Hum. Reprod. Advance Access originally published online on July 17, 2007
Human Reproduction 2007 22(9):2449-2454; doi:10.1093/humrep/dem223
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Clinical outcome with half-dose depot triptorelin is the same as reduced-dose daily buserelin in a long protocol of controlled ovarian stimulation for ICSI/embryo transfer: a randomized double-blind clinical trial (NCT00461916)
1 Department of Obstetrics and Gynecology, Dr. Shariati Hospital, Medical Sciences/University of Tehran, North Kargar Avenue, Tehran 14114, Iran 2 Department of Community and Preventive Medicine, Medical Sciences/University of Tehran, Poursina Street, Ghods Street, Enghelab Square, Tehran, Iran 3 Department of Anesthesiology and Critical Care Medicine, Medical Sciences/University of Tehran, Sina Hospital, Imam Khomeini Avenue, Tehran, Iran
4 Correspondence address. Tel: +98 912 38 38 464; Fax: +98 21 6671 6545; E-mail: medlars{at}gmail.com
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Abstract |
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BACKGROUND: Traditional doses of depot GnRH agonist may be excessive for ovarian stimulation. We compared half-dose depot triptorelin (Group I) with reduced-dose daily buserelin (Group II) in a long protocol ICSI/embryo transfer through a double-blind randomized clinical trial.
METHODS: Controlled ovarian stimulation (COS) was started by a pretreatment with oral contraceptives for 21 days. Then, 182 patients were randomized into two groups of 91. Group I received 1.87 mg triptorelin depot i.m. followed by daily s.c. injections of saline. Group II (reduced-dose protocol) received a bolus injection of i.m. saline followed by daily s.c. injections of 0.5 mg buserelin, which was then reduced to 0.25 mg at the start of human menopausal gonadotrophin stimulation. When transvaginal ultrasound showed at least two follicles of 16–20 mm diameter, HCG was given and ICSI was performed 40–42 h later.
RESULTS: No significant differences were seen in the mean (SD) number of follicles at HCG administration, as our primary outcome [10.3 (4.4) in Group I versus 11.1 (4.2) in Group II, P = 0.180, mean difference = 0.86, 95% confidence interval 0.39–2.11]. The other early results of COS, clinical and ongoing pregnancy rates, or early pregnancy loss were also not significantly different between the groups. Group I endured longer stimulation period [11.2 (1.8) days versus 10.6 (1.9), P = 0.030].
CONCULSIONS: Clinical outcomes were not significantly different between Group I and Group II.
Key words: depot triptorelin/daily buserelin/controlled ovarian stimulation/long protocol/ICSI
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Introduction |
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The use of a single-dose depot long-acting GnRH agonist (GnRHa) in controlled ovarian stimulation (COS) cycles instead of a daily low-dose preparation would be more comfortable for patients, as it eliminates multiple applications and facilitates this phase of IVF (Oyesanya et al., 1995
). However, when profound pituitary desensitization is induced, there is an increase in the number of gonadotropin ampoules used and of the duration of the COS cycle without improving pregnancy rates or other clinical outcomes (Albuquerque et al., 2005).
GnRHa are claimed to cause extra-pituitary side effects including direct inhibition of ovarian steroidogenesis (Dor et al., 2000) and effects on the differentiation of granulosa cells (Gerrero et al., 1993) and GnRH receptor messenger ribonucleic acids in these cells (Peng et al., 1994). Since, in a suppressed pituitary gland the dose of GnRHa needed to maintain suppression gradually decreases with the length of treatment (Sandow and Donnez, 1990), some authors recommend a reduction of both dose and/or duration of GnRHa administration. Since 1992, halving the dose of depot triptorelin, e.g. has been studied against its full-dose administration with rather similar clinical outcomes (Balasch et al., 1992; Yim et al., 2001; Dal Prato et al., 2004). Half-dose depot leuprolide acetate has also resulted in comparable clinical outcomes with standard daily injections in long GnRHa protocol (Tsai et al., 1995; Hsieh et al., 2000). Reducing the daily doses of short-acting GnRHa has been advocated to produce results comparable to standard daily doses (Simon et al., 1994; Elgendy et al., 1998; Dal Prato et al., 2001; Takeuchi et al., 2001; Fabregues et al., 2005; Lenton and Mohamed, 2005).
To our knowledge, however, reduced-dose daily GnRHa have not been evaluated against half-dose depot forms in long GnRHa protocols. Thus, we originally compared a half-dose depot triptorelin with reduced daily doses of short-acting buserelin in a long protocol for ICSI and embryo transfer cycles.
