Hum. Reprod. Advance Access originally published online on March 23, 2006
Human Reproduction 2006 21(7):1894-1900; doi:10.1093/humrep/del072
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GnRH agonist as luteal phase support in assisted reproduction technique cycles: results of a pilot study
1 To whom correspondence should be addressed at: Department of Gynecology, Cliniques Universitaires St Luc, Université Catholique de Louvain, B-1200 Brussels, Belgium. E-mail: donnez{at}gyne.ucl.ac.be
This research was presented in part at the European Society of Human Reproduction and Embryology 21st Annual Meeting, Copenhagen, Denmark, June 2005.
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Abstract |
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BACKGROUND: The aim of the study was to investigate whether intranasal (IN) administration of a GnRH agonist could provide luteal support in IVF/ICSI patients. METHODS: Controlled ovarian hyperstimulation (COH) was performed using hMG/FSH and a GnRH antagonist. Patients were then randomly allocated to either 10 000 IU hCG, followed by vaginal administration of micronized progesterone (3x 200 mg/day) (group A), or 200 µg IN buserelin followed by either 100 µg every 2 days (group B), or 100 µg every day (group C), or 100 µg twice a day (group D), or 100 µg three times a day (group E). Luteal support was continued for 15 days. RESULTS: Twenty-three patients were randomized. Groups B and C were discontinued prematurely in view of the short luteal phase. The luteal phase was significantly shorter in groups B, C and D, whereas group E was comparable with group A, 13.5 and 13.0 days, respectively. In the mid-luteal phase, median progesterone levels were significantly lower in groups B, C and D, whereas group E was comparable with group A, 68.9 and 98.0 ng/ml, respectively. Estradiol (E2) was significantly reduced in groups B and D but sustained in group E. In the hCG group, LH levels were undetectable (<0.1 IU/l), whereas LH was detectable and significantly higher in groups C, D and E. Two pregnancies were obtained in the hCG group (two of five), one ectopic and one ongoing. Three pregnancies were obtained in group E, one miscarriage and two ongoing twin pregnancies (three of five). CONCLUSION: IN administration of buserelin may be effective in triggering follicular maturation and providing luteal phase support in patients undergoing assisted reproduction techniques (ART).
Key words: ART/buserelin/GnRH agonist/GnRH antagonist/luteal support
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Introduction |
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TopAbstractIntroductionMaterials and methodsResultsDiscussion Acknowledgements References |
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Luteal phase deficiency is a common feature of cycles resulting from stimulation of follicular development. It has been reported in cycles stimulated with hMG/FSH alone, cycles down-regulated with a GnRH agonist and stimulated with hMG/FSH (Macklon and Fauser, 2000
; Pritts and Atwood, 2002) and cycles during which a GnRH antagonist is used in combination with hMG/FSH (Beckers et al., 2003; Kolibianakis et al., 2003).
Luteal phase supplementation or support is therefore common practice in infertility treatment to significantly improve the embryo implantation rate, clinical pregnancy rate and delivery rate. Two therapeutic agents are routinely used to supplement the luteal phase, natural progesterone and hCG (for review, see Pritts et al., 2002).
The recent introduction of GnRH competitive antagonists as a substitute for GnRH agonists to prevent mistimed LH surges has renewed the possibility of using a GnRH agonist to induce final follicular maturation (Olivennes et al., 1996; Fauser et al., 2002; Kol, 2004). However, this new treatment paradigm has also shown the luteal phase to be deficient, in need of added support (Albano et al., 1999; Beckers et al., 2003; Kolibianakis et al., 2003).
We therefore postulated that the LH-releasing property of a GnRH agonist could be exploited in non-down-regulated cycles, not only to trigger final follicular maturation but also as luteal support. This new approach would present several practical advantages over current treatment, such as convenient nasal administration compared with hCG injections or multiple daily vaginal administration of progesterone, use of purely synthetic polypeptide with no biological fluid residues, and the opportunity for early diagnosis of pregnancy and maintenance of corpus luteum, alleviating the need for continued luteal support beyond the fourth week of pregnancy. More speculatively, it may also improve pregnancy rates by restoring significant serum LH levels during the luteal phase (Stewart, 2001; Rao and Lei, 2002; Tesarik et al., 2003), as well as having a direct beneficial effect on embryo development potential (Tesarik et al., 2004).
