Human Reproduction, Vol. 15, No. 11, 2333-2340,
November 2000
© 2000 European Society of Human Reproduction and Embryology
Dose-finding study of triptorelin acetate for prevention of a premature LH surge in IVF: a prospective, randomized, double-blind, placebo-controlled study
Research Institute for Endocrinology, Reproduction and Metabolism, IVF Center, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
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Abstract |
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Gonadotrophin-releasing hormone agonists (GnRHa) are routinely used in IVF programmes to prevent an unwanted LH surge and consequent ovulation. Despite its widespread use in IVF, a convincing dose recommendation for GnRHa in IVF does not exist. In our opinion, the lowest possible dose of GnRHa should be used. Thus, we performed a prospective, randomized, double-blind, placebo-controlled study to determine the minimal daily dose of triptorelin acetate needed to suppress a premature LH surge during IVF treatment in a long protocol. A total of 240 women (60 in each group) was randomized to either placebo or to one of three doses of triptorelin, i.e. 15, 50 or 100 µg daily. Ovarian stimulation was performed with two or three ampoules of FSH daily. A premature LH surge occurred in 23% of placebo-treated patients, but in none of the triptorelin acetate-treated patients. There were significantly more oocytes and embryos in the 50 and 100 µg triptorelin groups. There was no dose relationship in rates of either implantation, pregnancy, ongoing pregnancy, live birth or baby take-home. In this study we showed that daily administration of 15 µg triptorelin is sufficient to prevent a premature LH surge, and that 50 µg is equivalent to 100 µg in terms of IVF results.
Key words: dose reduction/IVF/LH surge/triptorelin
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Introduction |
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The use of gonadotrophin-releasing hormone agonists (GnRHa) in IVF programmes facilitates the procedure and contributes to improvement of the results (Neveu et al., 1987
; Chetkowski et al., 1989; Antoine et al., 1990; Hughes et al., 1992; Tummon et al., 1992). Suppression of the undesired premature LH surge, which has a negative consequence for the success rate (Stanger and Yovich et al., 1985; Caspi et al., 1989; Abdalla et al., 1990) and for the convenience of the patient, is obtained with GnRHa. Thereby, planning of the IVF treatment, as well as the timing of oocyte retrieval, is significantly improved (Kubik et al., 1990).
GnRHa doses used in IVF are derived from treatment schedules used in disseminated prostate cancer, which aim at complete gonadal suppression under all circumstances. Some comparative studies indicate that the daily dose of agonist used in IVF may be decreased without compromising the results (Lefebvre et al., 1990; Polson et al., 1991; Simon et al., 1994). Nevertheless, a convincing dose recommendation for GnRHa in IVF treatment does not yet exist. Optimal doses of GnRHa for IVF are those that prevent a premature endogenous LH surge before oocyte retrieval, but immediately after oocyte retrieval allow pituitary LH secretion to be restored so that steroid hormones, necessary to support the luteal phase, may be stimulated.
More controlled clinical trials are needed to assess the dose of GnRHa required for optimal conduction of IVF treatment, i.e. absolute suppression of the LH surge, while retaining the beneficial effect on IVF outcome (Hughes et al., 1992). Determination of the minimal effective dose to suppress the premature LH surge emerges as the first step. Recently, we published results from a study about the effects of different daily doses of triptorelin acetate on the LH response to a 500 µg GnRH-challenge test before human chorionic gonadotrophin (HCG) injection in patients undergoing IVF treatment (Janssens et al., 1998). We showed that a daily dose of 15, 50 or 100 µg triptorelin was sufficient to prevent LH release to such an extent that spontaneous LH surges could no longer be expected. In the present study, we aimed to assess the minimal effective daily dose of triptorelin that would prevent a spontaneous endogenous LH surge during the stimulation phase in patients undergoing IVF.
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Materials and methods |
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Patients
A total of 240 patients scheduled for IVF treatment in our department, participated in the study. All patients were aged between 18 and 40 years, and had a spontaneous regular cycle between 26 and 32 days. Their infertility was caused by either a tubal, idiopathic or male factor. The tubal status as cause of infertility was confirmed by a hysterosalpingography, laparoscopy and/or laparotomy. Women with another cause of infertility, and those with an elevated serum FSH concentration on cycle day 3 (FSH >10 IU/l) were excluded from the study. Patients who had undergone a previous IVF attempt without application of a GnRHa, or an IVF treatment according to the so-called short protocol with a stimulation phase of <7 days, were also excluded.
