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Luteal phase rescue in high-risk OHSS patients by GnRHa triggering in combination with low-dose HCG: a pilot study
RBMOnline - Vol 18. No 5. 2009 630-634 Reproductive BioMedicine Online; www.rbmonline.com/Article/3699 on web 19 March 2009
Article Luteal phase rescue in high-risk OHSS patients by GnRHa triggering in combination with lowdose HCG: a pilot study Peter Humaidan obtained his MD degree in 1983 and the speciality degree in Obstetrics and Gynaecology in 1990 at the Sahlgrenska University Hospital, Gothenburg, Sweden. In the same year he obtained the Danish speciality degree in Obstetrics and Gynaecology. During the last 9 years he has been working as a specialist in reproductive endocrinology at The Fertility Clinic Skive, Viborg County, Denmark. He is a former board member of the Danish Fertility Society. His research interests include reproductive endocrinology, gonadotrophin function, sperm chromatin integrity in relation to outcome of assisted reproduction treatment and acupuncture related to infertility.
Dr Peter Humaidan P Humaidan The Fertility Clinic, Skive Regional Hospital, DK 7800 Skive, Denmark Correspondence: e-mail: [email protected]
Abstract Triggering of final oocyte maturation with gonadotrophin-releasing hormone agonist (GnRHa) has previously been shown to prevent ovarian hyperstimulation syndrome (OHSS), but at the same time a detrimental effect on clinical outcome parameters was usually reported. In this prospective, observational, proof-of-concept study, a new protocol was employed, using GnRHa to trigger final oocyte maturation in OHSS high-risk IVF/ICSI patients after co-treatment with GnRH antagonist. The aim was to avoid cycle cancellation in high-risk patients without increasing the risk of early onset OHSS and simultaneously secure the reproductive outcome. Twelve patients with ≥25 follicles ≥11 mm in diameter after ovarian stimulation were prospectively enrolled to have final oocyte maturation triggered with 0.5 mg buserelin s.c., followed by a single bolus of 1500 IU human chorionic gonadotrophin (HCG) 35 h later to rescue the luteal phase. A mean of 21.5 oocytes was retrieved. All patients underwent embryo transfer, resulting in an ongoing clinical pregnancy rate per cycle of 50% (6/12) and a live birth rate of 50% (6/12). One patient developed moderate, late onset OHSS that did not require hospitalization. GnRHa triggering of final oocyte maturation followed by one bolus of 1500 IU HCG seems to prevent early onset OHSS in high-risk patients and secure the reproductive outcome. Keywords: GnRH agonist, GnRH antagonist, hCG, IVF, OHSS
Introduction
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Ovarian hyperstimulation syndrome (OHSS) remains a clinical challenge in IVF/intracytoplasmic sperm injection (ICSI) treatment. It is a potentially life threatening condition, resulting in hospitalization in approximately 1.8% of patients (Mocanu et al., 2007). In its severe form, OHSS causes vascular permeability, haemoconcentration, accumulation of fluid in the peritoneal cavity and lungs and disruption of coagulation (Delvigne and Rozenberg, 2002). The triggering factor of OHSS is considered to be human chorionic gonadotrophin (HCG), exogenous or endogenous, resulting in an early and late development of the syndrome respectively (Al-Shawaf and Grudzinskas, 2003). Thus, early onset OHSS is described as occurring within 9 days after oocyte retrieval, and is related to the ovulatory dose of HCG, whereas late onset OHSS
occurs after the initial 10 day period as a consequence of the endogenously produced HCG by the trophoblast (Mathur et al., 2000). Overall risk factors of OHSS include young age, low body mass index (BMI), polycystic ovary syndrome (PCOS), polycystic ovarian morphology (Esinler et al., 2005) and patients with a previous history of high response to gonadotrophins. In order to avoid the use of HCG for ovulation induction, and thus possibly reduce the risk of early onset OHSS, gonadotrophin-releasing hormone agonist (GnRHa) has been suggested as an alternative trigger of ovulation (Nakano et al., 1973). However, the simultaneous use of GnRHa for downregulation and ovulation induction is not possible. Therefore,
© 2009 Published by Reproductive Healthcare Ltd, Duck End Farm, Dry Drayton, Cambridge CB23 8DB, UK
Article - Luteal phase rescue in high-risk OHSS patients - P Humaidan
with the advent of GnRH antagonist protocols to prevent a premature LH surge, it became an option again to trigger final oocyte maturation with a bolus of GnRHa, as GnRHa displaces the GnRH antagonist from the receptor in the pituitary eliciting a simultaneous LH and FSH surge (flare-up) prior to downregulation of the receptor. It has previously been shown that GnRHa is as effective as HCG for triggering of final oocyte maturation (Gonen et al., 1990; Imoedemhe et al., 1991; Itskovitz et al., 1991; Segal and Casper, 1992). Importantly, the half-life of LH is significantly shorter, (60 min), than that of HCG (>24 h) (Yen et al., 1968; Damewood et al., 1989). Moreover, GnRHa induces an FSH surge in addition to the LH surge, resembling the FSH surge of the natural cycle (Nakano et al., 1973). The exact role of the mid-cycle FSH surge is not fully understood, but FSH among others induces LH receptor formation in the corpus luteum (CL), optimizing the function of the CL and promotes nuclear maturation, i.e. resumption of meiosis (Zelinski-Wooten et al., 1995; Yding Andersen et al., 1999, 2002). There are, however, significant differences regarding the duration and the profile of the GnRHa induced LH surge as compared with the LH surge of the natural cycle (Hoff et al., 1983; Itskovitz et al., 1991), leading to a significantly reduced amount of gonadotrophins released when GnRHa is used to trigger final oocyte maturation. Although small-scale studies have suggested that triggering of final oocyte maturation with GnRHa prevents OHSS in high-risk patients (Kol and Itskovitz-Eldor, 2000; Kol 2003; Babayof et al., 2006; Griesinger et al., 2007; Engmann et al., 2008), two large randomized studies found a poor clinical outcome when GnRHa was used to trigger ovulation in normal responder patients, presumably due to a CL deficiency, despite luteal phase support with progesterone and oestradiol (Humaidan et al., 2005; Kolibianakis et al., 2005). Inspired by a previous study in intrauterine insemination patients (Emperaire et al., 2004), a pilot study was performed in IVF/ICSI patients following a GnRH antagonist protocol, in which a bolus of 1500 IU HCG was administered 12 h or 35 h after triggering of final oocyte maturation with GnRHa (Humaidan et al., 2006). The results of this pilot study showed that timing of the supplementary HCG dose plays an essential role for the rescue of the corpora lutea, and that HCG administered 35 h after final oocyte maturation with GnRHa resulted in a reproductive outcome similar to that of 10,000 IU HCG induced oocyte maturation (Humaidan et al., 2006). Encouraged by these results, a large prospective randomized trial including a total of 300 IVF/ICSI cycles was performed comparing HCG to trigger final oocyte maturation with GnRHa, supplemented with a bolus of 1500 IU HCG 35 h later. The results of this trial confirmed the findings of the pilot study (Humaidan et al., 2007). Furthermore, although the study was not powered to detect differences in OHSS, interestingly no OHSS case was seen in the GnRHa group, despite supplementation with 1500 IU HCG, whereas three cases (2%) were seen in the HCG group. Moreover, approximately one-third of patients in both study groups had more than 10 oocytes retrieved, indicating that they had at least 14 follicles ≥11 mm on the day of ovulation induction, a cut-off level that has previously been suggested to be predictive of the risk of RBMOnline®
developing OHSS (Papanikolaou et al., 2005). The aim of this prospective observational study was to explore the safety in terms of early onset OHSS and efficacy in terms of ongoing pregnancy rate and live birth rate of a new modified protocol (Humaidan et al., 2006) in a group of well-informed patients at high-risk of developing OHSS, i.e. patients with ≥25 follicles ≥11 mm on the day of triggering of final oocyte maturation.