Because GnRH agonists are prone to induce pituitary gonadotroph cell desensitization, we initially tested the concept in patients undergoing intrauterine insemination (IUI). We found that repeated administration of a GnRH agonist during the luteal phase, at a specific dose and frequency of administration, does not impair this phase but may actually promote progesterone secretion (Pirard et al., 2005). We therefore decided to test the concept in patients undergoing assisted reproduction techniques (ART).
The aim of this study was to assess whether a GnRH agonist administered intranasally can trigger final follicular maturation and support the luteal phase without inducing significant desensitization in patients undergoing controlled ovarian hyperstimulation (COH) with hMG/FSH and a GnRH antagonist, followed by IVF or ICSI.
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Materials and methods |
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TopAbstractIntroductionMaterials and methodsResultsDiscussion Acknowledgements References |
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Study design
This was a single centre, randomized, open, parallel group, pilot study, aimed at testing the feasibility of using a GnRH agonist (buserelin), administered intranasally, to trigger final follicular maturation and support the luteal phase in patients undergoing IVF/ICSI after stimulation of multiple follicular development with FSH/hMG. Four doses of buserelin were to be tested. Information on efficacy and safety was to be collected. The study protocol and the informed consent form were approved by the institution’s Ethics Committee.
Patients and treatment groups
Thirty infertile patients with indications for ART were admitted to the study. After signing the informed consent form, patients underwent COH using hMG/FSH (Menopur; Ferring, Brussels, Belgium/Puregon; Organon, Oss, the Netherlands) treatment at a dose of 150–300 IU daily, starting on day 3 following interruption of an oral contraceptive pill administered to programme the treatment cycle. When the leading follicle reached a mean diameter of 14 mm, daily administration of 0.25 mg of a GnRH antagonist (Orgalutran; Organon) was initiated up to the day before ovulation trigger. When patients met the criteria for triggering ovulation (at least three follicles 
18 mm), they were randomized to one of five treatment arms, initially designed to include six patients each: (i) 10 000 IU hCG (Pregnyl; Organon) followed by vaginal administration of 200 mg micronized progesterone three times daily (Utrogestan; Besins International Belgium, Brussels, Belgium) (group A); (ii) 200 µg intranasal (IN) buserelin (Suprefact; Aventis, Brussels, Belgium) followed by 100 µg IN buserelin/2 days (group B); (iii) 200 µg IN buserelin followed by 100 µg IN buserelin/day (group C); (iv) 200 µg IN buserelin followed by 100 µg IN buserelin twice a day (group D) and (v) 200 µg IN buserelin followed by 100 µg IN buserelin three times a day (group E).
Subsequently, in view of the failure of efficacy of the two treatment arms with the lower frequency of administration of buserelin, we decided to stop these arms.
The first dose of buserelin given to trigger ovulation was selected based on a previous dose-finding study (Buckett et al., 1998) and our previous experience (Pirard et al., 2005). The dose to be administered during the luteal phase was selected as that which could induce near-maximal LH and progesterone secretion during the luteal phase, as demonstrated in an earlier study (Lemay et al., 1983) and by our previous findings (Pirard et al., 2005).
Buserelin treatment was administered for a maximum of 15 days, whether or not the pregnancy test was positive. In the hCG group, micronized progesterone was administered up to the day of the pregnancy test. If the pregnancy test was positive, progesterone administration was then continued up to week 12 of pregnancy (common practice in our centre).
Pregnancy was diagnosed by measuring serum hCG levels on day 13 of the luteal phase (day of first hCG/buserelin administration = D0). Pregnancy outcome was monitored. A positive pregnancy test was defined as a serum hCG level >10 mIU/ml on luteal phase day 13 or after. A clinical pregnancy was defined as an ongoing pregnancy with an amniotic sac and a positive heartbeat visualized by ultrasound.
