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      Comparison of GnRH agonist and hCG for priming in vitro maturation cycles in cancer patients undergoing urgent fertility preservation

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          Abstract

          In vitro maturation (IVM) of oocytes retrieved at germinal vesicle or Metaphase I stage, followed by vitrification of Metaphase II (MII) oocytes, has recently emerged as an option for urgent fertility preservation (FP). Priming is usually achieved with an injection of hCG, 10,000 IU, 36 hours before retrieval. This study aimed to assess a new method of priming, using GnRH agonists, and compare it to hCG, in cancer patients undergoing urgent FP. From 2009 to 2015, 373 cancer patients underwent MII oocyte cryopreservation after IVM cycles primed either with GnRHa (triptorelin 0.2 mg) (n = 138) or hCG (10,000 IU) (n = 235). Patients’ characteristics were comparable between the two groups. The number of COC retrieved was significantly higher in the GnRHa group (9.1 ± 6.8 versus 7.7 ± 5.5 oocytes, p = 0.04). However, the maturation rates (59 ±25% versus 64 ±26%, p = 0.07, respectively), and the total number of MII oocytes frozen (5.2 ±4.2 versus 4.9 ±4.0, p = 0.6, respectively) were similar between the GnRha and hCG groups. We did not find any difference between GnRHa and hCG priming for IVM. GnRHa priming is more physiological since it stimulates endogenous FSH and LH activity, and is well suited for FP in hormone-sensitive cancers and urgent cases.

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          GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study.

          We aimed to determine the efficacy of ovarian hyperstimulation protocols employing a GnRH antagonist to prevent a premature LH rise allowing final oocyte maturation and ovulation to be induced by a single bolus of either a GnRH agonist or hCG. A total of 122 normogonadotrophic patients following a flexible antagonist protocol was stimulated with recombinant human FSH and prospectively randomized (sealed envelopes) to ovulation induction with a single bolus of either 0.5 mg buserelin s.c. (n = 55) or 10,000 IU of hCG (n = 67). A maximum of two embryos was transferred. Luteal support consisted of micronized progesterone vaginally, 90 mg a day, and estradiol, 4 mg a day per os. Ovulation was induced with GnRH agonist in 55 patients and hCG in 67 patients. Significantly more metaphase II (MII) oocytes were retrieved in the GnRH agonist group (P < 0.02). Significantly higher levels of LH and FSH (P < 0.001) and significantly lower levels of progesterone and estradiol (P < 0.001) were seen in the GnRH agonist group during the luteal phase. The implantation rate, 33/97 versus 3/89 (P < 0.001), clinical pregnancy rate, 36 versus 6% (P = 0.002), and rate of early pregnancy loss, 4% versus 79% (P = 0.005), were significantly in favour of hCG. Ovulation induction with a GnRH agonist resulted in significantly more MII oocytes. However, a significantly lower implantation rate and clinical pregnancy rate in addition to a significantly higher rate of early pregnancy loss was seen in the GnRH agonist group, most probably due to a luteal phase deficiency.
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            GnRH agonist for triggering of final oocyte maturation: time for a change of practice?

            GnRH agonist (GnRHa) triggering has been shown to significantly reduce the occurrence of ovarian hyperstimulation syndrome (OHSS) compared with hCG triggering; however, initially a poor reproductive outcome was reported after GnRHa triggering, due to an apparently uncorrectable luteal phase deficiency. Therefore, the challenge has been to rescue the luteal phase. Studies now report a luteal phase rescue, with a reproductive outcome comparable to that seen after hCG triggering. This narrative review is based on expert presentations and subsequent group discussions supplemented with publications from literature searches and the authors' knowledge. Moreover, randomized controlled trials (RCTs) were identified and analysed either in fresh IVF cycles with embryo transfer (ET), oocyte donation cycles or cycles without ET; risk differences were calculated regarding pregnancy rate and OHSS rate. In fresh IVF cycles with ET (9 RCTs) no OHSS was reported after GnRHa triggering [0% incidence in the GnRHa group: risk difference 5% (with 95% CI: -0.07 to 0.02)]. Importantly, the delivery rate improved significantly after modified luteal support [6% risk difference in favour of the HCG group (95% CI: -0.14 to 0.2)] when compared with initial studies with conventional luteal support [18% risk difference (95% CI: -0.36 to 0.01)]. In oocyte donation cycles (4 RCTs) the OHSS incidence is 0% [10% risk difference (95% CI: 0.02-0.40)]. GnRHa triggering is a valid alternative to hCG triggering, resulting in an elimination of OHSS. After modified luteal support there is now a non-significant difference of 6% in delivery rate in favour of hCG triggering.
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              Preventing ovarian hyperstimulation syndrome: guidance for the clinician.