Materials and methods The observational period was from May 2006 until August 2007, and the study was a one-centre, prospective, observational, proof-of-concept study. Patients were thoroughly informed about alternative options of OHSS prevention, i.e. cancellation, coasting and total freeze, before deciding to participate.
Patients Inclusion criteria were: (i) IVF or ICSI; (ii) female age between 20 and 40 years; (iii) body mass index (BMI) >18 and <35; (iv) high risk of OHSS, defined as ≥25 follicles ≥11 mm on the day of triggering of ovulation.
Hormonal treatment Ovarian stimulation was initiated with recombinant human FSH (r-hFSH; Puregon; Organon, Skovlunde, Denmark) from cycle day 2 and continued until the day of ovulation induction. A fixed dose of r-hFSH, 100–200 IU per day for the first 6 days was used, according to age, BMI, basal FSH, antral follicle count and ovarian volume. After 6 days, doses were adjusted according to ovarian response. Once the leading follicle had reached a size of 13 mm, co-treatment with the GnRH antagonist ganirelix (Orgalutran; Organon) 0.25 mg was initiated and continued up to and including the day of ovulation induction. Patients were enrolled in the study on the day of the last scan if ≥25 follicles ≥11 mm in diameter were present. When at least two follicles had reached a size of 17 mm, final oocyte maturation was triggered with a single bolus of 0.5 mg buserelin s.c. (Suprefact; Hoechst, Hørsholm, Denmark), followed by oocyte retrieval 34 h later. After oocyte retrieval, at 35 h after the buserelin injection, patients received a single injection of 1500 IU HCG i.m. (Pregnyl; Organon). A maximum of two embryos was transferred on day 2 or 3 after retrieval, following national criteria of single embryo transfer (SET), according to which patients below 35 years of age should receive a single embryo for transfer during their first IVF/ICSI attempt. All patients received luteal phase support in the form of micronized progesterone vaginally, 90 mg a day (Crinone; Serono Nordic, Copenhagen, Denmark) and oestradiol 4 mg a day orally (Estrofem; Novo Nordisk, Copenhagen, Denmark) commencing from the day following oocyte retrieval and continuing until the day of the pregnancy test, i.e. day 12 after embryo transfer. A biochemical pregnancy was defined by a plasma B-HCG concentration >10 IU/l on day 12 after embryo transfer. A clinical pregnancy was defined as an intrauterine gestational sac with a heartbeat 3 weeks after a positive HCG test. An ongoing pregnancy was defined as a viable pregnancy in week 11 of pregnancy.
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Article - Luteal phase rescue in high-risk OHSS patients - P Humaidan
Outcome measures Main outcome measure was the incidence of early and late onset OHSS (Golan et al., 1989; Mathur et al., 2000). Secondary outcome measures were the ongoing clinical pregnancy rate per cycle and live birth rate per cycle.
Results Patient characteristics and stimulation A total of 12 patients were enrolled in the study and all patients had an embryo transfer. Indications for IVF/ICSI treatment were: male factor (n = 7), tubal factor (n = 3), endometriosis (n = 1) and anovulation (n = 1). Table 1 summarizes the demographic data of patients enrolled. Stimulation days, total amount of exogenous FSH required, total dose of GnRH antagonist, fertilization rate and numbers of embryos transferred are summarized in Table 2.
OHSS No patient developed early onset OHSS. One patient developed late onset, moderate OHSS, that did not require hospitalization.
Pregnancy Twelve embryo transfers resulted in 10 positive HCG tests (83% per cycle). Six pregnancies, one twin pregnancy and five singleton pregnancies were ongoing in week 11 (50%/cycle). Subsequently one set of twins and five singletons were born giving a live birth rate of 50%/cycle. Two pregnancies were biochemical and two pregnancies were missed abortions (Table 3).
Discussion
63% in a group of 32 high-risk oocyte donors who had HCG to trigger final oocyte maturation, following a GnRH antagonist protocol. Donors were classified to be at high risk if they had a retrieval of more than 20 oocytes and the development of 20–30 follicles ≥12 mm. Thus patients in the present proof-of-concept study with ≥25 follicles ≥11 mm on the day of triggering of final oocyte maturation and a mean of 21.5 oocytes fulfilled the most recent criteria set to define high-risk patients. Compared with the Alvarez et al. study (2007), a surprisingly high reduction in the early onset OHSS rate was seen. In the present study, ovarian response parameters were used to identify the high risk group. Early onset OHSS is related to ovarian sensitivity, response to stimulation and the ovulatory dose of HCG, whereas late onset OHSS is only poorly related to ovarian response, but more to the endogenous HCG produced by the implanting embryo (Mathur et al., 2000). Thus, late onset OHSS is difficult to predict from ovarian response parameters, which was also reflected in this study, and although the OHSS rate in this small group of high risk patients was low, it is unlikely that the present protocol will prevent late onset OHSS. So far, in the OHSS high-risk patient, only two prospective randomized studies investigated the incidence of OHSS when GnRHa was used to trigger ovulation after GnRH antagonist co-treatment as compared with HCG (Babayof et al., 2006; Engmann et al., 2008) and first and foremost conflicting results regarding ongoing pregnancy rates exist.
Table 1. Demographic data. Baseline FSH (IU) Baseline LH (IU) Age (years) Body mass index (kg/m2) Cycle no.
5.5 ± 1.7 7.1 ± 3.4 30.7 ± 3.8 23.7 ± 2.4 1.7 ± 0.7
Values are mean ± SD
This is the first study to investigate the incidence of early onset OHSS in a group of high-risk patients in whom final oocyte maturation was triggered with GnRHa followed by a single bolus of 1500 IU HCG 35 h later to rescue the luteal phase. With this new modified protocol, no early onset OHSS was seen and a high live birth rate in patients at high risk of OHSS was achieved. One patient developed late onset moderate OHSS. This patient had an elective single embryo transfer and delivered a healthy child at term.