For the calculation of luteal phase duration, day 1 was the first day after ovulation trigger and the last day was the day before menstruation commenced.
IVF and ICSI were performed according to previously published procedures (Van Langendonckt et al., 2001). Zygotes were cultured up to day 3, in G1.2 medium (Vitrolife, Kungsbacka, Sweden). On day 3, embryos were graded according to previously described criteria (Van Langendonckt et al., 2001). One or two embryos were transferred, depending on the morphological score and the developmental stage of the embryo, as well as the age of the patient.
Twenty-three patients were randomized, and all but two completed treatment according to the protocol. Fertilization did not occur in one patient in group A, and no oocytes were retrieved from one patient in group E (Figure 1).
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Randomization process
A randomization list was computer-generated by an independent statistician. Treatment allocation instructions were placed in individually sealed envelopes to be opened at the centre in chronological order, on the day of ovulation trigger.
During the course of the study, it soon became apparent that administration of buserelin every 2 days and every day was associated with severe luteal deficiency and these two treatment arms were stopped before completion. Patients who would normally have been in group B or C received a further sealed envelope, with new allocation instructions, after discontinuation of these study arms.
Hormone assays
Serum estradiol (E2), serum progesterone, serum LH and serum hCG were assayed using commercially available kits in the accredited clinical centre’s central laboratory. E2, progesterone and LH were assayed using the Elecsys 2010 system (Roche Diagnostics GmbH, D-68298 Mannheim, Germany). The E2 intra-assay coefficient of variation (CV) was <6% and the inter-assay CV <6%; the progesterone intra-assay CV was <3% and the inter-assay CV <6%; the LH intra-assay CV was <2% and the inter-assay CV <5%. Serum hCG was assayed using the Beckman–Coulter system (Anablis, Namur, Belgium). The hCG intra-assay CV for a value <5 mIU/ml was <2% and the inter-assay CV <12%. Serum progesterone levels are expressed in ng/ml (x3.18 for nmol/l SI units). Serum E2 levels are expressed in pg/ml (x3.671 for pmol/l SI units). LH and hCG are expressed in mIU/ml (x1 for SI units).
Statistical analysis
Descriptive quantitative statistics (mean and SD) were calculated for the demographic and ovarian stimulation status parameters on the day of randomization, the IVF/ICSI and embryo transfer parameters and the luteal phase duration. Because of the small number of patients within each treatment arm, a non-parametric distribution parameter (the median) was included to address the comparison of the treatment groups. No formal statistical test was applied, but the comparison of the treatment groups with respect to luteal phase duration and hormone assays (progesterone, E2 and LH levels) was nevertheless performed on the basis of 95% confidence intervals (CIs).
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Results |
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TopAbstractIntroductionMaterials and methodsResultsDiscussion Acknowledgements References |
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Twenty-three patients were randomized. Groups B and C were prematurely discontinued in view of the short luteal phase and early menstrual bleeding observed. One patient dropped out of the hCG group following failure of oocyte fertilization and another out of group E following failure to retrieve oocytes (Figure 1). A total of 21 patients were therefore eligible for analysis. Baseline characteristics of patients and ovarian stimulation status on the day of randomization are presented in Table I. Because of the small number of patients in each group, strict comparability was difficult to establish. However, there was no trend favouring the buserelin groups over the hCG group. IVF/ICSI performance was also variable as a result of some variation in follicular development, but the number of oocytes retrieved per mature follicle and the number of cleaved embryos per retrieved oocyte do not show any evidence of difference (Table II).
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Finally, all 21 patients underwent embryo transfer. The median number of transferred embryos was two in all groups.
Luteal phase duration assessed in patients who did not become pregnant varied from woman to woman. It ranged between 7 and 16 days (Figure 2). A luteal phase lasting less than 10 days was recorded in the three buserelin groups with the lower frequencies of administration, i.e. B, C and D. On the basis of CI, the luteal phase was significantly shorter in groups B, C and D than in group A, whereas group E’s luteal phase duration was comparable with that of group A (Table III).
