fluker et al., 2001Go; European and Middle East Orgalutran Study Group, 2001Go; Al-Inany and Aboulghar, 2002Go; Loutradis et al., 2004Go).

Therefore, any protocols that use the least amount of GnRH antagonists would be less costly and, if live birth rates were not affected, could be to patients’ advantage. So far, no study has investigated the effect of less frequent than the daily administration of small doses of a GnRH antagonist on the occurrence of the endogenous LH surge and premature luteinization during ovulation induction with FSH. The present study was undertaken as a preliminary investigation to determine, in women during treatment with FSH in combination with the GnRH antagonist ganirelix, whether LH values were similar with injection daily and every other day.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Patients
Women with primary infertility undergoing IVF treatment volunteered for the study and gave written informed consent. The study was approved by the institutional ethics committee. Inclusion criteria were regular ovulatory cycles as assessed by ultrasound scans of the ovaries and serum progesterone measurements, healthy women with normal body mass index (BMI), good ovarian response as assessed from at least one but no more than four previous IVF/ICSI attempts. Exclusion criteria were polycystic ovary syndrome and/or endocrine or other medical abnormalities requiring medical treatment or not. The women were randomly allocated to group 1 (n = 37 women) or group 2 (n = 36 women) for only one treatment cycle each. The randomization process was conducted with sealed envelopes. Since all patients had previous IVF/ICSI attempts, they were given ≥2 months break before entering the study.

Ovarian stimulation protocol included the s.c. administration of recombinant FSH (Puregon 150 IU/0.5 ml; Organon, Athens, Greece) at the dose of 150 IU per day from cycle days 2 to 5. The dose of FSH was then individually adjusted according to ovarian response. On cycle day 7, i.e. the 6th day of FSH treatment, the GnRH antagonist ganirelix (Orgalutran 0.25 mg/0.5 ml; Organon) was added s.c. at multiple doses of 0.25 mg each (09:00). In group 1, the antagonist was given to the women on a daily basis, one dose every day, and in group 2 on alternate days, one dose every other day, i.e on days 7, 9, 11 etc.

HCG was injected i.m. at a single dose of 10000 IU (Pregnyl ampoules, 5000 IU per ampoule; Organon) when the leading follicle was 18–20 mm with at least three follicles >16 mm in diameter and serum estradiol (E2) concentrations not >3000 pg/ml. Oocyte recovery was performed 35–36 h after the administration of HCG. Embryo transfer was performed 2 days after the oocyte recovery. The luteal phase was supported in all women with micronized progesterone given intravaginally at the dose of 600 mg/day (Utrogestan capsules, 100 mg per capsule; Faran, Athens, Greece).

In both groups, blood samples were obtained from all women (09:00) on cycle day 2 before the onset of FSH treatment and then on days 5 and 7 and every day thereafter until the administration of HCG. Each time the blood samples were obtained before the administration of the antagonist and/or FSH. All blood samples were centrifuged and the serum was stored at –20°C until FSH, LH, E2 and progesterone were assayed.

Hormone assays
Measurement of FSH, LH and E2 was done using a Chemiluminescent Microparticle Immunoassay (Architect FSH, Architect LH and Architect Estradiol respectively; Abbott Laboratories). The results are expressed as IU/l for FSH and LH and as pg/ml for E2. Progesterone was measured in serum using a Microparticle Enzyme Immunoassay (AxSYM Progesterone; Abbott Laboratories, USA). The results are expressed as ng/ml. The lower limits of detection for FSH, LH, E2 and progesterone were 0.05 IU/l, 0.07 IU/l, 17.9 pg/ml and 0.2 ng/ml respectively. Inter- and intra-assay coefficients of variation were 3.1 and 3.4%, 2.0 and 3.4%, 4.5 and 6.0% and 6.0 and 6.7% respectively. The laboratory analysts were blinded to study allocation.