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The overall incidence of OHSS in high-risk groups undergoing IVF has been reported as 32% (Wada et al., 1993). However, the definition of high-risk groups differs somewhat in the literature. In 637 GnRHa down-regulated cycles, Asch et al. (1991) focusing only on severe OHSS (late onset) found a cutoff level of either oestradiol on the day of HCG >6000 pg/ml (19 nmol/l) or the retrieval of >30 oocytes to be predictive. This is contrasted by Papanikolau et al. (2006) who in 2524 GnRH antagonist cycles defined a threshold value of ≥18 follicles ≥11 mm on the day of HCG to have 83% specificity in predicting severe OHSS. Finally, in oocyte donors, Alvarez et al. (2007) reported an early onset OHSS rate (moderate and severe) of
Table 2. Stimulation, oocytes and fertilization. Stimulation (days) Total FSH (IU) Total dose of antagonist (mg) Serum oestradiol day of ovulation induction (nmol/l) Oocytes, n Fertilization rate, n (%) Cleavage rate, n (%) Embryos transferred, n
10.8 ± 4.9 1141.9 ± 460.3 1.0 ± 0.0 18.6 ± 10.5 21.5 ± 6.0 138/258 (53.5) 120/138 (87.0) 1.7 ± 0.5
Values are mean ± SD
Table 3. Pregnancy outcome. Positive HCG test/cycle, n (%) Early pregnancy loss, n (%) Clinical ongoing pregnancy/cycle, n (%) Live birth/cycle, n (%)
10/12 (83.3) 4/10 (40.0) 6/12 (50.0) 6/12 (50.0)
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Article - Luteal phase rescue in high-risk OHSS patients - P Humaidan
Thus, in the randomized study by Engmann et al. (2008), 30 high-risk patients following a GnRH antagonist protocol had final oocyte maturation triggered with a bolus of GnRHa. A mean of 20.2 oocytes was retrieved. Patients received intensive luteal phase support in the form of 50–70 mg progesterone i.m. daily to maintain a serum concentration above 60 nmol/l and three to four transdermal oestradiol patches every other day and/or addition of oral oestradiol to maintain a serum oestradiol concentration above 200 pg/ml. No patient developed OHSS, and a high ongoing pregnancy rate was reported. This is contrasted by the randomized study by Babayof et al. (2006). In this study, 15 patients considered at risk of developing OHSS and following a GnRH antagonist protocol had triggering of final oocyte maturation with GnRHa. A mean of 19.8 oocytes were retrieved and again the luteal phase was heavily supported with 50–100 mg progesterone i.m. daily to maintain serum progesterone concentrations above 40 nmol/l and oestradiol, 4 mg orally/day. No OHSS case was reported, but despite the intensive luteal phase support, resembling the luteal phase support of the Engmann study (2008), an early pregnancy loss rate of 80% in the GnRHa group was seen, similar to pregnancy loss rates previously reported when GnRHa was used to trigger final oocyte maturation in normal responder patients (Humaidan et al., 2005; Kolibianakis et al., 2005) and OHSS risk patients (Itskovitz-Eldor et al., 2000; Kol and Muchtar 2005). Apart from these randomized trials, a number of small scale studies in OHSS high-risk patients, either retrospective or observational, on GnRHa triggering of final oocyte maturation exist in the literature reporting only two cases of OHSS requiring either hospitalization or classified as severe (lateonset) after GnRHa triggering (Meltzer et al., 2002; Chun et al., 2005). However, clinical pregnancy rates range from 0 to 75% (Griesinger et al., 2006), most probably depending on the type of luteal phase support administered (Griesinger et al., 2006; Kol and Solt, 2008). Another way to circumvent the problems of adequate luteal phase support, early pregnancy loss and risk of OHSS, would be to trigger final oocyte maturation with GnRHa followed by elective cryopreservation and transfer in a subsequent frozen embryo replacement cycle. This procedure was recently investigated by Griesinger et al. (2007) in a proof of concept study including 20 patients at increased risk of developing OHSS, defined as ≥20 follicles ≥10 mm on the day of induction of final oocyte maturation. A mean of 16 oocytes was retrieved. No cases of moderate or severe OHSS were observed, and a good ongoing pregnancy rate per first frozen thawed embryo transfer cycle was reported. In the present study, early onset OHSS was prevented and a high live birth rate (50% per cycle) was seen in a small highrisk group of patients. The early pregnancy loss rate reported (40%) is higher than the mean pregnancy loss rate normally seen in the clinic (26%) when GnRH antagonist protocols are used in combination with 10,000 IU HCG to trigger ovulation. However, this material is too small to make any firm conclusions regarding early pregnancy loss. Interestingly, all patients had polycystic ovarian morphology and could have an increased early pregnancy loss rate similar to that of PCOS patients (Homburg, 2006). RBMOnline®
Taken together, the results of the present study are encouraging for GnRHa triggering, but need to be confirmed in a larger series. Approval of the Review Board was recently obtained to perform a larger prospective randomized multi-centre study focusing on a possible reduction in the OHSS rate when GnRHa is used to trigger final oocyte maturation in the high-responder patient. Patients in the control arm of this RCT will receive a reduced dose of HCG in order not to expose patients to an unnecessary high risk of early onset OHSS. The advantages of the present procedure compared with a total freeze are the avoidance of the psychological distress of a cancelled transfer, the avoidance of embryo loss due to the freezing and thawing procedure and lower pregnancy rates in embryo thaw cycles. In conclusion, the current proof-of-concept study suggests that GnRHa triggering of final oocyte maturation followed by a bolus of 1500 IU HCG on the day of aspiration prevents early onset OHSS and secures the clinical pregnancy outcome in highrisk patients. More and larger studies are needed to confirm the present and previous reports and to assess the optimal luteal phase support when GnRHa is used to trigger final oocyte maturation. However, GnRHa triggering after GnRH antagonist co-treatment leaves the clinician and the well-informed patient with several individually tailored options that seem to prevent/ reduce the risk of OHSS.
Acknowledgements The author wishes to thank the nurses and laboratory technicians of the Fertility Clinic, Skive Regional Hospital for their assistance during this study.