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Materials and Methods |
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Patients
After institutional review board approval and written informed consent, 182 patients, candidates for ICSI/embryo transfer, were enrolled in this double-blind randomized clinical trial. Patients were 35-years old or younger and had serum FSH under 10 IU/l on Day 3 of the previous menstrual cycle. They needed to have no more than one previous IVF/ICSI attempt, no hormone therapy for at least six months preceding the study, no planned percutaneous epididymal sperm aspiration or testicular sperm extraction, no known history or risk of severe hyperstimulation, no evidence of hydrosalpinx, no major systemic disease, no uterine abnormality and no previous ovarian surgery.
Stimulation protocol and ICSI procedure
All patients came to the hospital on the third day of menstruation for determination of serum concentrations of LH, FSH and estradiol. Then, they began a course of monophasic low-dose oral contraceptive pills (ethinyl estradiol 30 µg+levonorgestrel 150 µg) from Day 3 to Day 21 of the menstruation period (Gonen et al., 1990; Biljan et al., 1998). Pituitary desensitization was then enhanced by GnRHa in the mid-luteal phase. On the 21st day, the patients were randomly assigned into two groups of 91 patients. The patients in Group I received a half-dose (1.87 mg) of triptorelin depot (Diphérélin 3.75, Beaufour Ipsen, Paris, France) in a single i.m. injection, and patients in Group II received a single i.m. injection of the same volume of saline, as placebo. On the same day, the patients in Group II received a s.c. injection of buserelin acetate (Suprefact® 1 mg/ml, Aventis Pharma Deutschland Gmbh, Frankfurt, Germany) at the standard dose of 0.5 mg. This dose was repeated daily until the day before administration of human menopausal gonadotropin (hMG), when the daily doses were reduced to 0.25 mg. In Group I, the daily s.c. injections included the same volume of saline as the dose of buserelin, acting as placebo. The reduced dose of buserelin or the saline continued until the day before HCG administration. We instructed the patients on how to do their own daily drug or saline injections.
On the third day of their next menstruation, ovarian stimulation with HMG (Menogon®, 75 IU FSH/75 IU LH, Ferring Gmbh, Kiel, Germany) was started at a usual dose of 2–3 ampoules daily. We adjusted the initial and ongoing dosage according to the patient's age, BMI, clinical state, current follicular growth response and history of poor response.
We used transvaginal ultrasound (TVS) to track follicular growth (Murad, 1998) and enhanced it with clinical assessment for monitoring ovarian hyperstimulation syndrome (OHSS). We started TVS examination at Day 4 of gonadotropin stimulation, and if necessary, two more examinations every 48 h. An experienced faculty professor, blinded to the study groups, performed TVS examinations using a Siemens Sonoline G20TM ultrasound system with endovaginal (EV9-4) transducer. The mean maximal follicular diameter was calculated from four measurements of the leading follicles in two perpendicular directions. On Day 6, if all follicles had 14 mm diameter or less, we tried doubling the hMG dose for the next 48 h. Eventually, on Day 8, if less than three follicles with diameter >14 mm were seen, the cycle was then cancelled. Whenever two or more follicles reached a diameter of 16–20 mm, the patient received an i.m. injection of 10 000 IU HCG (Profasi, 10 000 IU; Serono Benelux, Den Haag, The Netherlands). Transvaginal oocyte retrieval under TVS guidance was performed 36 h after HCG administration.
The standard ICSI procedure was carried out 40–42 h after hCG administration. The maturational status of the oocytes and embryo grading was recorded according to published criteria (Veeck, 1999); embryos of Veeck grades 1 or 2 were considered of high quality. When the embryos were at the 4–8-cells stage (around 72 h after hCG), a maximum of five embryos per woman were then replaced guided by TVS. A beta-hCG test was performed on Day 16 after embryo transfer, using a commercial enzyme-linked immunosorbent assay kit.
For luteal phase support, all the patients received a daily dose of 400 mg vaginal progesterone pessaries (Cyclogest 200 mg, Alpharma Limited, Barnstaple, England), with a daily dose of 25 mg i.m. progesterone in oil (Gestone; Paines & Byrne, Surrey, UK) starting from the day of oocyte retrieval. If a biochemical pregnancy (see below) was ruled out, these adjuncts were stopped, but otherwise maintained until documentation of a clinical pregnancy. At confirmation of clinical pregnancy, the i.m. progesterone ceased, whereas, vaginal progesterone was continued in living embryos until the 11th week after embryo transfer. All patients received a daily dose of 100 mg aspirin from the day of embryo transfer until the beta-hCG check. Adjuvant prednisolone was prescribed 20 mg/day orally in four divided doses starting from the day of embryo transfer for 5 days (Tan et al., 2006). Every patient received just one cycle with follow-up until the 12th week after embryo transfer.
