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Hum. Reprod. Advance Access originally published online on September 11, 2006
Human Reproduction 2006 21(11):2830-2837; doi:10.1093/humrep/del059
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Ganirelix acetate causes a rapid reduction in estradiol levels without adversely affecting oocyte maturation in women pretreated with leuprolide acetate who are at risk of ovarian hyperstimulation syndrome*

Robert L. Gustofson1,2,3, James H. Segars1,2,3 and Frederick W. Larsen1,2,4

1 Combined Federal Fellowship in Reproductive Endocrinology and Infertility at NIH, Walter Reed Army Medical Center, National Naval Medical Center and Uniformed Services University of the Health Sciences, Bethesda, MD 2 WRAMC Assisted Reproductive Technology Program, Walter Reed Army Medical Center, Washington, DC and 3 Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

4 To whom correspondence should be addressed at: WRAMC Assisted Reproductive Technology Program, Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Ward 43, Washington, DC 20307, USA. E-mail: frederick.larsen{at}na.amedd.army.mil


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Disclosure
 Acknowledgements
 References
 
BACKGROUND: Elevated estradiol (E2) levels predispose to development of ovarian hyperstimulation syndrome (OHSS). Since GnRH antagonist is associated with a reduction in E2 levels, we hypothesized that GnRH-antagonist treatment of women down-regulated with GnRH agonist who are at risk of OHSS might reduce E2 levels and avoid cycle cancellation. METHODS: Retrospective study in a university-based assisted reproduction technology (ART) programme in 87 patients treated with long luteal (LL) or microdose flare (MDF) with ovarian hyperresponse and 87 control patients without ovarian hyperresponse. GnRH-antagonist (ganirelix acetate) treatment was started and leuprolide acetate discontinued in women who failed to respond to a reduction in gonadotrophin dosage. RESULTS: In the treatment group, there was a significant, reproducible reduction in serum E2 levels. Mean E2 at the start of ganirelix treatment was 4219.8 pg/ml and decreased in 24 h to 2613.7 pg/ml (36.7%; P < 0.001). An average of 24.9 ± 8.8 oocytes were obtained at retrieval and an average of 19.1 ± 8.0 were metaphase II (79.2%). Fertilization occurred in 13.9 ± 8.1 embryos (72.8%). In this high risk group, two cases of severe OHSS (2.3%) occurred. The ongoing pregnancy rate was 51.8%. Compared with the control group, there were no statistically significant differences in the rate of oocyte recovery, oocyte maturity, 2PN rate, fertilization, cancellation, OHSS or pregnancy. CONCLUSIONS: GnRH-antagonist treatment of women pretreated with GnRH agonist rapidly reduced circulating serum E2 without adversely affecting oocyte maturation, fertilization rates or embryo quality and resulted in a high pregnancy rate in this subgroup of patients at risk of OHSS.

Key words: cycle cancellation/estradiol/ganirelix acetate/GnRH agonist and antagonist/OHSS


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Disclosure
 Acknowledgements
 References
 
In conjunction with ultrasonographic evaluation of follicular growth, serum estradiol (E2) levels assist practitioners with adjustment of gonadotrophin dosage during ovarian stimulation cycles. Numerous studies have evaluated both the absolute and the relative E2 levels before, during and after HCG administration in an effort to predict cycle outcomes (Licciardi et al., 1995Go; Smotrich et al., 1995Go; Phelps et al., 1998Go; Khalaf et al., 2000Go; Kovacs and Witt, 2002Go; Kolibianakis et al., 2003Go). Over 20 years ago, before the use of GnRH agonist, a decrease in E2 before HCG was associated with a diminished likelihood of pregnancy (Jones et al., 1983Go). In women treated with GnRH agonist, it is unclear whether a spontaneous decrease in E2 before HCG has detrimental effects on cycle outcomes; however, an iatrogenic decrease in E2 does not appear to negatively impact cycles (Fisher et al., 2005Go; Styer et al., 2005Go).

Though elevated E2 levels during ovarian stimulation cycles are not generally associated with a reduction in embryo quality or pregnancy outcome (Sharara and McClamrock, 1999Go; Papageorgiou et al., 2002Go; Shapiro et al., 2005Go), significantly elevated or rapidly rising serum E2 levels have been associated with an increased likelihood of developing ovarian hyperstimulation syndrome (OHSS; Haning et al., 1983Go; Delvigne et al., 1993Go; Enskog et al., 1999Go). Conversely, women with lower E2 levels are at lower risk for developing OHSS (Morris et al., 1995Go; Chen et al., 1997Go; Aboulghar, 2003Go).