References Asch RH, Huey-PO L, Balmaceda J et al. 1991 Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups. Human Reproduction 6, 1395–1399. Al-Shawaf, Grudzinskas JG 2003 Prevention and treatment of ovarian hyperstimulation syndrome. Best Practice and Research, Clinical Obstetrics and Gynecology 17, 249–261 Alvarez C, Marti-Bonmati L, Novella-Maestre E et al. 2007 Dopamine agonist cabergoline reduces hemoconcentration and ascites in hyperstimulated women undergoing assisted reproduction. Journal of Endocrinology and Metabolism 92, 2931–2937. Babayof R, Margalioth EJ, Huleihel M et al. 2006 Serum inhibitn A, VEGF and TNFα levels after triggering oocyte maturation with GnRHa compared with hCG in women with polycystic ovary syndrome undergoing IVF treatment. Human Reproduction 21, 1260–1265. Chun E 2005 Severe OHSS can be prevented in GnRH antagonist protocol using GnRHa to trigger ovulation. Fertility and Sterility 84 (Suppl.1), S301 (P-149) Damewood MD, Shen W, Zacur HA et al. 1989 Disappearance of exogenously administered human chorionic gonadotropin. Fertility and Sterility 52, 398–400. Delvigne A, Rozenberg S 2002 Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Human Reproduction Update 8, 559–577. Emperaire JC, Parneix I, Ruffie A 2004 Luteal phase defects following agonist-triggered ovulation: a patient-dependent response. Reproductive BioMedicine Online 9, 22–27. Engmann L, Diluigi A, Schmidt D et al. 2008 The use of
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gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertility and Sterility 89, 84–91. Esinler I, Bayar U, Bozdag G et al. 2005 Outcome of intracytoplasmic sperm injection in patients with polycystic ovary syndrome. Fertility and Sterility 84, 932–937. Golan A, Ron-El R, Herman A 1989 Ovarian hyperstimulation syndrome: an update review. Obstetrical and Gynecological Survey 44, 430–440. Gonen Y, Balakier H, Powell W et al. 1990 Use of GnRH agonist to trigger follicular maturation for in vitro fertilization. Journal of Clinical Endocrinology and Metabolism 71, 918–922. Griesinger G, Von Otte S, Schroer A et al. 2007 Elective cryopreservation of all pronuclear oocytes after GnRH agonist triggering of final oocyte maturation in patients at risk of developing OHSS: a prospective, observational proof-of-concept study. Human Reproduction 22, 1348–1352. Griesinger G, Diedrich K, Tarlatzis BC et al. 2006 GnRH antagonists in ovarian stimulation for IVF in patients with poor response to gonadotrophins, polycystic ovary syndrome, and risk of ovarian hyperstimulation: a meta-analysis. Reproductive BioMedicine Online 13, 628–638. Hoff JD, Quigley ME, Yen SS 1983 Hormonal dynamics at midcycle: a revaluation. Journal of Clinical Endocrinology and Metabolism 57, 792–796. Homburg R 2006 Pregnancy complications in PCOS. Best Practise and Research in Clinical Endocrinology and Metabolism 20, 281–292. Humaidan P, Ejdrup Bredkjær, Westergaard L et al. 2007 1500 IU hCG secures a normal clinical pregnancy outcome in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist. Human Reproduction 22 (Suppl. 1), O-203. Humaidan P, Bungum L, Bungum L, Yding Andersen C 2006 Rescue of corpus luteum function with periovulatory hCG supplementation in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist – a pilot study. Reproductive BioMedicine Online 13, 173–178. Humaidan P, Ejdrup Bredkjær H, Bungum L et al. 2005 GnRH agonist (Buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomised study. Human Reproduction 20, 1213–1220. Imoedemhe DA, Sigue AB, Pacpaco EL et al. 1991 Stimulation of endogenous surge of luteinizing hormone with gonadotropinreleasing hormone analogue after ovarian stimulation for in vitro fertilization. Fertility and Sterility 55, 328–332. Itskovitz J, Boldes R, Levron J et al. 1991 Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertility and Sterility 56, 213–220. Itskovitz-Eldor J, Kol S, Mannaerts B 2000 Use of a single bolus of GnRH-atagonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hperstimulation syndrome: a preliminary report. Human Reproduction 15, 1965–1968. Kol S 2003 Prediction of ovarian hyperstimulation syndrome: why predict if we can prevent. Human Reproduction 18, 1557–1558 Kol S, Itskovitz–Eldor J 2000 severe OHSS: yes there is a strategy to prevent it! Human Reproduction 15, 2266–2267. Kol S, Muchtar M 2005 Recombinant gonadotrophin-based, ovarian hyperstimulation syndrome-free stimulation of the high responder: suggested protocol for further research. Reproductive BioMedicine Online 10, 575–577. Kol S, Solt I 2008 GnRH agonist for triggering final oocyte maturation in patients at risk of ovarian hyperstimulation syndrome: still a controversy? Journal of Assisted Reproduction and Genetics 25, 63–66. Kolibianakis EM, Schultze-Mosgau A, Schroer A et al. 2005 A lower ongoing pregnancy rate can be expected when GnRH agonist
is used for triggering final oocyte maturation instead of hCG in patients undergoing IVF with GnRH antagonists. Human Reproduction 10, 2887–2892. Mathur RS, Akande AV, Keay SD et al. 2000 Distinction between early and late ovarian hyperstimulation syndrome. Fertility and Sterility 73, 901–907. Meltzer S, Girsch E, Shults A et al. 2002 Prevention of ovarian hyperstimulation syndrome in high responders undergoing IVF treatment with GnRH antagonist combined with single dose of GnRHa, instead of hCG, for the induction of oocyte maturation. Abstracts of the 18th Annual Meeting of the ESHRE, Vienna,Austria, O-258, p. 89. Mocanu E, Redmond ML, Hennelly B et al. 2007 Odds of ovarian hyperstimulation syndrome (OHSS)- time for reassessment. Human Fertility 10, 175–181. Nakano R, Mizuno T, Kotsuji F et al. 1973 ‘Triggering’ of ovulation after infusion of synthetic luteinizing hormone releasing factor (LRF). Acta Obstetrica et Gynecologica Scandinavica 52, 269– 272. Papanikolaou EG, Pozzobo C, Kolibianakis E et al. 2006 Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles. Fertility and Sterility 85, 112–120. Papanikolaou EG, Tournaye H, Verpoest W et al. 2005 Early and late ovarian hyperstimulation syndrome: early pregnancy outcome and profile. Human Reproduction 20, 636–641. Segal S, Casper RF 1992 Gonadotropin-releasing hormone agonist versus human chorionic gonadotropin for triggering follicular maturation in in vitro fertilization. Fertility and Sterility 57, 1254–1258. Wada I, Matson PL, Troup SA et al. 1993 Assisted conception using buserelin and human menopausal gonadotrophins in women with polycystic ovary syndrome. British Journal of Obstetrics and Gynecology 100, 365–369. Yding Andersen C 2002 Effects of FSH and its different isoforms on maturation of oocytes from pre-ovulatory follicles. Reproductive BioMedicine Online 5, 232–239. Yding Andersen C, Leonardsen L, Ulloa-Aguirre A et al. 1999 FSH-induced resumption of meiosis in mouse oocytes: effect of different isoforms. Molecular Human Reproduction 5, 726–731. Yen SS, Llerena O, Little B et al. 1968 Disappearance rates of endogenous luteinizing hormone and chorionic gonadotropin in man. Journal of Clinical Endocrinology and Metabolism 28, 1763–1767. Zelinski-Wooten MB, Hutchison JS, Hess DL et al. 1995 Follicle stimulating hormone alone supports follicle growth and oocyte development in gonadotrophin-releasing hormone antagonisttreated monkeys. Human Reproduction 10, 1658–1666.