Assignment, concealment and blinding
We used the Random Allocation Software, version 1.0 (Saghaei, 2004) to generate the allocation sequence in 9 permutated blocks of 20 patients. Opaque sealed envelopes with serial numbers printed on, from 1 to 182, contained the name of either group, according to the randomization list. Envelopes were opened sequentially, by a nurse blinded to the patients, to assign the eligible patients to one of the two study groups during their mid-luteal phase visit. Patients were kept blinded to the study drug and were instructed on how to prepare and administer the drug.
Definitions
We applied the term biochemical pregnancy to a positive beta-hCG result (serum concentrations >50 IU/l) but no intrauterine or extrauterine pregnancy as demonstrated by TVS (Penarrubia et al., 2003). A clinical pregnancy was referred to the presence of one or more intrauterine gestational sacs or fetal heartbeat on TVS performed at least 4 weeks after embryo transfer. Ongoing pregnancy was defined as presence of fetal heartbeat at 12 weeks after oocyte retrieval (Janssens et al., 2000). Early pregnancy loss was the term applied to patients with initially positive beta-hCG in whom pregnancy failed to develop by 12 weeks of gestation. Therefore, the early pregnancy losses included biochemical pregnancies, ectopic pregnancies and first trimester abortions (Fatemi et al., 2006). Miscarriages before and after documentation of a clinical pregnancy were termed preclinical and clinical miscarriages respectively. Poor response cycles included cancelled cycles due to development of less than three mature follicles, in addition to cycles with three or less oocytes retrieved after hCG administration. The poor response rate was defined as the number of poorly responding patients per COS cycle. Implantation rate was defined as the proportion of the sum of gestational sacs to the sum of replaced embryos in each group.
Sample size and statistical analysis
The primary endpoint was the number of oocytes retrieved from patients who received HCG. According to our pilot study, a sample size of 90 patients in each group would have 90% power and a significance level of 0.05 to detect a difference in the mean number of oocytes of 1.21 (SD 3.52).
The Statistical Package for the Social Sciences 15.0 software was used to analyse data of all randomized patients who received COS. Independent samples t-test was used for continuous response measures in both groups. Dichotomous variables were analysed by chi-square test, Fisher's exact test, or Mann–Whitney test as appropriate.
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Results |
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Between May 2005 and December 2006, we randomized 182 patients at the assisted reproduction technologies (ART) department of a famous referral University-hospital in Tehran, Iran. The patients' age and BMI were comparable between the two groups, as well as the type and duration of infertility (Table 1).
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Two patients withdrew from the protocol after administration of GnRHa and before starting gonadotropin stimulation: one in Group I for personal reasons and one in Group II for non-compliance to the study protocol. Therefore, gonadotropin stimulation was instituted on the remaining 180 patients (90 in each group). No cycles were cancelled because every cycle produced three or more mature follicles. Therefore, all the 180 patients received hCG followed by oocyte retrieval. Seven patients, however, did not produce oocytes (4 in Group I and 3 in Group II) and the remaining 173 patients underwent ICSI. Subtracting the three patients with failed oocyte fertilization (two in Group I and one in Group II), finally 170 patients completed the study up to embryo transfer (Fig. 1).
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Among those who received embryo transfer (84 in Group I and 86 in Group II), as it is shown in Fig. 2, 70 patients produced positive beta-hCG tests (37 in Group I and 33 in Group II). These 70 patients further constituted 62 clinical pregnancies (31 in each group), 5 biochemical pregnancies (all in Group I) and 3 ectopic pregnancies (1 in Group I and 2 in Group II). All the biochemically pregnant women experienced preclinical miscarriage. From those 62 clinically pregnant women, finally, 12 patients ended with clinical miscarriage (5 in Group I and 7 in Group II) and 50 sustained an ongoing pregnancy (26 in Group I and 24 in Group II).
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Adding the number of patients who did not produce oocytes (4 in Group I and 3 in Group II) with patients who produced three oocytes or less on retrieval (6 in Group I and 3 in Group II), the poor responders constituted 10 patients in Group I and 6 in Group II. Although four patients among the poor responders (three in Group I and one in Group II) became clinically pregnant, these four patients miscarried before 12 weeks after embryo transfer.
There were no significant differences in the early results of COS (Table 2) or the clinical outcomes (Table 3) between the groups, except for longer duration of ovarian stimulation by hMG in Group I, with a mean difference of 0.61 days (P = 0.030, 95% confidence interval 0.06–1.16). The number of hMG ampoules tended to be higher in Group I but this was not significant. No instances of OHSS occurred in the study patients.
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Discussion |
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There is insufficient evidence to show an advantage of daily doses over a single-depot dose GnRHa administration in the long protocol for pituitary desensitization. Depot GnRHa in long protocols offers the advantages of better compliance, convenience, and economy for patients with less stress of injections and risk of infection. However, depot formulations require more gonadotropin ampoules, which are needed for ovarian stimulation and a significantly longer duration of ovarian stimulation than daily GnRHa (Albuquerque et al., 2005
).