Patients were informed about the risk of a (premature) LH surge, and if this were to occur, such patients were offered a free treatment.
The protocol was approved by the Committee on Ethics of Research involving Human Subjects of the Vrije Universiteit Medical Center. All participants signed an informed consent.
Treatment protocol
Assignment
The 240 patients were randomized into four groups, each comprising 60 patients. Three groups were treated with different doses of triptorelin (Decapeptyl; Ferring B.V., Hoofddorp, The Netherlands), namely 15, 50 or 100 µg, and one group received a placebo. Randomization took place according to a computer-generated random list in 12 permutated blocks of 20 patients, each block containing five of each dose group. In a sequential fashion, following the list from 1 to 240, the corresponding treatment (having the same sequential number as the subject) was allocated to individual subjects. The randomization list was kept by Ferring B.V. and not known to the executors of the study. Randomization took place at the start of the study medication.
Masking
The placebo injections contained 0.2 ml of a sterile isotonic aqueous solution in a ready-to-use syringe. The triptorelin injections contained 0.2 ml triptorelin in a sterile isotonic aqueous solution in respectively 500 µg/ml, 250 µg/ml and 75 µg/ml concentrations, again in a ready-to-use syringe; this resulted in the following doses per syringe: 100 µg, 50 µg and 15 µg. The study medication was provided by Ferring B.V., uniformly blindly packed and labelled according to the randomization list. Sealed and numbered envelopes, each containing the dose regimen for one subject, were locked in the pharmacy at the site of the investigation. Only in the event of an emergency would the code be broken for individual subjects, without exposing the sequence of treatment for other subjects, thus maintaining the integrity of the double-blind procedure.
Protocol
The treatment protocol is illustrated in Figure 1. All patients came to the hospital on the second day of a period (menses 1/visit 1). A transvaginal ultrasound (TVS) was performed to exclude the presence of an ovarian cyst, and a blood sample was drawn to determine serum concentrations of LH, FSH, oestradiol, progesterone and HCG. If an ovarian cyst >3 cm in diameter was present, a TVS-guided puncture was carried out. Patients started with a basal body temperature (BBT) on the third day of menses 1. Daily administration of study medication (triptorelin or placebo) was started 7 days following the temperature rise, and continued until and including the day of HCG administration (Profasi, 10 000 IU; Serono Benelux, Den Haag, The Netherlands) preceding oocyte retrieval. Patients were instructed to contact the IVF department on the first day of bleeding after the start of triptorelin (menses 2). They had to come to the hospital on the second day of menses 2 (visit 2) to determine serum LH, FSH, oestradiol and HCG concentrations, and for a TVS to make an inventory of the ovaries. If an ovarian cyst >3 cm diameter was present, study medication was continued and a TVS-guided puncture performed. Ovarian stimulation with FSH (Metrodin, 75 IU; Serono Benelux) was started on cycle day 3, or 2 days after cyst puncture, with two ampoules i.m. daily when the patient was aged <35 years, or three ampoules i.m. in patients aged 
35 years. Patients were monitored routinely from day 5 of the stimulated cycle onwards. This involved blood sampling for measurement of LH and oestradiol, and TVS to estimate the number and diameter of the follicles, as well as morning urinary LH (uLH). This procedure was carried out on alternate days until the leading follicle(s) reached a diameter of 12 mm, after which the patients were monitored every day and uLH was checked three times each day (7:00, 15:00 and 23:00 h) (De Lauretis et al., 1994). Basal uLH was defined as the average of the uLH concentrations determined during the follicular phase until the leading follicle reached a diameter of 12 mm. A spontaneous uLH surge was defined as two successive increasing uLH concentrations of which the first was at least 2-fold higher than the basal uLH level and, in addition, the second elevated uLH level needed to be equal to or higher than the first. The time of onset of the uLH surge was defined as the time when the first elevated uLH concentration was measured (Ransil et al., 1981). A uLH surge was defined as premature when it had occurred before the criteria for HCG administration were met, these being the presence of at least three follicles >16 mm diameter, of which at least one was 18 mm diameter, and