Oral GnRH antagonists for ovulation suppression during ovarian stimulation protocols: systemic review and meta-analysis.

Purpose The impact of oral GnRH antagonists on IVF treatment outcomes remains unclear. The aim of the study is to investigate the impact of GnRH antagonist over the outcomes of IVF.

We performed an electronic search using MEDLINE® with the OvidSP interface PUBMED, Embase, Web of Science, and Cochrane Library up to December 16, 2024. We included experimental and non-experimental studies, assessing the role of oral GnRH during controlled ovarian stimulation protocols. Our main outcomes were cycle cancelation rate and mean number of mature oocytes retrieved at oocyte pickup (OPU) day.

We included four studies comprising 813 patients, of whom 452 women received oral GnRH antagonists and 294 received injectable subcutaneous GnRH antagonists. No statistical differences were noted in the meta-analysis between each outcome measured (cycle cancelation, mean overall and mature oocytes, fertilization rate, and blastulation rate). Using the GRADE criteria, the overall quality of the existing evidence was determined as moderate.

This is the first systemic review and meta-analysis to examine the usage of oral GnRH antagonists for ovulation suppression during IVF treatments. Our findings suggest the use of oral GnRH antagonists may be beneficial in infertility treatments; however, caution should be taken, as robust establishment of their effectivity and safety in clinical practice is still pending. Trial registration Registration Number: PROSPERO study ID: CRD42024599730 Supplementary Information The online version contains supplementary material available at 10.1007/s10815-025-03496-4.

Meta-analysis, Oral GnRH, Elagolix, Relugolix, Ovulation suppression

Controlled ovarian stimulation (COS) refers to the induced hyperstimulation of the ovarian follicles, with the purpose of achieving as many mature oocytes as possible [1]. In the context of in vitro fertilization, these oocytes would be further retrieved, usually by vaginal sonography based ovarian puncture, and could be utilized for different applications, such as cryopreservation and fertilization [2]. The basis for the COS protocols relies upon different follicular stimulants (i.e., gonadotropins) along with different premature ovulation inhibitors (i.e., GnRH analogs). GnRH analogs are synthesized by utilizing the native GnRH decapeptide structure, into the commonly used subcutaneous, intramuscular, and nasal formulation [3, 4]. The different formulation abovementioned have been used for several decades with good outcomes and relatively minor side effects and include GnRH agonists and antagonists. The oral GnRH is a bioavailable nonpeptide GnRH antagonist that provides flexibility for greater control over pituitary gonadotropin secretion than peptide depots, as well as avoiding injections or implants and their associated liabilities [5]. It was thus far extensively researched in the context of pituitary suppression, and as safety and effectiveness were proven, it became a common treatment option for endometriosis patients and patients with symptomatic fibroid uterus [6–9]. We aimed to determine the role of oral GnRH antagonists in COS cycles for preventing premature ovulation.