‘Coasting’, or withholding all gonadotrophin treatment, has been used in an effort to prevent or lessen the incidence of OHSS for ovarian hyperresponse manifested by elevated serum E2 levels in both GnRH agonist and antagonist cycles (Delvigne et al., 2001Go; Fatemi et al., 2002Go). With this strategy, gonadotrophin treatment is withheld until the E2 level falls into a range considered safe or at lower risk for OHSS. However, reduction in E2 levels is not observed in the first 24–48 h of coasting, even when preceded by decreased gonadotrophin dosage (Sullivan et al., 1999Go; Egbase et al., 2000Go). In fact, on the first day after coasting is initiated, E2 levels may continue to rise by as much as 20% (Egbase et al., 2000Go), thereby limiting its usefulness for rapid E2 reduction. Coasting is especially problematic when initiated as the ovarian follicle cohort is nearing appropriate size for HCG administration since this method requires 2 days or more of observation before E2 falls to satisfactory levels. During this time, gonadotrophin support of the follicles is withheld, sometimes for a more extended duration of treatment, resulting in significantly lower oocyte recovery rates (Dhont et al., 1998Go; Egbase et al., 2000Go; Tozer et al., 2004Go). In addition, prolonged coasting has been shown to impair IVF cycle outcomes (Tortoriello et al., 1998Go; Mansour et al., 2005Go).

Another strategy to prevent OHSS includes cryopreservation of fertilized embryos with subsequent embryo transfer in another cycle. Cryopreservation and concurrent treatment with GnRH agonist have been reported to prevent the incidence of early severe OHSS; however, they did not avoid moderate OHSS (Endo et al., 2002Go). The pregnancy rate of frozen embryo transfer when performed for OHSS risk has been equivocal in several studies comparing it to fresh embryo transfer (Ferraretti et al., 1999Go), intravenous albumin use (Shaker et al., 1996Go) or coasting (Benadiva et al., 1997Go). In contrast, other studies of embryo cryopreservation have reported excellent pregnancy rates; however, they have been unable to entirely prevent OHSS (Queenan et al., 1997Go). In addition to mixed results in reducing the rate of OHSS, cryopreservation offers logistical concerns: it requires an additional patient treatment cycle; cryopreservation is not available to all assisted reproduction technology (ART) centres due to local legislation or other factors; there are already a surplus of cryopreserved embryos and there is a moral dilemma for embryo disposition in some couples. As such, a method to decrease the risk of OHSS that would avoid repeat cycles and the concerns of cryopreservation would be preferable.

GnRH antagonists, such as ganirelix acetate, have been extensively compared with GnRH agonists (leuprolide, buserelin and triptorelin; Borm and Mannaerts, 2000Go; European and Middle East Orgalutran Study Group, 2001Go; Fluker et al., 2001Go). The use of antagonist for LH surge prevention unequivocally reduces peak serum E2 levels in comparison with agonists while maintaining similar pregnancy rates. During GnRH-antagonist-treated cycles, the pituitary is capable of responding to supraphysiologic doses of GnRH agonist (Fauser et al., 2002Go), as demonstrated by its ability to initiate an endogenous LH surge resulting in final oocyte maturation.

The use of GnRH antagonists after GnRH-agonist suppression has been reported in a small series of patients. We anecdotally noted that GnRH antagonists might decrease E2 levels in a small group of hyperresponding GnRH-agonist-treated women (Gustofson et al., 2004Go). This finding was unexpected because the pituitary receptors were presumed to have been reduced in number by standard GnRH-agonist treatment. Therefore, we tested whether GnRH-antagonist treatment of a large cohort of women at significant risk of OHSS who were already down-regulated with GnRH agonist might reduce E2 levels. The E2 levels and their relative changes during ganirelix treatment were also evaluated. Further, we assessed follicular growth, oocyte maturation, embryo quality, pregnancy outcome and rate of OHSS stratified by leuprolide down-regulation protocol and compared these parameters with a control group.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Disclosure
 Acknowledgements
 References
 
Retrospective review of the data was performed after approval from the Department of Clinical Investigation Institutional Review Board at Walter Reed Army Medical Center.