a serum oestradiol concentration of 1500 pmol/l. According to the individual ovarian response, the dose of FSH was increased with one or two ampoules, and monitoring was continued until the criteria for HCG injection were met or until a uLH surge occurred. The HCG injection was withheld when oestradiol concentrations reached >30 000 pmol/l in order to avoid the risk of ovarian hyperstimulation syndrome. Oocyte retrieval was carried out 35 h after HCG injection. In case a spontaneous uLH surge was observed, oocyte retrieval was performed ~32–36 h following its first detection (Ramsewak et al., 1990). Embryo transfer was performed 48 h after oocyte retrieval in cases of one or two embryos present, and at 72 h after oocyte retrieval when more than two embryos were available. This strategy enabled the selection of the most advanced and morphologically superior embryos for transfer. Remaining embryos were cryopreserved in liquid nitrogen at –196°C. Luteal support was generally accomplished by vaginal administration of 200 mg micronized progesterone (Progestan; Organon, Oss, The Netherlands) three times daily. Patients who preferred injections rather than vaginal tablets received 1500 IU HCG (Pregnyl®; Organon) i.m. on days 2, 4, 6, 8 and 10 after oocyte retrieval, but only when the oestradiol concentration on the day of the HCG injection was <8000 IU/l.
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Ultrasound
All ultrasound examinations were performed transvaginally by either of two of the authors (R.J. and J.B.) using Toshiba ultrasound equipment (Tosbee, Model SSA-240A, probe 5 MHz model PVE-582V). To determine the diameter of the follicle, the mean of measurements in two perpendicular directions was taken. Ultrasound guidance was used in all cases for follicle aspiration and oocyte recovery.
Serum assays
Blood samples for LH, FSH, oestradiol and progesterone were collected in heparinized tubes and centrifuged at 1800 g for 10 min. To determine FSH and LH, a commercially available immunometric assay kit (Amerlite, Amersham, Bucks, UK) was used. For measuring concentrations of oestradiol and progesterone, a commercially available competitive immunoassay (Amerlite) was used. Intra- and inter-assay coefficients of variation were 6% and 9% for FSH, 5% and 10% for LH, 9% and 11% for oestradiol, and 11% and 17% for progesterone.
Urinary LH assay
Urinary LH was measured by immunometric assay (Amerlite) for LH in serum, after the following modification. An aliquot of each urine sample was diluted with four aliquots of zero calibrator in order to compose a serum matrix. Values were calculated allowing for the dilution. The intra- and inter-assay coefficient of variation was between 6% and 10% respectively.
Statistical analysis
An overall dose–response test for linear trend with dose was performed for all efficacy data. The statistical hypothesis of no treatment effect (H0:µ0 = µ15 = µ50 = µ100) was tested against the ordered alternative hypothesis that at least one triptorelin dose is superior to placebo and that the response is improved (or at least as good as those of the previous dose) when increasing the dose (Halt: µ0 µ15 µ50 µ100).
For continuous normally distributed data, a linear contrast of dose was tested in a one-way analysis of variance (ANOVA); for ordinal (ordered categorical) data, a Jonckheere–Terpstra test (Hollander and Wolfe, 1973), and for binary data a Cochran–Armitage test (Cochran, 1954; Armitage, 1955) were used.
ANOVA was applied for comparisons between hormone concentrations, and differences in hormone concentrations. A log transformation was applied to the hormone concentrations to achieve homogeneity of variance and normality of residuals. For oestradiol, no transformation could be found to satisfy these assumptions, and therefore non-parametric methods were used. To determine the minimal effective dose, comparison between adjacent doses was performed using a published method (Sidak, 1967).
A Jonckheere–Terpstra test was applied for analysing hormone area under the curve (AUC), follicle, oocyte, embryo and fertilization data. The test was also used for analysis of oestradiol values. Adjustments to the significance levels for multiple testing were made (Sidak, 1967).
The Cochran–Armitage test was applied for comparisons in occurrence of urinary LH surge and of premature urinary LH surge, for rates of (ongoing) pregnancy, live-birth and baby take-home. To determine the minimal effective dose, comparisons between the adjacent doses were performed using a continuity corrected chi-square test or, when the incidence was <5 in all dose groups, a Fisher's exact test.