Data analysis
Sample size calculation
The sample size was based on the primary outcome measure, i.e. the frequency of LH values ≥10 IU/l during the whole stimulation period. We hypothesized that with alternate day treatment the frequency of LH values ≥10 IU/l would be ≥50% of that seen with daily treatment. In previous studies LH rises were found in 2.7–28.5% of stimulation cycles with gonadotrophins alone or combined with clomiphene citrate (Albano et al., 2000Go; Borm and Mannaerts, 2000Go; Felberbaum et al., 2000Go; Tavaniotou et al., 2003Go). With power of 80%, to detect reductions of ≤50% in frequencies of 6, 14, 30 and 60% respectively would require 603, 244, 98 and 35 patients in each group, assuming a significance level of 0.05 based on the difference in two proportions. An interim analysis was planned (with {alpha} = 0.001) after 35 patients were recruited in each study arm to evaluate final sample size.

Statistical analysis
Hormone values were logarithmically transformed to attain a normal distribution (one sample Kolmogorov–Smirnov test). However, the arithmetic means with SEM of values are presented. Statistical analysis was performed by c2-test with continuity correction, Student’s t-test and one-way analysis of variance for repeated measurements. The statistical software package used was NCSS 2001 (Number Cruncher Statistical Systems, Kaysville, UT, USA).


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
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Clinical and hormonal characteristics of the women taken before the study was initiated are shown in Table I. There were no significant differences between the two groups in terms of age, body mass index (BMI), number of previous IVF attempts, duration and type of infertility and basal hormone values. All women had normal serum testosterone and prolactin levels. There were no drop-outs or cancellations, therefore the method of data analysis was simultaneously intention to treat and per protocol. In three patients of group 2, embryo transfer was not performed due to failed fertilization in two of them and the risk of ovarian hyperstimulation syndrome (OHSS) in one. In group 1, all women received the last dose of the antagonist on the day of HCG administration, while this occurred only in 14 patients of group 2. The remaining 22 patients of group 2 received the last dose of the antagonist the day before the injection of HCG.


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Table I. Clinical and hormonal characteristics of the women (mean ± SEM)

 

Serum FSH and E2 values increased significantly in both groups from cycle day 2 to day 12 (P < 0.05) with no significant difference between the two groups at any point (Figure 1a). LH values (mean ± SEM) increased significantly on day 7 in both groups (P < 0.05) and further on day 9 in group 2 (6.00 ± 1.04 IU/l) (P < 0.01) and were then significantly higher than in group 1 (P < 0.01, Figure 1a). For the rest of the time, LH concentrations showed fluctuations. Serum progesterone values (mean ± SEM) were low up to cycle day 10 with no difference between group 1 and group 2 (Figure 1a). On cycle day 10 (1.91 ± 0.32 and 1.55 ± 0.20 ng/ml respectively), progesterone values were significantly higher than on days 2 (0.64 ± 0.08 and 0.56 ± 0.05 ng/ml respectively) and 5 (0.80 ± 0.25 and 0.75 ± 0.19 ng/ml respectively). A significant increase in serum progesterone concentrations was seen on days 11 and 12 as compared to day 10 in both groups (P < 0.01). When hormone values were analysed in relation to the day of HCG administration (day 0), the patterns of changes were similar to those described above (Figure 1b). E2 concentrations were significantly higher in group 2 than in group 1 on days –2, –1 and +1 (P < 0.05, Figure 1b).



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Figure 1. Serum FSH, LH, estradiol and progesterone concentrations (mean ± SEM) during the follicular phase of cycles superovulated with recombinant FSH, starting on cycle day 2 plus multiple doses (0.25 mg each) of the GnRH antagonist ganirelix, starting on cycle day 7. The antagonist was given either (d) on a daily basis (group 1, n = 37 women) or (s) on alternate days (group 2, n = 36 women). Values were normalized (a) to cycle day 2 and (b) to the time of HCG administration (day 0). *P < 0.05 and **P < 0.01 (significant differences from group 1). Women with LH rises were included in the calculations.