Optimal doses of GnRHa for COS are those that prevent a premature endogenous LH surge before oocyte retrieval, but allow pituitary LH secretion to be restored immediately after oocyte retrieval so that steroid hormones, necessary to support the luteal phase, may be stimulated. Traditional GnRHa doses used in IVF seem to be immoderately derived from treatment schedules used in disseminated prostate cancer, which aim at complete gonadal suppression under all circumstances (Janssens et al., 2000). The fear that these doses may adversely affect oocyte quality and endometrial receptivity is reflected through the recent trend for a reduction in both dosage and duration of GnRHa administration (Hugues and Cedrin-Durnerin, 1998).
Reducing daily GnRHa dosage has auspiciously attained comparable outcomes with standard-dose short-acting GnRHa administration, through both the existing protocols: either reducing after an initial period on the standard dose, which is also known as step-down or reduced-dose protocol (Simon et al., 1994; Elgendy et al., 1998; Takeuchi et al., 2001; Fabregues et al., 2005); or instituting a lower dose from the inception of treatment (Lenton and Mohamed, 2005). The reduced-dose protocol, also compares well with single injections of standard dose depot GnRHa (Dal Prato et al., 2001).
We did not exclude women with a history of poor response or failure in their previous IVF/ICSI cycle. While a universally accepted definition for low responders is still lacking, we tailored our COS protocol to optimize overall outcome not only for poor responders, but also for those undergoing their first cycle. Furthermore, we individualized the gonadotropin dosage for those with a history of poor response. Patients on their second treatment attempt were not equally distributed between the two groups, since we believe cancellation of a first cycle is not predictive of a subsequent failure (Baka et al., 2006); as it was, there was no significantly different distribution of such patients between the groups.
We regarded severe male factor infertility (Burney et al., 2006) or presence of a history of fertilization failure with conventional IVF (Hamberger et al., 1998) as absolute indications for ICSI. Notwithstanding these or other indications, we selected ICSI as the sole form of ART for all the patients to eliminate the occurrence of fertilization failures dependent on factors unrelated to the quality of the ovarian stimulation (Kilani et al., 2003). Moreover, ICSI has comparable clinical outcomes among couples with and without male factor infertility (Assisted reproductive technology in the United States: 2000, 2004).
We did not initially tend to show equivalence between the two study drug regimens, as it demands a high-power study, a small effect size, and a very large sample size. However, we tried to keep the study power as high as 90% and reduced the effect size to a rather not-clinically important level (a difference of 1.21 in the mean number of oocytes). Now, when we cannot reject the null hypothesis, and the primary outcomes are not significantly different between the two groups, we can reasonably interpret it as a well indicator of non-inferiority/superiority of the studied drugs.
Our findings are in overall agreement with similar studies evaluating half-dose depot GnRHa or reduced daily administration of short-acting forms. Differences in the study populations and protocols may contribute to some variations in the results between different studies. Underlying diseases and rate of egg dysfunction also differ among IVF, ICSI, or donor egg patients. Some of the outcomes have different challenging definitions among the studies. For example, the definition of poor response has differed widely in the literature (Turhan, 2006), as has ‘implantation rate’. Ongoing pregnancy is also described differently in terms of duration of intrauterine pregnancy, for instance from 11 to 12 weeks after oocyte retrieval (Janssens et al., 2000; Fatemi et al., 2006) to >20 weeks gestation (Penarrubia et al., 2003).
We would have certainly employed the depot and short-acting forms of the same drug if they had been available for our study. Tsai et al. (2005) showed higher incidence of DNA fragmentation and apoptotic bodies in granulosa cells with short-acting buserelin than with leuprolide depot treatment. This could partly explain some of the differences between the groups in our study, but we still have a vague understanding of the effects of GnRHa on embryo quality (Hugues and Cedrin-Durnerin, 1998).
The clinical outcomes in this study were not significantly different between half-dose depot triptorelin and reduced daily doses of short-acting buserelin. Half-dose depot triptorelin did not increase the required number of hMG ampoules, although full-dose depot preparations would do so. Nevertheless, the mean duration of gonadotropin stimulation was still longer with half-dose depot triptorelin, akin to full-dose regimens, than with daily short-acting buserelin. This difference was statistically significant but clinically trivial. To eliminate possible random errors affecting these results and to assess the optimal dose of GnRHa required for pituitary desensitization during COS, one can think of replicating this study with greater power and improved protocol, e.g. increasing sample size, using depot and short-acting formulations of the same drug, or dose-finding studies of a single GnRHa formulation, i.e. either depot or short-acting forms.
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Submitted on April 22, 2007; resubmitted on June 7, 2007; accepted on June 21, 2007.
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