              To reevaluate ovarian hyperstimulation syndrome (OHSS) prevention techniques and provide a classification system for grading OHSS and evidence-based treatment strategies for preventing OHSS. A literature search was conducted in PubMed for articles published in the last 5 years using the keywords "controlled ovarian stimulation," "controlled ovarian hyperstimulation," "ovarian hyperstimulation syndrome," "OHSS," "prevention," "chorionic gonadotropin," "hCG," "GnRH agonist," "GnRH antagonist," "coasting," and "cryopreservation." We reviewed randomized controlled trials (RCTs), retrospective studies, pilot studies, case studies, reviews, and meta-analyses. There is a shortage of large, prospective RCTs reporting OHSS prediction and prevention strategies. Our review showed that risk factors such as antral follicle count and baseline anti-Müllerian hormone level may identify women at high OHSS risk. Preventative strategies that appear highly effective at reducing or preventing OHSS include GnRH antagonist protocols and the use of GnRH agonists to trigger final oocyte maturation. Moreover, alternative therapies, such as dopamine receptor agonists (Cabergoline), have also emerged as potential new treatment modalities in the management of this disease. These findings suggest that current treatment guidelines should be updated to incorporate findings from recent literature that show that GnRH antagonist protocols consistently reduce OHSS and that GnRH agonist triggering has considerable promise in preventing OHSS, although further RCTs will be needed to confirm this. Copyright 2010 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: ValidationRole: Writing – review & editing
                Role: InvestigationRole: MethodologyRole: SupervisionRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                6 December 2018
                2018
                : 13
                : 12
                : e0208576
                Affiliations
                [1 ] Department of Reproductive Medicine, Ovo Clinic, Montreal, Quebec, Canada
                [2 ] Department of Obstetrics and Gynecology, University of Montreal, Montreal, Quebec, Canada
                [3 ] Department of Reproductive Medicine & Fertility Preservation, Hôpital Jean Verdier, Bondy, France
                [4 ] Inserm U1185, Université Paris-Sud, Le Kremlin Bicêtre, France
                [5 ] University Paris XIII, Paris, France
                [6 ] Department of Cytogenetic and Reproductive Biology, Hôpital Jean Verdier, Bondy, France
                [7 ] Inserm U1133, Université Paris-Diderot, Paris, France
                John Hopkins University School of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                ‡ These authors also contributed equally to this work.

                Author information
                http://orcid.org/0000-0003-2030-2623
                Article
                PONE-D-17-38061
                10.1371/journal.pone.0208576
                6283534
                30521621
                340c6d6e-75a0-4908-9f74-0e1dfac1b8ca
                © 2018 El Hachem et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 October 2017
                : 20 November 2018
                Page count
                Figures: 0, Tables: 2, Pages: 11
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Germ Cells
                OVA
                Oocytes
                Biology and Life Sciences
                Cryobiology
                Cryopreservation
                Research and Analysis Methods
                Specimen Preparation and Treatment
                Specimen Preservation
                Cryopreservation
                Biology and Life Sciences
                Developmental Biology
                Embryology
                Embryos
                Medicine and Health Sciences
                Diagnostic Medicine
                Diagnostic Radiology
                Ultrasound Imaging
                Research and Analysis Methods
                Imaging Techniques
                Diagnostic Radiology
                Ultrasound Imaging
                Medicine and Health Sciences
                Radiology and Imaging
                Diagnostic Radiology
                Ultrasound Imaging
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Cycle and Cell Division
                Metaphase
                Medicine and Health Sciences
                Oncology
                Cancer Treatment
                Biology and Life Sciences
                Biochemistry
                Hormones
                Gonadotropins
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Germ Cells
                OVA
                Zygotes
                Custom metadata
                Data are available upon request. The Jean Verdier Hospital review board has enforced the restriction, in order to protect the identity of the participants involved in the cohort. However, we are willing to make our data available upon request, since we consider it important to promote open and consistent scientific research. We will ensure that all interested and qualified researchers will be granted access. Data access requests can be made to the corresponding author, Hady El Hachem, via the following email address: hadyhachem@ 123456hotmail.com or to Pr Vincent Levy, at the following email address: Vincent.levy@ 123456aphp.fr .

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