 

Analysis of LH and progesterone values in individual patients showed a similar trend in the two groups (Figure 2). In the interim analysis of the primary outcome, LH values ≥10 IU/l were seen in 13 patients of group 1 (35.1%) and in 14 patients of group 2 (38.8%) (P = 0.929). To evaluate the difference between 35.1 and 38.8% would require 2148 patients in each group, and the study was terminated at this point. In eight women of group 1 (21.6%) and 10 women of group 2 (27.7%) the LH rises were seen during the treatment with the antagonist. Luteinization, i.e. serum progesterone values >2 ng/ml, occurred before the onset of the antagonist administration in three of the five women of group 1 and in two of the four women of group 2, while during the antagonist treatment it occurred only in one patient of each group (12.5 versus 10.0%) (Table II). Overall, only 2.7% of the women of each group showed luteinization during the administration of ganirelix. When the two groups were combined, the percentage of women with high LH (≥10 IU/l) who showed luteinization during the GnRH antagonist administration (two out of 18 women, 11.1%) was significantly lower than that before the onset of the administration (five out of nine women, 55.5%) (P = 0.044). Peak LH values in patients with luteinization were 13.0, 53.7, 11.8 and 11.9 IU/l in group 1 and 27.7, 21.3 and 14.0 IU/l in group 2. The increase in serum progesterone levels in these patients was maintained at >4 ng/ml until the HCG administration (maximum values 10 ng/ml). None of the seven patients with increased progesterone values became pregnant. However, two women of group 1 and three women of group 2 with LH rises ≥10 IU/l and no progesterone increase became pregnant after embryo transfer.



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Figure 2. Individual serum values of LH in patients superovulated with recombinant FSH, starting on cycle day 2 plus multiple doses (0.25 mg each) of the GnRH antagonist ganirelix, starting on cycle day 7. The antagonist was given either (A; upper panel) on a daily basis (group 1, n = 37 women) or (B; lower panel) on alternate days (group 2, n = 36 women).

 

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Table II. Distribution of patients in the two groups with LH rises $10 IU/I according to the time of their occurrence and luteinization

 

Table III shows the results of IVF/ICSI treatment. There were no significant differences in the total dose of FSH used, the duration of treatment, the number of follicles, the number of oocytes recovered, fertilization, implantation and clinical pregnancy rates between the two groups. However, the total dose of the GnRH antagonist was significantly smaller in group 2 than in group 1 (P < 0.001). In total, there were six pregnancies in group 1 and seven in group 2 with only two multiples (twins) in group 1. So far, there are three term deliveries, one of them twins, in group 1 and four term deliveries in group 2 and the neonates are normal. All rest pregnancies are ongoing.


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Table III. Results of IVF/ICSI treatment (mean ± SEM) in women superovulated with FSH plus the GnRH antagonist ganirelix, given every day (group 1) or on alternate days (group 2)

 


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The present study shows that in FSH-superovulated women, the administration of a GnRH antagonist every other day could be as effective in preventing the endogenous LH surge as daily administration and the concept is worth evaluating in a trial powered to show non-inferiority with respect to live birth rate. The changes in LH values were not significantly different during the two treatments. Although the increase in circulating levels of FSH was expected during administration of this hormone, circulating LH could be derived only from the pituitary. In both groups, mean LH values showed multiple fluctuations due to premature LH rises (≥10 IU/l) which during the stimulation period were seen in a rather high incidence in both groups (35.1 versus 38.8%) as in women treated with FSH without the use of any GnRH analogue (Janssens et al., 2000Go). Additional peaks of LH ranging from 5 to 10 IU/l were also found on several occasions in both groups (data not shown), a finding that can explain the increasing trend of serum progesterone levels during the late follicular phase, although on average they remained <2 ng/ml.