Population
All patients, 26–41 years old, who had ovarian stimulation for ART from January 2004 to April 2005 (n = 893) and had ovarian hyperresponse that were considered for cycle cancellation (n = 87) were included in the analysis. Serum E2 level >2000 pg/ml on cycle day 6 and/or a projected serum E2 level on the day of HCG administration expected to be >5000 pg/ml with >25 total ovarian follicles were the criteria for ovarian hyperresponse. Serum E2 level was measured in units of pg/ml; the conversion factor to pmol/l is multiplication by 3.671. The E2 level criterion was selected as most previously published studies regarding risk factors for OHSS would suggest that patients with this E2 elevation would be at significant risk of the syndrome.

After ovarian hyperresponse was diagnosed, gonadotrophin dosages were reduced; however, no patient had gonadotrophin therapy completely suspended (coasting). If patients continued to exhibit ovarian hyperresponse despite decreased gonadotrophins, they were treated with GnRH antagonist and included in analysis. All infertility diagnoses were included.

A control group not treated with ganirelix acetate was selected from the pool of 893 patients. Control patients were matched to the treatment group at a 1:1 ratio. Controls were matched for age ±1 year, leuprolide acetate down-regulation protocol and infertility diagnosis. In the event there was more than one available match, the patient whose treatment date was closest to that of the treatment subject was selected.

Intervention
Long luteal (LL) leuprolide acetate or microdose flare (MDF) protocols were used to treat patients based on initial clinical assessment of probable ovarian response determined by age, diagnosis, prior stimulation response (if applicable), cycle day 3 FSH level, ovarian volume, antral follicle count and clomiphene citrate challenge test (Navot et al., 1987Go). All patients (LL and MDF) received 14–42 days of 30 µg of ethinyl E2/300 µg of norgestrel oral contraceptive pills (OCP) that were discontinued on ART cycle day 0. Beginning day 21 of the OCP cycle, patients receiving LL leuprolide acetate were treated with 1 mg/day s.c. of GnRH agonist. LL patients were evaluated by screening transvaginal ultrasound and serum E2 level to confirm ovarian suppression after at least 10 days of leuprolide injections. After ovarian quiescence was confirmed, leuprolide acetate dosage was decreased to 0.25 mg/day s.c., followed by exogenous gonadotrophin therapy initiation 3 days later. After screening transvaginal ultrasound and serum E2, MDF patients began 40 µg of leuprolide acetate s.c. every 12 h beginning on cycle day 3 (Leondires et al., 1999Go). For both stimulation regimens, dosages of recombinant FSH and HMG were individualized based on anticipated ovarian response and given in twice daily dosing.

If rapidly rising E2 levels were observed, gonadotrophin dosage was decreased without complete cessation. Once patients were noted to have continued ovarian hyperresponse as previously defined, the following cycle stimulation changes were made: leuprolide acetate discontinued, ganirelix acetate 250 µg s.c. administered daily until HCG injection and all patients received 37.5–75 IU HMG at night with or without 75–150 IU recombinant FSH in divided doses after starting ganirelix.

Duration of ganirelix acetate therapy was dependent on follicular size criteria for HCG administration and not on a specific E2 level, although it was preferable to allow the E2 level to decrease <3000 pg/ml. HCG 5000 IU (E2 ≥ 5000 pg/ml at ganirelix initiation) or 10000 IU (E2 < 5000 pg/ml at ganirelix initiation) was typically administered when at least four follicles were ≥16 mm in diameter. Peak E2 was obtained the morning after HCG injection. Oocyte retrieval was performed 35–36 h after HCG administration. ICSI was performed where clinically indicated. High-grade embryos were defined as <20% fragmentation with eight symmetric cells on post-retrieval day 3. Embryo transfers were routinely performed on day 3 after retrieval or day 5, as described (Frattarelli et al., 2003Go). After retrieval, luteal support was progesterone in oil 50 mg/day i.m. (or 200 mg micronized progesterone intravaginally three times daily if allergic to oil preparations) and was continued until either a negative serum pregnancy test or 8 weeks of gestation. All patients who were 35 years or older were treated additionally with 200 mg daily of intravaginal micronized progesterone. Serum pregnancy test was performed 14 days after oocyte retrieval and repeated in 48 h if positive. The presence of a gestational sac with fetal cardiac activity on transvaginal ultrasound at 6–8 weeks consistent with gestational age was the definition of ongoing clinical pregnancy.

