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      Comparisons of GnRH antagonist protocol versus GnRH agonist long protocol in patients with normal ovarian reserve: A systematic review and meta-analysis

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          Abstract

          Objective

          To evaluate the effectiveness and safety of gonadotropin-releasing hormone antagonist (GnRH-ant) protocol and gonadotropin-releasing hormone agonist (GnRH-a) long protocol in patients with normal ovarian reserve.

          Methods

          We searched the PubMed (1992–2016), Cochrane Library (1999–2016), Web of Science (1950–2016), Chinese Biomedical Database (CBM, 1979–2016), and China National Knowledge Infrastructure (CNKI, 1994–2016). Any randomized controlled trials (RCTs) that compared GnRH-ant protocol and GnRH-a long protocol in patients with normal ovarian reserve were included, and data were extracted independently by two reviewers. The meta-analysis was performed by Revman 5.3 software.

          Results

          Twenty-nine RCTs (6399 patients) were included in this meta-analysis. Stimulation days (mean difference (MD) [95% confidence interval (CI)] = -0.8 [-1.36, -0.23], P = 0.006), gonadotrophin (Gn) dosage (MD [95% CI] = -3.52 [-5.56, -1.48], P = 0.0007), estradiol (E2) level on the day of human chorionic gonadotrophin (HCG) administration (MD [95% CI] = -365.49 [-532.93, -198.05], P<0.0001), the number of oocytes retrieved (MD [95% CI] = -1.41 [-1.84, -0.99], P<0.00001), the embryos obtained (MD [95% CI] = -0.99 [-1.38, -0.59], P<0.00001), incidence of ovarian hyperstimulation syndrome (OHSS) (OR [95% CI] = 0.69 [0.57, 0.83], P<0.0001) were statistically significantly lower in GnRH-ant protocol than GnRH-a long protocol. However, the clinical pregnancy rate (OR [95% CI] = 0.90 [0.80, 1.01], P = 0.08), ongoing pregnancy rate (OR [95% CI] = 0.88 [0.77, 1.00], P = 0.05), live birth rate (OR [95% CI] = 0.95 [0.74, 1.09], P = 0.27), miscarriage rate (OR [95% CI] = 0.98 [0.69, 1.40], P = 0.93), and cycle cancellation rate (OR [95% CI] = 0.86 [0.52, 1.44], P = 0.57) showed no significant differences between the two groups.

          Conclusion

          GnRH-ant protocol substantially decreased the incidence of OHSS without influencing the pregnancy rate and live birth rate compared to GnRH-a long protocol among patients with normal ovarian reserve.

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          Most cited references41

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          Gonadotrophin-releasing hormone antagonists for assisted reproductive technology.

          Hesham Al-Inany, Mohamed Youssef, Reuben Olugbenga Ayeleke … (2016)
          Gonadotrophin-releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo-oestrogenic side-effects, flare-up, or long down-regulation period associated with agonists. The antagonists directly and rapidly inhibit gonadotrophin release within several hours through competitive binding to pituitary GnRH receptors. This property allows their use at any time during the follicular phase. Several different regimens have been described including multiple-dose fixed (0.25 mg daily from day six to seven of stimulation), multiple-dose flexible (0.25 mg daily when leading follicle is 14 to 15 mm), and single-dose (single administration of 3 mg on day 7 to 8 of stimulation) protocols, with or without the addition of an oral contraceptive pill. Further, women receiving antagonists have been shown to have a lower incidence of ovarian hyperstimulation syndrome (OHSS). Assuming comparable clinical outcomes for the antagonist and agonist protocols, these benefits would justify a change from the standard long agonist protocol to antagonist regimens. This is an update of a Cochrane review first published in 2001, and previously updated in 2006 and 2011.
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            Among patients treated for IVF with gonadotrophins and GnRH analogues, is the probability of live birth dependent on the type of analogue used? A systematic review and meta-analysis.