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Five positive pregnancy tests were recorded during the study (Table III). Three pregnancies were confirmed as ongoing clinical pregnancies based on the criteria defined above. No pregnancies were recorded in groups B, C and D. Two pregnancies were obtained in the hCG group (two of five), one ectopic and one ongoing clinical singleton. Three pregnancies were obtained in buserelin group E, one culminating in early miscarriage and two ongoing clinical twin pregnancies resulting from a two-embryo transfer (three of five).
Median serum progesterone levels of patients who did not become pregnant are presented in Figure 3. Serum progesterone levels increased in all five groups as soon as ovulation was triggered, with the highest levels encountered in the hCG group. In addition, a clear-cut positive correlation between the frequency of buserelin administration and serum progesterone levels was observed. In the mid-luteal phase, on day 7, progesterone levels (median; 95% CI) were 98.0 ng/ml (57.0–202.8), 1.4 ng/ml (0.5–2.2), 13.6 ng/ml (1.0–31.7), 24.6 ng/ml (0.0–104.7) and 68.9 ng/ml (13.0–124.8) in groups A, B, C, D and E, respectively. On the basis of CI, groups B and C differ from group A, whereas groups D and E do not. On day 11 of the luteal phase, when the hCG effect was diminishing, progesterone levels (median; 95% CI) were 17.0 ng/ml (9.8–28.2), 0.8 ng/ml (not applicable), 2.3 ng/ml (0.4–3.0), 10.1 ng/ml (0.0–35.6) and 30.0 ng/ml (17.7–42.3) in groups A, B, C, D and E, respectively. Based on CI, groups B and C differ from groups A and E.
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Median serum E2 levels of patients who did not become pregnant are presented in Figure 4. Serum E2 declined in all groups during the luteal phase. A positive correlation between the frequency of buserelin administration and serum E2 levels was observed in the mid-luteal phase. On day 7, E2 levels (median; 95% CI) were 1517 pg/ml (1320–1842), 196 pg/ml (697–822), 569 pg/ml (452–904), 732 pg/ml (413–1253) and 956 pg/ml (0.0–1940) in groups A, B, C, D and E, respectively. On the basis of CI, groups B C and D differ from group A, whereas group E does not. On day 11 of the luteal phase, when the hCG effect was diminishing, E2 levels (median; 95% CI) were 126 pg/ml (0–496), 29 pg/ml (10–47), 115 pg/ml (8–287), 281 pg/ml (108–557) and 658 g/ml (0–1009) in groups A, B, C, D, and E, respectively (non-significant).
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Median serum LH levels of patients who did not become pregnant are presented in Figure 5. In the hCG group, serum LH levels were below the limit of detection (<0.1 IU/l) in most samples taken between day 2 and day 9 of the luteal phase, whereas LH was detectable (>0.1 IU/l) in all samples from patients in groups C, D and E throughout the luteal phase. At the end of the luteal phase, from day 11 onwards, LH levels started to rise in non-pregnant women. In the mid-luteal phase, on day 7, LH levels (median; 95% CI) were <0.1 IU/l (<0.1), 0.4 IU/l (0.0–0.8), 1.0 IU/l (0.5–1.3), 2.3 IU/l (0.3–5.5) and 3.0 IU/l (2.0–4.0) in groups A, B, C, D, and E, respectively. On the basis of CI, all the buserelin groups, except group B, presented significantly higher LH levels than the hCG group.
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Buserelin treatment was well tolerated by all patients. There was no further drop-out, and no significant adverse events were reported in terms of local or systemic tolerance. No ovarian hyperstimulation syndrome (OHSS) was recorded.
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Discussion |
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TopAbstractIntroductionMaterials and methodsResultsDiscussion Acknowledgements References |
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This pilot study demonstrates that repeated administration of buserelin during the luteal phase of GnRH antagonist-treated ART cycles is able to support the luteal phase and is compatible with ongoing, viable pregnancy. This study also suggests that a regimen of three intranasal administrations per day could be at least as effective as 10 000 IU hCG administered s.c. followed by 3x 200 mg/day micronized progesterone administered vaginally.