Declaration: The authors report no financial or commercial conflicts of interest. Received 2 June 2008; revised and resubmitted 1 October 2008; refereed 23 October 2008; accepted 25 February 2008.
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Article Luteal phase rescue in high-risk OHSS patients by GnRHa triggering in combination with lowdose HCG: a pilot study Peter Humaidan obtained his MD degree in 1983 and the speciality degree in Obstetrics and Gynaecology in 1990 at the Sahlgrenska University Hospital, Gothenburg, Sweden. In the same year he obtained the Danish speciality degree in Obstetrics and Gynaecology. During the last 9 years he has been working as a specialist in reproductive endocrinology at The Fertility Clinic Skive, Viborg County, Denmark. He is a former board member of the Danish Fertility Society. His research interests include reproductive endocrinology, gonadotrophin function, sperm chromatin integrity in relation to outcome of assisted reproduction treatment and acupuncture related to infertility.
Dr Peter Humaidan P Humaidan The Fertility Clinic, Skive Regional Hospital, DK 7800 Skive, Denmark Correspondence: e-mail: [email protected]
Abstract Triggering of final oocyte maturation with gonadotrophin-releasing hormone agonist (GnRHa) has previously been shown to prevent ovarian hyperstimulation syndrome (OHSS), but at the same time a detrimental effect on clinical outcome parameters was usually reported. In this prospective, observational, proof-of-concept study, a new protocol was employed, using GnRHa to trigger final oocyte maturation in OHSS high-risk IVF/ICSI patients after co-treatment with GnRH antagonist. The aim was to avoid cycle cancellation in high-risk patients without increasing the risk of early onset OHSS and simultaneously secure the reproductive outcome. Twelve patients with ≥25 follicles ≥11 mm in diameter after ovarian stimulation were prospectively enrolled to have final oocyte maturation triggered with 0.5 mg buserelin s.c., followed by a single bolus of 1500 IU human chorionic gonadotrophin (HCG) 35 h later to rescue the luteal phase. A mean of 21.5 oocytes was retrieved. All patients underwent embryo transfer, resulting in an ongoing clinical pregnancy rate per cycle of 50% (6/12) and a live birth rate of 50% (6/12). One patient developed moderate, late onset OHSS that did not require hospitalization. GnRHa triggering of final oocyte maturation followed by one bolus of 1500 IU HCG seems to prevent early onset OHSS in high-risk patients and secure the reproductive outcome. Keywords: GnRH agonist, GnRH antagonist, hCG, IVF, OHSS
Introduction
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Ovarian hyperstimulation syndrome (OHSS) remains a clinical challenge in IVF/intracytoplasmic sperm injection (ICSI) treatment. It is a potentially life threatening condition, resulting in hospitalization in approximately 1.8% of patients (Mocanu et al., 2007). In its severe form, OHSS causes vascular permeability, haemoconcentration, accumulation of fluid in the peritoneal cavity and lungs and disruption of coagulation (Delvigne and Rozenberg, 2002). The triggering factor of OHSS is considered to be human chorionic gonadotrophin (HCG), exogenous or endogenous, resulting in an early and late development of the syndrome respectively (Al-Shawaf and Grudzinskas, 2003). Thus, early onset OHSS is described as occurring within 9 days after oocyte retrieval, and is related to the ovulatory dose of HCG, whereas late onset OHSS
occurs after the initial 10 day period as a consequence of the endogenously produced HCG by the trophoblast (Mathur et al., 2000). Overall risk factors of OHSS include young age, low body mass index (BMI), polycystic ovary syndrome (PCOS), polycystic ovarian morphology (Esinler et al., 2005) and patients with a previous history of high response to gonadotrophins. In order to avoid the use of HCG for ovulation induction, and thus possibly reduce the risk of early onset OHSS, gonadotrophin-releasing hormone agonist (GnRHa) has been suggested as an alternative trigger of ovulation (Nakano et al., 1973). However, the simultaneous use of GnRHa for downregulation and ovulation induction is not possible. Therefore,
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Article - Luteal phase rescue in high-risk OHSS patients - P Humaidan
with the advent of GnRH antagonist protocols to prevent a premature LH surge, it became an option again to trigger final oocyte maturation with a bolus of GnRHa, as GnRHa displaces the GnRH antagonist from the receptor in the pituitary eliciting a simultaneous LH and FSH surge (flare-up) prior to downregulation of the receptor. It has previously been shown that GnRHa is as effective as HCG for triggering of final oocyte maturation (Gonen et al., 1990; Imoedemhe et al., 1991; Itskovitz et al., 1991; Segal and Casper, 1992). Importantly, the half-life of LH is significantly shorter, (60 min), than that of HCG (>24 h) (Yen et al., 1968; Damewood et al., 1989). Moreover, GnRHa induces an FSH surge in addition to the LH surge, resembling the FSH surge of the natural cycle (Nakano et al., 1973). The exact role of the mid-cycle FSH surge is not fully understood, but FSH among others induces LH receptor formation in the corpus luteum (CL), optimizing the function of the CL and promotes nuclear maturation, i.e. resumption of meiosis (Zelinski-Wooten et al., 1995; Yding Andersen et al., 1999, 2002). There are, however, significant differences regarding the duration and the profile of the GnRHa induced LH surge as compared with the LH surge of the natural cycle (Hoff et al., 1983; Itskovitz et al., 1991), leading to a significantly reduced amount of gonadotrophins released when GnRHa is used to trigger final oocyte maturation. Although small-scale studies have suggested that triggering of final oocyte maturation with GnRHa prevents OHSS in high-risk patients (Kol and Itskovitz-Eldor, 2000; Kol 2003; Babayof et al., 2006; Griesinger et al., 2007; Engmann et al., 2008), two large randomized studies found a poor clinical outcome when GnRHa was used to trigger ovulation in normal responder patients, presumably due to a CL deficiency, despite luteal phase support with progesterone and oestradiol (Humaidan et al., 2005; Kolibianakis et al., 2005). Inspired by a previous study in intrauterine insemination patients (Emperaire et al., 2004), a pilot study was performed in IVF/ICSI patients following a GnRH antagonist protocol, in which a bolus of 1500 IU HCG was administered 12 h or 35 h after triggering of final oocyte maturation with GnRHa (Humaidan et al., 2006). The results of this pilot study showed that timing of the supplementary HCG dose plays an essential role for the rescue of the corpora lutea, and that HCG administered 35 h after final oocyte maturation with GnRHa resulted in a reproductive outcome similar to that of 10,000 IU HCG induced oocyte maturation (Humaidan et al., 2006). Encouraged by these results, a large prospective randomized trial including a total of 300 IVF/ICSI cycles was performed comparing HCG to trigger final oocyte maturation with GnRHa, supplemented with a bolus of 1500 IU HCG 35 h later. The results of this trial confirmed the findings of the pilot study (Humaidan et al., 2007). Furthermore, although the study was not powered to detect differences in OHSS, interestingly no OHSS case was seen in the GnRHa group, despite supplementation with 1500 IU HCG, whereas three cases (2%) were seen in the HCG group. Moreover, approximately one-third of patients in both study groups had more than 10 oocytes retrieved, indicating that they had at least 14 follicles ≥11 mm on the day of ovulation induction, a cut-off level that has previously been suggested to be predictive of the risk of RBMOnline®
developing OHSS (Papanikolaou et al., 2005). The aim of this prospective observational study was to explore the safety in terms of early onset OHSS and efficacy in terms of ongoing pregnancy rate and live birth rate of a new modified protocol (Humaidan et al., 2006) in a group of well-informed patients at high-risk of developing OHSS, i.e. patients with ≥25 follicles ≥11 mm on the day of triggering of final oocyte maturation.