Laboratory analysis
Serum E2 levels were determined with an electrochemiluminescence immunoassay (Modular Analytics E-170; Roche Laboratories, Switzerland). With this assay, both the inter-assay and intra-assay coefficients of variation (CVs) were hormone-concentration dependent and, at the lowest E2 concentration, were 4.7 and 3.3%, respectively. The largest CV was noted at the lowest E2 concentration.

Statistical analysis
Independent Student’s t-test or Chi-square test was used to compare group demographic parameters as appropriate. Chi-square test of homogeneity was used to compare treated and control group diagnoses. Friedman’s test was used to compare E2 levels of the same patient during stimulation, ganirelix treatment and after HCG administration. Binomial proportion testing was used to compare rates as appropriate. P < 0.05 was considered statistically significant. The time frame of data collection determined the patient sample size. All data are presented as mean ± SD unless otherwise noted.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Disclosure
 Acknowledgements
 References
 
Eighty-seven patients met criteria for treatment with ganirelix acetate after agonist suppression during the study interval and were included in the analysis. Additionally, 87 control patients were matched and selected for comparison. Patient and cycle characteristics of the two groups, LL and MDF, and controls are described in Table I. Notably, the MDF group was significantly older (P < 0.001) and required more recombinant FSH ampoules than the LL group (P = 0.002). Also, diagnoses of diminished ovarian reserve and unexplained infertility were more common in the MDF group, however not statistically significant. Our programme uses the MDF regimen frequently for both its cost benefits and efficacy compared with the LL regimen (Leondires et al., 1999Go), and this difference accounts for the greater number of patients in the MDF group compared with the LL group.


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  		Table I. Cycle characteristics

 
Individually, patients suppressed with LL or MDF demonstrated a significant reduction in E2 levels within 24 h (P < 0.001) after beginning treatment with ganirelix acetate despite continuing gonadotrophins (LL group; Figure 1). Daily E2 levels during ovarian stimulation for a representative patient on either LL or MDF regimen with ovarian hyperresponse are depicted in Figure 2. The E2 response curve using either regimen was similar in appearance. The E2 level exceeded 4000 pg/ml on day 10 of stimulation, but within 12 h of initiating ganirelix there was a significant decline in serum E2. By the morning following administration of HCG, the serum E2 peaked at a level comparable to the E2 concentration when ganirelix was initiated. For the cohort of LL- and MDF-treated patients, the average E2 reduction was 42.4 and 35.4%, respectively, and post-HCG E2 levels were minimally elevated (15.2 and 29.7%, respectively) over E2 levels when ganirelix therapy was started (Table II). With continued days of GnRH-antagonist therapy in the MDF group, the E2 levels continually decreased to a nadir of 58.8% the starting E2 level.


Figure 1
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  		Figure 1. Plot of estradiol values from individuals (n=13) treated with long-luteal suppression followed by ganirelix. Serum levels on the first day of ganirelix treatment, day of hCG and peak estradiol one day after hCG are plotted. The mean estradiol levels for the 13 subjects is indicated by the dashed black line.

 

Figure 2
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  		Figure 2. Representative estradiol curve of a patient on microdose flare stimulation regimen. Note that the patient had an estradiol level exceeding 4,000 pg/ml at the time of ganirelix initiation. After ganirelix treatment, the estradiol decreased significantly with subsequent increase after hCG administration.

 

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  		Table II. Relative changes in estradiol (E2)

 
Ovarian follicle characteristics on the first day of ganirelix treatment and HCG administration compared with controls are reported in Table III. Compared with the control group, patients in both LL- and MDF-treatment groups had significantly more total follicles, oocytes retrieved, mature oocytes and 2PN embryos at 24 h. There were, however, no differences in the E2 level on the day of HCG administration, use of ICSI, maturity rate, 2PN rate or fertilization rate. Ovarian follicles in the treatment group continued to exhibit growth despite rapid, significant decreases in E2 (Table III); an equivalent number of oocytes and metaphase II oocytes were obtained at retrieval when comparing the LL and MDF group. The cumulative cycle outcomes for the LL and MDF groups and all patients are summarized in Tables III and IV. The rate of implantation, overall pregnancy, ongoing pregnancy, cancellation and severe OHSS were all statistically similar between the respective treatment groups compared with controls.