These results differ from findings in previous studies in which LH rises of ≥10 IU/l were seen in a smaller percentage of women, although overall premature luteinization in the present study (2.7%) was not much higher than in previous studies (~1%) (Table IV). In the previous studies, however, a progesterone level >1 ng/ml instead of >2 ng/ml was adopted (Ganirelix Dose-finding Study Group, 1998Go; Albano et al., 2000Go; Felberbaum et al., 2000Go; European and Middle East Orgalutran Study Group, 2001Go). This difference in the frequency of LH rises is unlikely to be explained by patients’ compliance with drug injection or the protocol of GnRH antagonist administration, since in group 1 of our study the protocol was the same as that in the previous studies. The GnRH antagonist was injected s.c. via pre-filled syringes at regular intervals, i.e. in group 1 every morning (09:00). Furthermore, established assays were used for hormone measurements, and to avoid variation all blood samples from each individual patient were assayed in the same batch while the laboratory analysts were blind to study allocation. Regardless of the difference from previous studies, it is interesting that with the minimal effective dose of 0.25 mg ganirelix (Ganirelix Dose-finding Study Group, 1998Go), the frequency of endogenous LH surge occurrence and premature luteinization in the present study was similar in the two groups.


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Table IV. Numbers and percentages of patients with LH rises ≥10 IU/I and luteinization in previous and the present study

 

Our data are consistent with the notion that an endogenous LH surge occurs invariably during superovulation induction in women (Messinis and Templeton, 1987Go; Glasier et al., 1988Go) and suggest that the GnRH antagonist at the daily dose of 0.25 mg hardly prevents it. In fact, premature LH rises that could by definition belong to an LH surge (Messinis et al., 1985Go) were seen in this study in ~50% of the women during the administration of ganirelix. However, these LH rises were followed by luteinization only in two out of 18 cases with LH ≥10 IU/l (Table II) or in two out of 40 cases with LH ≥5 IU/l (data not shown). They therefore differ from what has been described previously in superovulated women as attenuated LH surges that always resulted in luteinization (Messinis et al., 1985Go; Messinis and Templeton, 1986Go). It has been suggested that a gonadotrophin surge-attenuating factor (GnSAF) produced by the overstimulated ovaries is responsible for the attenuation of the LH surge (Messinis and Templeton, 1989Go). Since in this study luteinization following a premature LH rise ≥10 IU/l occurred more frequently before the onset of GnRH antagonist administration than during the administration, it is possible that in FSH-treated cycles, as a result of the synergistic action of the antagonist and GnSAF, the LH surge either is blocked or becomes abortive, i.e. unable to induce luteinization in the vast majority of women. As a matter of fact, pregnancies after embryo transfer occurred in such cases in the present study, although high LH levels in the follicular phase during treatment with a GnRH antagonist are detrimental for clinical outcome (Kolibianakis et al., 2003aGo). Increased bioactivity of GnSAF is particularly evident during the first 5 days of FSH-treated cycles but is subsequently counteracted at least in part by E2 (Messinis et al., 1998Go). This can explain the first significant rise of LH in the present study at the earliest on cycle day 7. However, due to high rate of LH rise on this day it might be worth starting the administration of the GnRH antagonist at least 1 day earlier as has been already suggested (Kolibianakis et al., 2003aGo).

Previous studies have suggested that the GnRH antagonists may affect ovarian steroidogenesis and have an impact on the endometrium and the implantation (Kol et al., 1999Go; Hernandez, 2000Go; Kolibianakis et al., 2003bGo). The present study shows a similar pregnancy rate in the two groups, but does not have the power to address this point, since our main purpose was to investigate changes in LH values. Whether the subtle increase in serum progesterone concentrations seen in late follicular phase can affect endometrium maturation needs to be investigated.

In conclusion, in this pragmatic trial, the incidence of premature LH rises during FSH treatment was not significantly different with GnRH antagonist ganirelix 0.25 mg given daily or on alternate days, although the incidence was higher in both groups than in previous efficacy studies. However, premature luteinization was markedly reduced during the period of treatment with the antagonist as compared to the period preceding the onset of its administration. Although underpowered for clinical outcomes, the present study shows that alternate day administration of GnRH antagonist may not increase the risk of premature LH surge, and ethically could be evaluated in larger trials.


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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Submitted on December 6, 2005; resubmitted on June 2, 2005; accepted on June 3, 2005.





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