Materials and methods The observational period was from May 2006 until August 2007, and the study was a one-centre, prospective, observational, proof-of-concept study. Patients were thoroughly informed about alternative options of OHSS prevention, i.e. cancellation, coasting and total freeze, before deciding to participate.
Patients Inclusion criteria were: (i) IVF or ICSI; (ii) female age between 20 and 40 years; (iii) body mass index (BMI) >18 and <35; (iv) high risk of OHSS, defined as ≥25 follicles ≥11 mm on the day of triggering of ovulation.
Hormonal treatment Ovarian stimulation was initiated with recombinant human FSH (r-hFSH; Puregon; Organon, Skovlunde, Denmark) from cycle day 2 and continued until the day of ovulation induction. A fixed dose of r-hFSH, 100–200 IU per day for the first 6 days was used, according to age, BMI, basal FSH, antral follicle count and ovarian volume. After 6 days, doses were adjusted according to ovarian response. Once the leading follicle had reached a size of 13 mm, co-treatment with the GnRH antagonist ganirelix (Orgalutran; Organon) 0.25 mg was initiated and continued up to and including the day of ovulation induction. Patients were enrolled in the study on the day of the last scan if ≥25 follicles ≥11 mm in diameter were present. When at least two follicles had reached a size of 17 mm, final oocyte maturation was triggered with a single bolus of 0.5 mg buserelin s.c. (Suprefact; Hoechst, Hørsholm, Denmark), followed by oocyte retrieval 34 h later. After oocyte retrieval, at 35 h after the buserelin injection, patients received a single injection of 1500 IU HCG i.m. (Pregnyl; Organon). A maximum of two embryos was transferred on day 2 or 3 after retrieval, following national criteria of single embryo transfer (SET), according to which patients below 35 years of age should receive a single embryo for transfer during their first IVF/ICSI attempt. All patients received luteal phase support in the form of micronized progesterone vaginally, 90 mg a day (Crinone; Serono Nordic, Copenhagen, Denmark) and oestradiol 4 mg a day orally (Estrofem; Novo Nordisk, Copenhagen, Denmark) commencing from the day following oocyte retrieval and continuing until the day of the pregnancy test, i.e. day 12 after embryo transfer. A biochemical pregnancy was defined by a plasma B-HCG concentration >10 IU/l on day 12 after embryo transfer. A clinical pregnancy was defined as an intrauterine gestational sac with a heartbeat 3 weeks after a positive HCG test. An ongoing pregnancy was defined as a viable pregnancy in week 11 of pregnancy.
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Article - Luteal phase rescue in high-risk OHSS patients - P Humaidan
Outcome measures Main outcome measure was the incidence of early and late onset OHSS (Golan et al., 1989; Mathur et al., 2000). Secondary outcome measures were the ongoing clinical pregnancy rate per cycle and live birth rate per cycle.
Results Patient characteristics and stimulation A total of 12 patients were enrolled in the study and all patients had an embryo transfer. Indications for IVF/ICSI treatment were: male factor (n = 7), tubal factor (n = 3), endometriosis (n = 1) and anovulation (n = 1). Table 1 summarizes the demographic data of patients enrolled. Stimulation days, total amount of exogenous FSH required, total dose of GnRH antagonist, fertilization rate and numbers of embryos transferred are summarized in Table 2.
OHSS No patient developed early onset OHSS. One patient developed late onset, moderate OHSS, that did not require hospitalization.
Pregnancy Twelve embryo transfers resulted in 10 positive HCG tests (83% per cycle). Six pregnancies, one twin pregnancy and five singleton pregnancies were ongoing in week 11 (50%/cycle). Subsequently one set of twins and five singletons were born giving a live birth rate of 50%/cycle. Two pregnancies were biochemical and two pregnancies were missed abortions (Table 3).
Discussion
63% in a group of 32 high-risk oocyte donors who had HCG to trigger final oocyte maturation, following a GnRH antagonist protocol. Donors were classified to be at high risk if they had a retrieval of more than 20 oocytes and the development of 20–30 follicles ≥12 mm. Thus patients in the present proof-of-concept study with ≥25 follicles ≥11 mm on the day of triggering of final oocyte maturation and a mean of 21.5 oocytes fulfilled the most recent criteria set to define high-risk patients. Compared with the Alvarez et al. study (2007), a surprisingly high reduction in the early onset OHSS rate was seen. In the present study, ovarian response parameters were used to identify the high risk group. Early onset OHSS is related to ovarian sensitivity, response to stimulation and the ovulatory dose of HCG, whereas late onset OHSS is only poorly related to ovarian response, but more to the endogenous HCG produced by the implanting embryo (Mathur et al., 2000). Thus, late onset OHSS is difficult to predict from ovarian response parameters, which was also reflected in this study, and although the OHSS rate in this small group of high risk patients was low, it is unlikely that the present protocol will prevent late onset OHSS. So far, in the OHSS high-risk patient, only two prospective randomized studies investigated the incidence of OHSS when GnRHa was used to trigger ovulation after GnRH antagonist co-treatment as compared with HCG (Babayof et al., 2006; Engmann et al., 2008) and first and foremost conflicting results regarding ongoing pregnancy rates exist.
Table 1. Demographic data. Baseline FSH (IU) Baseline LH (IU) Age (years) Body mass index (kg/m2) Cycle no.
5.5 ± 1.7 7.1 ± 3.4 30.7 ± 3.8 23.7 ± 2.4 1.7 ± 0.7
Values are mean ± SD
This is the first study to investigate the incidence of early onset OHSS in a group of high-risk patients in whom final oocyte maturation was triggered with GnRHa followed by a single bolus of 1500 IU HCG 35 h later to rescue the luteal phase. With this new modified protocol, no early onset OHSS was seen and a high live birth rate in patients at high risk of OHSS was achieved. One patient developed late onset moderate OHSS. This patient had an elective single embryo transfer and delivered a healthy child at term.