            E Kolibianakis, J Collins, B C Tarlatzis … (2015)
            This systematic review and meta-analysis aimed to answer the following clinical question: among patients treated for IVF with gonadotrophins and GnRH analogues, is the probability of live birth per randomized patient dependent on the type of analogue used? Eligible studies were randomized controlled trials (RCTs), published as a full manuscript in a peer-reviewed journal, that contained sufficient information to allow ascertainment of whether randomization was true and whether equality was present between the groups compared. A literature search identified 22 RCTs comparing GnRH antagonists and GnRH agonists that involved 3176 subjects. Where live birth was not reported in a study that fulfilled the inclusion criteria, an effort was made to contact the corresponding authors to retrieve the missing information. If this was not possible, the reported outcome measure, clinical pregnancy or ongoing pregnancy was converted to live birth in 12 studies using published data (Arce et al., 2005). No significant difference was present in the probability of live birth between the two GnRH analogues [odds ratio (OR), 0.86; 95% confidence intervals (CI), 0.72 to 1.02]. This result remains stable in subgroup analysis that ordered the studies by type of population studied, gonadotrophin type used for stimulation, type of agonist protocol used, type of agonist used, type of antagonist protocol used, type of antagonist used, presence of allocation concealment, presence of co-intervention and the way the information on live birth was retrieved. In conclusion, the probability of live birth after ovarian stimulation for IVF does not depend on the type of analogue used for pituitary suppression.
            Article 0 comments Cited 51 times – based on 0 reviews     Review now
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              Gonadotrophin-releasing hormone antagonists for assisted reproductive technology.

              Frank J Broekmans, Abdulhadi H Al-Marri, Janine Smit … (2010)
              Gonadotrophin-releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo-estrogenic side-effects, flare-up, or long down-regulation period associated with agonists. The antagonists directly and rapidly inhibit gonadotropin release within several hours through competitive binding to pituitary GnRH receptors. This property allows their use at any time during the follicular phase. Several different regimes have been described including multiple-dose fixed (0.25 mg daily from day six to seven of stimulation), multiple-dose flexible (0.25 mg daily when leading follicle is 14 to 15 mm), and single-dose (single administration of 3 mg on day 7 to 8 of stimulation) protocols, with or without the addition of an oral contraceptive pill. Further, women receiving antagonists have been shown to have a lower incidence of ovarian hyperstimulation syndrome (OHSS). Assuming comparable clinical outcomes for the antagonist and agonist protocols, these benefits would justify a change from the standard long agonist protocol to antagonist regimens. This is an update of a Cochrane review first published in 2001, and previously updated in 2006. To evaluate the effectiveness and safety of gonadotrophin-releasing hormone (GnRH) antagonists with the standard long protocol of GnRH agonists for controlled ovarian hyperstimulation in assisted conception cycle We performed electronic searches of major databases, for example Cochrane Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL, MEDLINE, EMBASE (from 1987 to April 2010); and handsearched bibliographies of relevant publications and reviews, and abstracts of major scientific meetings, for example the European Society of Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM). A date limited search of Cochrane Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL from April 2010 to April 2011 was run. Eighteen studies have been entered into the Classification pending references section of this update. These studies will be appraised for inclusion or exclusion in the next update of this review, due April 2012. Two review authors independently screened the relevant citations for randomised controlled trials (RCTs) comparing different agonist versus antagonist protocols in women undergoing IVF or ICSI. Two review authors independently assessed trial risk of bias and extracted data. If relevant data were missing or unclear, the authors were contacted for clarification. Forty-five RCTs (n = 7511) comparing the antagonist to the long agonist protocols fulfilled the inclusion criteria. There was no evidence of a statistically significant difference in rates of live-births (9 RCTs; odds ratio (OR) 0.86, 95% CI 0.69 to 1.08) or ongoing pregnancy (28 RCTs; OR 0.87, 95% CI 0.77 to 1.00). There was a statistically significant lower incidence of OHSS in the GnRH antagonist group (29 RCTs; OR 0.43, 95% CI 0.33 to 0.57). The use of antagonist compared with long GnRH agonist protocols was associated with a large reduction in OHSS and there was no evidence of a difference in live-birth rates.
              Article 0 comments Cited 50 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Qing-Yuan Sun: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 24 April 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 4
                Electronic Location Identifier: e0175985
                Affiliations
                [1 ]Reproductive Medical Center, Peking University Shenzhen Hospital, Shenzhen, China
                [2 ]Medical College of Shantou University, Shantou, China
                Institute of Zoology Chinese Academy of Sciences, CHINA
                Author notes