A result was considered statistically significant if the P-value was < 0.05. The minimal effective dose was that where LH suppression occurred in 95% of the patients.
Intention to treat analysis (ITT, of all patients who were included in the study) and protocol population analysis (PP, of evaluable patients) were performed. The results from the analysis of the protocol population were identical to those from the ITT population. Therefore, only the results of the ITT population are presented in detail.
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Results |
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Baseline characteristics
The baseline characteristics, i.e. actual age, age of menarche, number of smokers, cycle length, duration of infertility and body mass index were comparable between the four groups. Furthermore, no significant differences were found in type of infertility or hormone (LH, FSH, oestradiol, progesterone) concentrations. Values are shown in Table I
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Participant flow and follow-up
Among the 240 patients, there were 11 withdrawals divided over the four dose groups: one withdrew from the placebo group, four from the 15 µg group, four from the 50 µg group, and two from the 100 µg group. Three patients quit triptorelin treatment after a few days, for different reasons: one patient in the 15 µg group stopped because her husband became ill, and two patients in the 50 µg group conceived spontaneously while using triptorelin. Two other patients had a withdrawal bleeding after triptorelin, but did not start with the FSH stimulation because one (15 µg) did not contact the IVF centre and simply continued with triptorelin only, while the other patient (100 µg) was hospitalized for other reasons and had to stop the IVF procedure. Of the 235 patients who started with FSH stimulation, four did not finish this stimulation, failing to conform to the protocol due to relational problems (placebo group, n = 1), violation of the protocol by using the standard triptorelin of 100 µg instead of her study medication (15 µg group, n = 1) and drug interruption for 48 h (which was more than the 6 h permitted in the protocol) (50 µg group, n = 1), while one patient in the 100 µg group withdrew her consent. Two other patients (one each in the 15 µg and 50 µg groups) were ultimately not considered eligible for the study because they did not respond exactly to our inclusion criteria. A total of 229 patients was recorded as completing the study according to protocol, and considered to be evaluable per protocol for efficacy.
Desensitization phase
The interval between initiation of study medication and start of FSH stimulation was defined as the desensitization phase. The time lapse between the start of the triptorelin acetate and the onset of subsequent menses was shorter in the placebo group than in the active medication groups (P < 0.001) (Table II).
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In order to characterize the endocrine pituitary and ovarian response to triptorelin or placebo, differences were measured between serum concentrations of LH and oestradiol on day 2 of menses 1 (visit 1), and immediately prior to FSH stimulation, i.e. day 2 of menses 2 (visit 2). Mean LH concentrations ranged from 3.6 to 4.1 IU/l in all dose groups at visit 1. After desensitization (at visit 2), mean LH concentrations were lower compared with the values at visit 1 in all dose groups, except for the placebo group. Linear trend tests on log transformed values showed a highly significant dose response (P < 0.001) for both the value at visit 2 and the difference between values at visit 1 and visit 2. For both parameters, adjacent comparisons showed a statistically significant difference between the effect of placebo and 15 µg triptorelin, but not between 15 and 50 µg, or between 50 and 100 µg (Table II
).
At visit 1 the mean oestradiol concentrations ranged from 106 to 119 pmol/l. There was a highly significant dose-dependent decline of oestradiol after placebo/triptorelin treatment at visit 2 (P < 0.001) (Table II), as well as for the difference between visit 1 and visit 2 (P = 0.009) (Table II).
Desensitization/FSH stimulation phase
The interval between the start of FSH in combination with study medication until HCG injection or spontaneous LH surge, was defined as the desensitization/FSH stimulation phase.
Luteinizing hormone
Fourteen (23%) of the placebo-treated patients had an LH surge, of whom 10 (17%) were premature, i.e. before the criteria for HCG were met. None of the triptorelin-treated patients had an LH surge. Statistical analysis for linear trend with dose was highly significant (P < 0.001) (Figure 2). Adjacent comparison for the occurrence of both LH surges and premature LH surges showed significance between placebo and 15 µg (P < 0.05).
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LH secretion during combined agonist and FSH treatment was estimated by AUC per stimulation day (LH-AUC/day). There was strong decrease upon increasing doses (P < 0.001) (Figure 3
). Adjacent comparison showed a significant difference in dose means between 15 and 50 µg, but not between placebo and 15 µg, nor between 50 and 100 µg.