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The overall incidence of OHSS in high-risk groups undergoing IVF has been reported as 32% (Wada et al., 1993). However, the definition of high-risk groups differs somewhat in the literature. In 637 GnRHa down-regulated cycles, Asch et al. (1991) focusing only on severe OHSS (late onset) found a cutoff level of either oestradiol on the day of HCG >6000 pg/ml (19 nmol/l) or the retrieval of >30 oocytes to be predictive. This is contrasted by Papanikolau et al. (2006) who in 2524 GnRH antagonist cycles defined a threshold value of ≥18 follicles ≥11 mm on the day of HCG to have 83% specificity in predicting severe OHSS. Finally, in oocyte donors, Alvarez et al. (2007) reported an early onset OHSS rate (moderate and severe) of
Table 2. Stimulation, oocytes and fertilization. Stimulation (days) Total FSH (IU) Total dose of antagonist (mg) Serum oestradiol day of ovulation induction (nmol/l) Oocytes, n Fertilization rate, n (%) Cleavage rate, n (%) Embryos transferred, n
10.8 ± 4.9 1141.9 ± 460.3 1.0 ± 0.0 18.6 ± 10.5 21.5 ± 6.0 138/258 (53.5) 120/138 (87.0) 1.7 ± 0.5
Values are mean ± SD
Table 3. Pregnancy outcome. Positive HCG test/cycle, n (%) Early pregnancy loss, n (%) Clinical ongoing pregnancy/cycle, n (%) Live birth/cycle, n (%)
10/12 (83.3) 4/10 (40.0) 6/12 (50.0) 6/12 (50.0)
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Article - Luteal phase rescue in high-risk OHSS patients - P Humaidan
Thus, in the randomized study by Engmann et al. (2008), 30 high-risk patients following a GnRH antagonist protocol had final oocyte maturation triggered with a bolus of GnRHa. A mean of 20.2 oocytes was retrieved. Patients received intensive luteal phase support in the form of 50–70 mg progesterone i.m. daily to maintain a serum concentration above 60 nmol/l and three to four transdermal oestradiol patches every other day and/or addition of oral oestradiol to maintain a serum oestradiol concentration above 200 pg/ml. No patient developed OHSS, and a high ongoing pregnancy rate was reported. This is contrasted by the randomized study by Babayof et al. (2006). In this study, 15 patients considered at risk of developing OHSS and following a GnRH antagonist protocol had triggering of final oocyte maturation with GnRHa. A mean of 19.8 oocytes were retrieved and again the luteal phase was heavily supported with 50–100 mg progesterone i.m. daily to maintain serum progesterone concentrations above 40 nmol/l and oestradiol, 4 mg orally/day. No OHSS case was reported, but despite the intensive luteal phase support, resembling the luteal phase support of the Engmann study (2008), an early pregnancy loss rate of 80% in the GnRHa group was seen, similar to pregnancy loss rates previously reported when GnRHa was used to trigger final oocyte maturation in normal responder patients (Humaidan et al., 2005; Kolibianakis et al., 2005) and OHSS risk patients (Itskovitz-Eldor et al., 2000; Kol and Muchtar 2005). Apart from these randomized trials, a number of small scale studies in OHSS high-risk patients, either retrospective or observational, on GnRHa triggering of final oocyte maturation exist in the literature reporting only two cases of OHSS requiring either hospitalization or classified as severe (lateonset) after GnRHa triggering (Meltzer et al., 2002; Chun et al., 2005). However, clinical pregnancy rates range from 0 to 75% (Griesinger et al., 2006), most probably depending on the type of luteal phase support administered (Griesinger et al., 2006; Kol and Solt, 2008). Another way to circumvent the problems of adequate luteal phase support, early pregnancy loss and risk of OHSS, would be to trigger final oocyte maturation with GnRHa followed by elective cryopreservation and transfer in a subsequent frozen embryo replacement cycle. This procedure was recently investigated by Griesinger et al. (2007) in a proof of concept study including 20 patients at increased risk of developing OHSS, defined as ≥20 follicles ≥10 mm on the day of induction of final oocyte maturation. A mean of 16 oocytes was retrieved. No cases of moderate or severe OHSS were observed, and a good ongoing pregnancy rate per first frozen thawed embryo transfer cycle was reported. In the present study, early onset OHSS was prevented and a high live birth rate (50% per cycle) was seen in a small highrisk group of patients. The early pregnancy loss rate reported (40%) is higher than the mean pregnancy loss rate normally seen in the clinic (26%) when GnRH antagonist protocols are used in combination with 10,000 IU HCG to trigger ovulation. However, this material is too small to make any firm conclusions regarding early pregnancy loss. Interestingly, all patients had polycystic ovarian morphology and could have an increased early pregnancy loss rate similar to that of PCOS patients (Homburg, 2006). RBMOnline®
Taken together, the results of the present study are encouraging for GnRHa triggering, but need to be confirmed in a larger series. Approval of the Review Board was recently obtained to perform a larger prospective randomized multi-centre study focusing on a possible reduction in the OHSS rate when GnRHa is used to trigger final oocyte maturation in the high-responder patient. Patients in the control arm of this RCT will receive a reduced dose of HCG in order not to expose patients to an unnecessary high risk of early onset OHSS. The advantages of the present procedure compared with a total freeze are the avoidance of the psychological distress of a cancelled transfer, the avoidance of embryo loss due to the freezing and thawing procedure and lower pregnancy rates in embryo thaw cycles. In conclusion, the current proof-of-concept study suggests that GnRHa triggering of final oocyte maturation followed by a bolus of 1500 IU HCG on the day of aspiration prevents early onset OHSS and secures the clinical pregnancy outcome in highrisk patients. More and larger studies are needed to confirm the present and previous reports and to assess the optimal luteal phase support when GnRHa is used to trigger final oocyte maturation. However, GnRHa triggering after GnRH antagonist co-treatment leaves the clinician and the well-informed patient with several individually tailored options that seem to prevent/ reduce the risk of OHSS.
Acknowledgements The author wishes to thank the nurses and laboratory technicians of the Fertility Clinic, Skive Regional Hospital for their assistance during this study.