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  		Table III. Characteristics of estradiol (E2) levels, follicles and oocytes with GnRH-antagonist treatment

 

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  		Table IV. Cycle outcomes

 
In the group of patients with multiple risk factors for developing OHSS that were treated with ganirelix, only four patients (4.6%) were diagnosed with OHSS: two patients (2.3%) had mild symptoms responding to oral antiemetics and two (2.3%) were diagnosed with severe OHSS requiring paracentesis and overnight hospitalization for intravenous fluids. The control group had only one patient (1.2%) with severe OHSS. There was no statistically significant difference in the rate of severe OHSS between the treated group and the control group.

An error in HCG administration and a large endometrial polyp resulted in cycle cancellation for two patients. Two patients administered medications incorrectly by (i) using ganirelix and MDF leuprolide simultaneously or (ii) continuing gonadotrophins at the incorrect prescribed dosage; however, both proceeded to retrieval without complications or OHSS. The patient who erroneously took ganirelix and leuprolide simultaneously had an increase in E2 the first day after starting ganirelix rather than the anticipated decrease. After discontinuation of leuprolide, the E2 decreased.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Disclosure
 Acknowledgements
 References
 
In this retrospective cohort, treatment of hyperresponding patients with GnRH antagonists after agonist pituitary suppression resulted in a reproducible and reliable decrease in E2 levels. Despite a significant, rapid decline in E2 level, this treatment strategy appeared not to have any adverse effects on follicular growth, oocyte maturity, fertilization rate, embryo quality or pregnancy outcome compared with control group. Compared with spontaneous decreases in E2 levels, ganirelix-induced declines in serum E2 did not appear to impact negatively on the resultant embryo quality. The decline in E2 appears to mitigate the risk of developing OHSS: 4.6% compared with the expected 9–38% based on previous reports (Asch et al., 1991Go; Morris et al., 1995Go). The percentage of patients who developed OHSS was similar to that seen in patients who were treated by coasting in other studies, without the deleterious effects on embryology or pregnancy rates observed with coasting (Ulug et al., 2002Go; Aboulghar, 2003Go).

GnRH agonists reduce the GnRH receptors in the pituitary, whereas antagonists reversibly block the signalling cascade. Logically, one might expect no effect of GnRH antagonists when administered to patients pretreated with GnRH agonist. We noted, however, that GnRH-antagonist treatment resulted in reduction of serum E2 in women despite GnRH-agonist pituitary suppression. Studies have revealed that both GnRH-I and GnRH-II receptors are present in the granulosa cells of the ovary (Kang et al., 2003Go; Khosravi and Leung, 2003Go; Leung et al., 2003Go). Theoretically, ovarian receptors may represent a possible mechanism of action for GnRH antagonist, perhaps through a direct effect upon the granulosa cells.

The day 3 embryo and overall implantation rates of patients treated with LL suppression were significantly higher (Table IV, P = 0.017) than in patients treated with MDF. Patients in the MDF group were approximately 5 years older than the patients in the LL group, possibly accounting for the difference in implantation rate. Hull et al. (1996)Go has described that age is inversely proportional to implantation rate, consistent with our findings. Alternatively, sampling error may account for the difference as the LL group has only 13 patients compared with 72 patients in the MDF group. Further study is necessary to clarify this finding.

No treatment strategies have proven effective at eliminating the risk of OHSS, short of cycle cancellation in randomized, prospective, double-blind studies. Coasting, the most commonly used method of preventing OHSS in hyperresponse, and embryo cryopreservation have resulted in inconsistent embryo quality, pregnancy rates, cycle cancellations and incidence of OHSS (D’Angelo and Amso, 2002Go; Delvigne and Rozenberg, 2002Go). Often, it is necessary to coast for 3 or 4 days to decrease the patient’s E2 level. With the immediate and predictable drop in E2 level utilizing this protocol, the repeated monitoring visits and blood draws can be minimized with a potential for cost savings. Additionally, increased duration of gonadotrophin-free intervals resulted in both diminished embryo quality and pregnancy rates (Isaza et al., 2002Go; Ulug et al., 2002Go; Mansour et al., 2005Go).