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Duration of FSH stimulation and number of FSH ampoules
The mean duration of FSH stimulation (days) increased with the dose of triptorelin (P < 0.001) (Table III
). Adjacent comparison showed a significant difference between the placebo and 15 µg groups. The mean daily dose of FSH (mean number of ampoules/day) was similar in all dose groups; therefore, the total number of FSH ampoules used showed a clear increase with higher dose of triptorelin (P < 0.001) (Table III).
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Oestradiol and progesterone
During FSH stimulation there was a statistically significant difference on dose–response effect for oestradiol secretion expressed as AUC per stimulation day (E2-AUC/day) (P < 0.05) (Table IV
).
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The dose–response for log-transformed progesterone data was statistically significant on the day of HCG injection (P < 0.001), with highest progesterone values in the placebo group. Adjacent comparisons showed a statistically significant difference between the placebo and 15 µg groups (Table IV
).
Number of follicles
The number of follicles of >12 mm diameter on the day of HCG/LH surge was analysed. There was a statistically significant dose–response relationship for the number of follicles >12 mm diameter (P = 0.032) (Table IV).
IVF outcome
There was a significant dose dependence in the number of oocytes retrieved (P = 0.001) and the number of embryos obtained (P = 0.001) (Table V). For the number of oocytes per study entrance (ITT), adjacent comparisons showed a significant difference between the 15 and 50 µg groups, but not between the placebo and 15 µg groups, nor between the 50 and 100 µg groups. The mean numbers of oocytes were higher in the 50 µg and 100 µg groups (11 and 12 respectively) compared with the placebo and 15 µg groups (seven and nine respectively).
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For the number of embryos per study entrance, adjacent comparisons showed significant differences between the placebo and 15 µg groups and between the 15 and 50 µg groups, but not between the 50 and 100 µg groups. The mean number of embryos was higher in the 50 and 100 µg groups (seven in each group) compared with the placebo and 15 µg groups (three and five respectively).
The number of embryos transferred was comparable between the four groups (Table V). However, in the placebo group, 22% of the patients did not reach an embryo transfer, this being highly significant compared with the 8% who did not reach transfer in the other three dose groups (
2 test, P = 0.0039).
The fertilization rate (number of fertilized oocytes/number of retrieved oocytes, as %) increased significantly with the dose of triptorelin used (P = 0.029), but adjacent comparison of doses did not show any significant differences (Table V).
The implantation rate (total number of pregnancies with one or more gestational sacs/embryo transfer, as %) was not significantly different, and there was no evidence of any dose–response relationship (Table V).
There was no significant linear trend with dose for pregnancy rate (number of positive pregnancy tests/number of ITT patients, as %), either for ongoing pregnancy rate (number of pregnancies with positive fetal heart beat action at 11 weeks after oocyte retrieval/number of ITT patients, as %), or for live birth rate (number of babies born alive/number of ITT patients, as %) or baby take-home rate (number of babies taken home after the IVF treatment/number of ITT patients, as %) (Table V).
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Discussion |
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We describe here the results of the first placebo-controlled, double-blind study to determine the lowest effective dose for the GnRH agonist triptorelin to prevent an LH surge during IVF. This is more than a decade after the introduction and wide application of this treatment strategy. From the outset, empirical doses were chosen that warranted full desensitization of the pituitary, and thus its inability to secrete LH. These doses originated from oncological treatment schedules for disseminated prostate cancer (Tolis et al., 1982
). In these regimens the advised dose for triptorelin—which was the drug of choice in our study—was estimated to be at least 100 µg daily. Several authors suggested that partial desensitization of the pituitary would be feasible (Broekmans et al., 1996; Scheele et al., 1996) and applicable in IVF (Ron-El et al., 1992), and that dose reduction should be possible. We have shown in an earlier study that graded desensitization could be achieved under IVF conditions (Janssens et al., 1998); moreover, it appeared that a daily dose of 50 µg triptorelin creates a state of pituitary desensitization comparable with the `standard' dose of 100 µg, and this endocrine finding was confirmed in the current study. The power of the current study now also allows us to conclude that, from a clinical point of view, no differences exist between these two doses. From the present study it clearly follows that a lower daily dose of triptorelin (50 µg or 15 µg) than is currently used is capable of preventing a LH surge, but with a lower grade of pituitary desensitization, as shown by the higher LH secretion in the stimulatory phase. In terms of implantation rate, pregnancy rate and baby take-home rate, the results of the higher dose groups appear to be better, although the differences were not significant. Therefore, on the basis of these observations we conclude that a reduction of the daily dose of triptorelin by 50% is possible, without negatively affecting the success rate.