References Asch RH, Huey-PO L, Balmaceda J et al. 1991 Severe ovarian hyperstimulation syndrome in assisted reproductive technology: definition of high risk groups. Human Reproduction 6, 1395–1399. Al-Shawaf, Grudzinskas JG 2003 Prevention and treatment of ovarian hyperstimulation syndrome. Best Practice and Research, Clinical Obstetrics and Gynecology 17, 249–261 Alvarez C, Marti-Bonmati L, Novella-Maestre E et al. 2007 Dopamine agonist cabergoline reduces hemoconcentration and ascites in hyperstimulated women undergoing assisted reproduction. Journal of Endocrinology and Metabolism 92, 2931–2937. Babayof R, Margalioth EJ, Huleihel M et al. 2006 Serum inhibitn A, VEGF and TNFα levels after triggering oocyte maturation with GnRHa compared with hCG in women with polycystic ovary syndrome undergoing IVF treatment. Human Reproduction 21, 1260–1265. Chun E 2005 Severe OHSS can be prevented in GnRH antagonist protocol using GnRHa to trigger ovulation. Fertility and Sterility 84 (Suppl.1), S301 (P-149) Damewood MD, Shen W, Zacur HA et al. 1989 Disappearance of exogenously administered human chorionic gonadotropin. Fertility and Sterility 52, 398–400. Delvigne A, Rozenberg S 2002 Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Human Reproduction Update 8, 559–577. Emperaire JC, Parneix I, Ruffie A 2004 Luteal phase defects following agonist-triggered ovulation: a patient-dependent response. Reproductive BioMedicine Online 9, 22–27. Engmann L, Diluigi A, Schmidt D et al. 2008 The use of
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634
gonadotropin-releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high-risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospective randomized controlled study. Fertility and Sterility 89, 84–91. Esinler I, Bayar U, Bozdag G et al. 2005 Outcome of intracytoplasmic sperm injection in patients with polycystic ovary syndrome. Fertility and Sterility 84, 932–937. Golan A, Ron-El R, Herman A 1989 Ovarian hyperstimulation syndrome: an update review. Obstetrical and Gynecological Survey 44, 430–440. Gonen Y, Balakier H, Powell W et al. 1990 Use of GnRH agonist to trigger follicular maturation for in vitro fertilization. Journal of Clinical Endocrinology and Metabolism 71, 918–922. Griesinger G, Von Otte S, Schroer A et al. 2007 Elective cryopreservation of all pronuclear oocytes after GnRH agonist triggering of final oocyte maturation in patients at risk of developing OHSS: a prospective, observational proof-of-concept study. Human Reproduction 22, 1348–1352. Griesinger G, Diedrich K, Tarlatzis BC et al. 2006 GnRH antagonists in ovarian stimulation for IVF in patients with poor response to gonadotrophins, polycystic ovary syndrome, and risk of ovarian hyperstimulation: a meta-analysis. Reproductive BioMedicine Online 13, 628–638. Hoff JD, Quigley ME, Yen SS 1983 Hormonal dynamics at midcycle: a revaluation. Journal of Clinical Endocrinology and Metabolism 57, 792–796. Homburg R 2006 Pregnancy complications in PCOS. Best Practise and Research in Clinical Endocrinology and Metabolism 20, 281–292. Humaidan P, Ejdrup Bredkjær, Westergaard L et al. 2007 1500 IU hCG secures a normal clinical pregnancy outcome in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist. Human Reproduction 22 (Suppl. 1), O-203. Humaidan P, Bungum L, Bungum L, Yding Andersen C 2006 Rescue of corpus luteum function with periovulatory hCG supplementation in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist – a pilot study. Reproductive BioMedicine Online 13, 173–178. Humaidan P, Ejdrup Bredkjær H, Bungum L et al. 2005 GnRH agonist (Buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomised study. Human Reproduction 20, 1213–1220. Imoedemhe DA, Sigue AB, Pacpaco EL et al. 1991 Stimulation of endogenous surge of luteinizing hormone with gonadotropinreleasing hormone analogue after ovarian stimulation for in vitro fertilization. Fertility and Sterility 55, 328–332. Itskovitz J, Boldes R, Levron J et al. 1991 Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist. Fertility and Sterility 56, 213–220. Itskovitz-Eldor J, Kol S, Mannaerts B 2000 Use of a single bolus of GnRH-atagonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hperstimulation syndrome: a preliminary report. Human Reproduction 15, 1965–1968. Kol S 2003 Prediction of ovarian hyperstimulation syndrome: why predict if we can prevent. Human Reproduction 18, 1557–1558 Kol S, Itskovitz–Eldor J 2000 severe OHSS: yes there is a strategy to prevent it! Human Reproduction 15, 2266–2267. Kol S, Muchtar M 2005 Recombinant gonadotrophin-based, ovarian hyperstimulation syndrome-free stimulation of the high responder: suggested protocol for further research. Reproductive BioMedicine Online 10, 575–577. Kol S, Solt I 2008 GnRH agonist for triggering final oocyte maturation in patients at risk of ovarian hyperstimulation syndrome: still a controversy? Journal of Assisted Reproduction and Genetics 25, 63–66. Kolibianakis EM, Schultze-Mosgau A, Schroer A et al. 2005 A lower ongoing pregnancy rate can be expected when GnRH agonist
is used for triggering final oocyte maturation instead of hCG in patients undergoing IVF with GnRH antagonists. Human Reproduction 10, 2887–2892. Mathur RS, Akande AV, Keay SD et al. 2000 Distinction between early and late ovarian hyperstimulation syndrome. Fertility and Sterility 73, 901–907. Meltzer S, Girsch E, Shults A et al. 2002 Prevention of ovarian hyperstimulation syndrome in high responders undergoing IVF treatment with GnRH antagonist combined with single dose of GnRHa, instead of hCG, for the induction of oocyte maturation. Abstracts of the 18th Annual Meeting of the ESHRE, Vienna,Austria, O-258, p. 89. Mocanu E, Redmond ML, Hennelly B et al. 2007 Odds of ovarian hyperstimulation syndrome (OHSS)- time for reassessment. Human Fertility 10, 175–181. Nakano R, Mizuno T, Kotsuji F et al. 1973 ‘Triggering’ of ovulation after infusion of synthetic luteinizing hormone releasing factor (LRF). Acta Obstetrica et Gynecologica Scandinavica 52, 269– 272. Papanikolaou EG, Pozzobo C, Kolibianakis E et al. 2006 Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles. Fertility and Sterility 85, 112–120. Papanikolaou EG, Tournaye H, Verpoest W et al. 2005 Early and late ovarian hyperstimulation syndrome: early pregnancy outcome and profile. Human Reproduction 20, 636–641. Segal S, Casper RF 1992 Gonadotropin-releasing hormone agonist versus human chorionic gonadotropin for triggering follicular maturation in in vitro fertilization. Fertility and Sterility 57, 1254–1258. Wada I, Matson PL, Troup SA et al. 1993 Assisted conception using buserelin and human menopausal gonadotrophins in women with polycystic ovary syndrome. British Journal of Obstetrics and Gynecology 100, 365–369. Yding Andersen C 2002 Effects of FSH and its different isoforms on maturation of oocytes from pre-ovulatory follicles. Reproductive BioMedicine Online 5, 232–239. Yding Andersen C, Leonardsen L, Ulloa-Aguirre A et al. 1999 FSH-induced resumption of meiosis in mouse oocytes: effect of different isoforms. Molecular Human Reproduction 5, 726–731. Yen SS, Llerena O, Little B et al. 1968 Disappearance rates of endogenous luteinizing hormone and chorionic gonadotropin in man. Journal of Clinical Endocrinology and Metabolism 28, 1763–1767. Zelinski-Wooten MB, Hutchison JS, Hess DL et al. 1995 Follicle stimulating hormone alone supports follicle growth and oocyte development in gonadotrophin-releasing hormone antagonisttreated monkeys. Human Reproduction 10, 1658–1666.
Declaration: The authors report no financial or commercial conflicts of interest. Received 2 June 2008; revised and resubmitted 1 October 2008; refereed 23 October 2008; accepted 25 February 2008.
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