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

                • Conceptualization: RW WQ LZ.

                • Data curation: RW SL YW.

                • Formal analysis: RW SL YW.

                • Funding acquisition: LZ.

                • Investigation: RW SL YW.

                • Methodology: RW WQ LZ.

                • Project administration: RW WQ LZ.

                • Resources: RW SL YW.

                • Software: RW SL YW.

                • Supervision: RW WQ LZ.

                • Validation: RW WQ LZ.

                • Visualization: RW WQ LZ.

                • Writing – original draft: RW SL.

                • Writing – review & editing: RW WQ LZ.

                Article
                Publisher ID: PONE-D-17-06471
                DOI: 10.1371/journal.pone.0175985
                PMC ID: 5402978
                PubMed ID: 28437434
                SO-VID: f3357939-fbfa-4103-94df-485c1a8d09f0
                Copyright © © 2017 Wang et al
                License:

                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
                Date received : 21 February 2017
                Date accepted : 3 April 2017
                Page count
                Figures: 13, Tables: 1, Pages: 19
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 30900817
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100003785, Guangdong Medical Research Foundation;
                Award ID: A2015397
                Award Recipient :
                LZ received the National Natural Science Foundation of China (30900817); Guangdong Medical Research Foundation (A2015397). LZ as the correspondence author of this article, conceived and designed the study, revised the paper and finally approved the version.
                Categories
                Subject: Research Article
                Subject: Research and Analysis Methods
                Subject: Mathematical and Statistical Techniques
                Subject: Statistical Methods
                Subject: Meta-Analysis
                Subject: Physical Sciences
                Subject: Mathematics
                Subject: Statistics (Mathematics)
                Subject: Statistical Methods
                Subject: Meta-Analysis
                Subject: Medicine and Health Sciences
                Subject: Women's Health
                Subject: Maternal Health
                Subject: Pregnancy
                Subject: Medicine and Health Sciences
                Subject: Women's Health
                Subject: Obstetrics and Gynecology
                Subject: Pregnancy
                Subject: People and Places
                Subject: Demography
                Subject: Birth Rates
                Subject: Medicine and Health Sciences
                Subject: Endocrinology
                Subject: Endocrine Physiology
                Subject: Menstrual Cycle
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Endocrine Physiology
                Subject: Menstrual Cycle
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Endocrine Physiology
                Subject: Menstrual Cycle
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Reproductive Physiology
                Subject: Menstrual Cycle
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Reproductive Physiology
                Subject: Menstrual Cycle
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Germ Cells
                Subject: OVA
                Subject: Oocytes
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Embryology
                Subject: Embryos
                Subject: Medicine and Health Sciences
                Subject: Women's Health
                Subject: Maternal Health
                Subject: Pregnancy
                Subject: Pregnancy Complications
                Subject: Miscarriage
                Subject: Medicine and Health Sciences
                Subject: Women's Health
                Subject: Obstetrics and Gynecology
                Subject: Pregnancy
                Subject: Pregnancy Complications
                Subject: Miscarriage
                Subject: Research and Analysis Methods
                Subject: Database and Informatics Methods
                Subject: Database Searching
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

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