During the menstrual cycle, a normal luteal phase is required for embryo implantation and evolution of pregnancy. The luteal phase is the result of intermittent stimulation of the corpus luteum by pituitary LH. During the luteal phase, pituitary LH pulses are of low frequency, leading to extended episodes of progesterone secretion at a rate of 3–5 per 24 h (Yen, 1991).
Luteal phase deficiency is a common feature of cycles resulting from stimulation of follicular development (Tavaniotou et al., 2002a), including GnRH antagonist-treated cycles (Albano et al., 1999; Tavaniotou et al., 2002b; Beckers et al., 2003). It is characterized by premature regression of the corpus luteum, leading to a shortened luteal phase (<10 days), low serum progesterone levels and delayed secretory transformation of the endometrium (Smitz et al., 1993). The consequences of luteal phase deficiency are a reduced embryo implantation rate, a lower pregnancy rate and an increased miscarriage rate when pregnancy is established (Pritts et al., 2002). Luteal phase supplementation or support is therefore common practice in infertility treatment to significantly improve embryo implantation rate, clinical pregnancy rate and delivery rate (Pritts et al., 2002).
Because the recent introduction of GnRH competitive antagonists as a substitute for GnRH agonists to prevent mistimed LH surges has renewed the possibility of using GnRH agonists to induce final follicular maturation (Olivennes et al., 1996; Fauser et al., 2002; Kol, 2004), we reasoned that GnRH agonists could be used not only as a trigger but also as luteal phase support. This new approach has several advantages over current treatment in terms of convenience as well as, more speculatively, efficacy, as discussed above.
However, because GnRH super-agonists tend to rapidly induce desensitization of pituitary gonadotroph cells (Loumaye, 1990), the choice of dose and frequency of administration of GnRH agonist is critical to maintaining an agonistic effect without inducing desensitization. We have recently shown that in patients undergoing mild stimulation before IUI, daily IN administration of 100 µg of buserelin not only does not impair the luteal phase, but actually moderately stimulates progesterone secretion (Pirard et al., 2005). Hence, we embarked on testing the concept in ART patients.
In this reported study, our first observation was that the luteal phase duration correlated well with the frequency of buserelin administration. ‘Infrequent’ buserelin administration, such as once every 2 days and even once a day, was associated with luteal phase deficiency, as illustrated by individual luteal phase durations under 10 days, significantly shorter than with hCG + micronized progesterone (Figure 2). This observation is further supported by the serum progesterone levels, which were found to be significantly lower in these groups (Figure 3). By contrast, and within the limits of the small sample size, patients receiving three administrations per day did not appear to differ from the hCG group with respect to the luteal phase (Figure 3).
E2 levels mirrored progesterone levels, with reduced levels in groups B and D and prolonged, sustained levels in group E.
These observations corroborate our previous findings that luteal phase duration, as well as progesterone and E2 secretion, can be enhanced by repeated IN administration of buserelin. In ART patients, the optimal frequency differs because it is necessary to administer buserelin at least three times a day, whereas after mild stimulation, once a day is sufficient (Pirard et al., 2005).
Our second important observation was that measurable LH levels were recorded at all time points in patients treated with buserelin at a frequency of at least once a day, whereas LH remained below the level of detection (<0.1 IU/l) in all patients treated with hCG up to day 11 of the luteal phase (Figure 5). In the mid-luteal phase, buserelin groups C, D and E showed significantly higher levels of LH than the hCG group. In addition, on the basis of this random sampling, a relationship between the frequency of buserelin administration and the median level of LH was recorded, indicating that ‘frequent’ buserelin administration did not induce desensitization, but rather further increased LH levels. This strongly suggests that the observed luteal benefit of buserelin is at least partially pituitary-mediated. Finally, during the last days of the luteal phase, in the absence of pregnancy, steroid levels declined and LH increased in all groups, suggesting a recovery of endogenous GnRH secretion.