Ulug et al. (2002)Go reported their experience with coasting for ovarian hyperresponse in a large ART patient population. We observed the following differences between coasting in their study and utilizing the application of GnRH antagonist as described: similar E2 levels when ganirelix or coasting initiated (4219.8 cumulative versus 4590.8 pg/ml calculated group total); similar E2 levels on the day of HCG administration (2590.0 cumulative versus 2644.4 pg/ml); greater oocytes retrieved (24.9 cumulative versus a maximum of 19.15 at 1 day coasted); equivocal fertilization rates (71.3 cumulative versus a maximum of 74% at 1 day coasted); a higher overall implantation rate (36.6 cumulative versus a maximum of 27.9% at 2 days coasted); less embryos transferred (2.25 cumulative versus 4.18 calculated group total); higher overall pregnancy rate (62.4 versus 50.4%) and equal risk of severe OHSS (2.4 versus 1.9%).

Mansour et al. (2005)Go reported a large series of patients (n = 1223) who had been coasted via a standardized protocol based on lead follicle size and E2 level. In comparison with their report, we noted the following differences when compared with our protocol: higher E2 level when coasting was initiated (6538 pg/ml); similar E2 level at HCG administration (2755 pg/ml); fewer oocytes retrieved (16.21) and 2PN oocytes (8.11) and modestly lower rates of fertilization (63%), implantation (25%), clinical pregnancy rate (48%) and OHSS (1.3%). Their study of coasting is one of few with a standardized regimen applied to a large group of patients.

Studies by Egbase et al. (2000)Go and Tozer et al. (2004)Go have also reported a reduction in oocyte recovery (28.3 and 43.3%, all values from studies by Egbase and Tozer, respectively), decreased fertilization (58.4 and 45.6%) and lower pregnancy outcome (33.3 and 28.9%) when using coasting versus the strategy we report. Comparatively, we have observed excellent oocyte recovery (83.2% LL and 96.4% MDF) compared with our control group (P = NS)—a notable difference when evaluating studies of coasting. Though there are inherent problems when comparing outcomes by different programmes, this treatment strategy yielded similar pregnancy results in comparison with our control group. Most important, these effects are reliably observed in an average of 1.4 days of therapy with GnRH antagonist compared with an average of 2.9 days coasting reported by Ulug et al. (2002)Go, Tozer et al. (2004)Go and Mansour et al. (2005)Go. The therapeutic use of ganirelix we describe offers a reduction in E2, no apparent adverse effect upon embryo development and satisfactory pregnancy outcome with a similar risk of OHSS compared with these studies of coasting.

The current study is limited by its retrospective nature. In addition, our programme utilized the LL regimen less than most ART centres and this particular group will need further study to confirm its applicability to patients down-regulated with LL. In conclusion, in this high risk group, OHSS occurred at an acceptable rate and at a rate similar to that reported in other studies of coasting. The ganirelix salvage treatment strategy may prove to be a reliable alternative to coasting or cycle cancellation due to elevated E2 levels in GnRH-agonist-treated cycles.


   Disclosure
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Disclosure
Acknowledgements
 References
 
The views expressed in this article are those of the author and do not reflect the official policy of the Department of the Army, Department of Defense or US Government.


   Acknowledgements
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Disclosure
 Acknowledgements
References
 
We thank Mark R. Bush, MD, for thoughtful discussions regarding the concept. We gratefully acknowledge the WRAMC ART nursing (Donna Materia Hoover, RN, Darshana Naik, RN, Stephanie Hosid, RN and Tessa Damon, RN) and embryology staff (Aidita James, PhD, Sasha Hennessy, BSc, Brett Reggio, PhD, Julie Stoops, BS and Jacques Cohen, PhD) for their support of this research.

This research was supported, in part, by the Intramural Research Program of the Reproductive Biology and Medicine Branch, NICHD, NIH.


   Footnotes
 
* Paper presented at the Annual Meeting of the American Society of Reproductive Medicine, Montreal, Quebec, Canada, October 2005. Back


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Disclosure
 Acknowledgements
 References
 
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Submitted on August 23, 2005; resubmitted on January 4, 2006; resubmitted on February 2, 2006; accepted on February 7, 2006.


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