In our study, the number of patients who did not receive embryo transfer was reduced by 50% when GnRHa was given, compared with placebo. This is in line with other observations (Kubik et al., 1990; Polson et al., 1991), and again substantiates the usefulness of agonists in IVF.
Our study also shows the dose dependency of several other remarkable features on the use of GnRHa in IVF. Various studies have reported the recovery of more oocytes in GnRH-treated IVF cycles than in non-GnRH cycles (Neveu et al., 1987; Testart et al., 1989; Maroulis et al., 1991; Ron-El et al., 1991), and the improvement of ovarian responsiveness with microdoses of GnRHa during ovulation induction for IVF in poor responders (Feldberg et al., 1994; Scott and Novot, 1994; Olivennes et al., 1996). However, we are the first to report a dose effect of the GnRHa on the number of oocytes and embryos in normal responders. This may be related to possible direct ovarian influence of the agonist on the ovary (Hsueh and Jones, 1981), though the strong dose dependency does not rule out indirect effects. One explanation would be that a longer duration of stimulation with FSH with higher daily doses of agonist enables more follicles to enter the stage of FSH-dependent growth. Another explanation might be the greater suppression of endogenous LH than FSH by the higher doses of GnRHa, resulting in an increase in the FSH/LH ratio during the follicular phase (Stone et al., 1989). Both explanations are in line with the theory that multiple follicle growth is achieved by extending the time when FSH is above threshold (`widening the gate'), as proposed previously (Baird, 1987). In our study there was indeed a dose-dependent increase in the number of follicles >12 mm diameter, and a larger number of oocytes with higher agonist doses. With regard to this point, it is remarkable that a dose-finding study with a GnRH-antagonist, in contrast, suggests less follicle growth and lower oocyte yield with higher doses (The Ganirelix Dose-Finding Study Group, 1998).
We confirm an increase in fertilization rate with the use of a GnRH agonist (Neveu et al., 1987; Antoine et al., 1990), and substantiate its dose dependency. This indicates the apparent improvement of oocyte quality which, currently, is believed to be the beneficial result of the lower LH concentrations during the stimulation phase found with the increasing dose of agonist. High LH concentrations during follicular development may influence oocyte quality, fertilization rate and embryo quality (Stanger and Yovich, 1985; Howles et al., 1987).
So far, a higher fertilization rate, no difference in number and quality of embryos (data not shown), and no difference in implantation rate underscore the relative safety of the use of GnRH agonists in these stages of development.
A final remarkable finding in our study is the apparent dissociation between numbers of growing follicles and the dynamics of oestradiol secretion. This is probably due to the GnRH dose-dependent suppression of LH, and thus blockade of granulosa cell steroid production, while concomitantly an increasing number of follicles develop. The practical consequence of this is the relative uselessness (and even potential danger) of monitoring by means of oestradiol measurements without frequent ultrasound when it comes to preventing ovarian hyperstimulation syndrome in IVF cycles with GnRHa treatment.
In conclusion, in this study design a daily dose of 15 µg triptorelin is seen to be sufficient to prevent an undesired premature LH surge during IVF treatment. Considering the outcomes of the IVF harvest, and the requirement that the dose should be optimal for all parameters, a daily dose of 50 µg triptorelin might be considered.
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Acknowledgments |
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The authors wish to thank Ferring B.V., Hoofddorp, The Netherlands for financial support, and especially Dr S.Mak for her contribution in writing the protocol.
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Notes |
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1 To whom correspondence should be addressed at: Department of Obstetrics and Gynaecology, Free University Hospital, IVF Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. E-mail: cb.lambalk{at}azvu.nl
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Submitted on March 7, 2000; accepted on July 11, 2000.
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