Our third observation was that, although the number of patients was small, all the pregnancies obtained in the buserelin groups were in group E. In addition, two of three are ongoing, clinical twin pregnancies, resulting from two two-embryo transfers. This indicates that IN administration of buserelin three times a day during the luteal phase provides a luteal environment compatible with normal implantation and pregnancy evolution.
Very recently, two large, prospective, randomized studies compared the use of GnRH agonist with hCG to trigger final follicular maturation before IVF/ICSI in cycles treated with GnRH antagonist (Humaidan et al., 2005; Kolibianakis et al., 2005). In these studies, standard luteal support was provided by vaginal administration of natural progesterone and oral administration of E2. In one study, luteal support was continued up to 7 weeks of gestation in the presence of a positive hCG test (Kolibianakis et al., 2005). Both studies confirmed the ability of GnRH agonist to trigger final follicular and oocyte maturation before IVF/ICSI, as indicated by the similar number of oocytes retrieved, the number of MII oocytes, the fertilization rate, the proportion of patients with embryos suitable for transfer and the number and quality of embryos transferred. It should be noted, however, that in both studies, the pregnancy rate was somewhat reduced in the GnRH agonist-treated cycles and that the early pregnancy loss rate was extremely high, i.e. around 80% in this patient group.
As discussed by the authors, it is unlikely that embryo viability is impaired by such brief exposure to a GnRH agonist. Buserelin and other GnRH agonists have been tested in standard toxicology studies, which include a teratogenicity assessment. The peptides were not found to be teratogenic (Suprefact Patient Information Leaflet). Furthermore, inadvertent administration of a GnRH agonist during a conception cycle has been reported by numerous groups (Ron-El et al., 1990; Smitz et al., 1991; Golan et al., 1992; Wilshire et al., 1993; Young et al., 1993; Elefant et al., 1995; Gartner et al., 1997; Chardonnens et al., 1998). The pregnancy outcome did not raise any concerns. Finally, long-acting, depot preparations of GnRH agonist are widely used in ART to prevent a premature LH surge. Considering the very long half-life of these preparations, it is obvious that significant peptide exposure is encountered during the luteal phase. Taken together, these data support the safety of using buserelin as luteal support.
These elements and the surprisingly high early pregnancy loss point to a severe endometrial defect, despite exogenous progesterone and E2 administration. The dose of steroids able to support the luteal phase in ART patients has been established for cycles using hCG, which ensures continuous and supra-physiological LH activity for up to 10 days. The dose and frequency of administration of these steroids may not be suitable for GnRH antagonist-/GnRH agonist-treated cycles. It is also possible that early luteolysis occurs by lack of LH stimulation of the corpus luteum, whose negative impact cannot be overcome by rising levels of embryo-derived hCG, nor by prolonging steroid administration up to 7 weeks of pregnancy (Kol, 2004). Moreover, one cannot exclude the possibility that an optimal luteal phase requires some LH activity, which may play a role beyond stimulation of corpus luteum steroid production, such as promoting the expression and secretion of relaxin (Loumaye et al., 1984), angiogenic and growth factors, as well as cytokines involved in implantation (Licht et al., 2001). These beneficial effects of LH on the endometrium may be mediated through classic stimulation of the corpus luteum, but also through LH receptors expressed in the endometrium (Stewart, 2001; Rao et al., 2002; Tesarik et al., 2003). Although preliminary, our data suggest that maintaining LH secretion throughout the luteal phase by repeated administration of a GnRH agonist could overcome the drawbacks of GnRH-agonist-induced final follicular maturation, followed by steroid-only luteal support.
In conclusion, the evidence provided by this pilot study is consistent with our previous observations in mildly stimulated cycles and suggests that GnRH agonist may be used for luteal support in patients undergoing COH before IVF/ICSI. A larger, more statistically robust study is now ongoing, which we hope will validate the efficacy of the proposed protocol.
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Acknowledgements |
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We thank Laurence Beausaert, our data manager, Catherine Rousseau, our head nurse, Dominique Demylle, the biologist in charge of the IVF laboratory, and their teams for their contribution to this study.
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References |
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Submitted on November 17, 2005; resubmitted on January 3, 2006; accepted on February 10, 2006.
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