This systematic review and meta-analysis of the literature were conducted according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [10]. Searches were conducted by an experienced research librarian in the following databases: MEDLINE(R) using the OvidSP interface and PubMed, Embase, Web of Science, Cochrane Library, Scopus, and its Secondary Documents, up to November 13, 2024. The study protocol was registered under PROSPERO in the following link: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024599730, with the PROSPERO ID number CRD42024599730. We considered for inclusion both experimental and non-experimental study designs including randomized controlled trials, observational studies such as case-controlled studies, cohort studies, and cross-sectional studies evaluating the effectiveness of oral GnRH antagonists in ovulation suppression. Case reports, reviews, editorials, and non-human studies were excluded. Abstracts of studies were excluded if the full article had not been published. Among the articles with overlapping populations (e.g., studies where a larger study included patients from a previously reported smaller sample), only the larger study was included. The authors of the studies were contacted when they reported unclear results, incomprehensible statistical methods, or conclusions not supported by the reported results. We included patients undergoing controlled ovarian stimulation (COS) treatment with either oral GnRH antagonist (study group) or injectable GnRH antagonist (control). We included all patients undergoing COS cycles for any indication (such as IVF/ICSI or fertility preservation) who were treated with oral GnRH antagonist for ovulation suppression purposes. The control group included all patients undergoing COS cycles for any indication (such as IVF/ICSI or fertility preservation) who were treated with injectable GnRH antagonist (i.e., subcutaneous) for ovulation suppression purposes. Our main outcomes included cycle cancelation rate and mean number of mature oocytes retrieved. Secondary outcomes included fertilization rate and blastulation rate. Data selection Two authors independently screened the titles and abstracts of all articles to determine which studies should be further assessed. Any disagreement or uncertainty was resolved through discussion with a third reviewer. Data extraction The data were collected using a predetermined electronic Excel spreadsheet file with predetermined outcome measures. In addition to outcome data, a detailed list of study characteristics related to patient demographics, intervention details, and study methodology was gathered. This data were then used to construct evidence tables. Data presented as percentages were recalculated to obtain absolute numbers. The Cochrane Collaboration’s Risk of Bias tool was used to evaluate the quality of randomized controlled trials. Two independent reviewers assessed trial quality, and any disagreements were resolved through consensus adjudication. Methodological quality assessment of observational studies was conducted using the Newcastle–Ottawa Quality Assessment Scale. Two independent reviewers assessed trial quality, and any disagreements were resolved through consensus adjudication. Additionally, two reviewers independently assessed the overall quality of the evidence using criteria recommended by the Grading of Recommendations Assessment, Development and Evaluation Working Group (GRADE). The MOOSE checklist for this study design was followed. Heterogeneity across studies was assessed using the χ2 test and the I2 statistic. Pooling of the results was performed using either the fixed-effects model or the random-effects model. If neither the χ2 analysis nor the I2 test indicated significant heterogeneity between the studies, the fixed-effects model was used. In cases of high statistical heterogeneity (I2 > 50%, considered as substantial heterogeneity), the random-effects model was used. Sensitivity analyses were conducted by omitting studies one by one from the analyses. The Cochrane Collaboration software (RevMan version 5.4.1) was used for analysis. A two-tailed P < 0.05 was considered statistically significant. All patients received daily recombinant FSH injections for the follicular stimulation phase of the COS protocol except for one study that used recombinant FSH or hMG for ovarian stimulation [11]. The administration of GnRH antagonists commenced once a lead follicle reached either 13 mm [12],14 mm [13, 14], or 16 mm [11] as observed via transvaginal sonography in both study and control groups. Elagolix dosing varied among studies: 200 mg once daily [13], 50 mg every other day [12], and 200 mg twice daily [14], whereas relugolix dose was given at 40 mg once daily [11]. GnRH antagonist suppression was discontinued 24 h prior to ovulation induction. Ovulation was then induced using either GnRH agonist alone [13], human chorionic gonadotropin alone [11, 12], or a combination of both [14].

A total of 573 studies were identified through database searching, with 205 duplicates removed. Figure 1 describes the data collection and selection process. We selected four references comprising 813 patients, of whom 452 women received oral GnRH antagonists (elagolix [12–14] and relugolix [11]; study group) and 294 received injectable subcutaneous GnRH antagonists (ganirelix [11–14], cetrorelix [11, 12]; control group). Studies included in the meta-analysis data and characteristics are presented in Table 1. List of studies excluded from the analysis is detailed in Supplementary 1 table. Table 1. | First author | Year | Country | Type of article | Main outcomes | Inclusion | Exclusion | Secondary outcomes | Study group | Control group | |---|---|---|---|---|---|---|---|---|---| | Boniface | 2023 | USA | Prospective cohort study with the use of historical controls | Premature ovulation rate Total oocytes Mature oocytes Maximum estradiol Luteinizing hormone Progesterone levels | Oocyte donors Aged 21–30 years Nonsmokers BMI 2 ng/ml FSH < 10 IU/l | Chronic medical conditions First degree relatives with hereditary disorders Known carriers of x-linked disorders | Maximum E2, LH, and P4 levels Fertilization rate Blastocyst development | 75 | 75 | | Mouanness | 2024 | USA | Retrospective | Percentage change between pre- and post-LH surge | Age < 42 years Day 3 FSH level of < 15 IU/l | None | IVF cycle outcomes | 173 | 96 | | Soliman | 2024 | Canada | Retrospective | Cycle cancellation Biochemical pregnancy Sustained implantation rates | Patients with infertility Aged 23–50 BMI 15–42 | Patients who were receiving either drug for a reason other than cos | Miscarriage Fertilization Blastulation rates | 71 | 123 | | Nakao | 2021 | Japan | Retrospective | Premature ovulation rate | Age < 42 | Elevated basal LH Premature ovarian insufficiency PCOS Ovarian endometriomas Azoospermia | Clinical outcomes in IVF treatment | 106 | 94 | Table 1 summarizes the studies’ main characteristics. Three studies were retrospective [11, 12, 14], and one was a prospective cohort study using historical controls [13]. The risk of bias summary, according to the Cochrane Collaboration’s Risk of Bias tool (for RCTs) and the Risk of Bias in Non-randomized Studies–of Interventions (ROBINS-I) assessment tool, is presented in Supplementary Table 2. All studies were found to have moderate bias or minor concerns. Synthesis of results Primary soutcome measures The forest plot for cycle cancelation rate is presented in Fig. 2. No difference was noted between the oral GnRH and injectable GnRH groups (OR 1.28 [95% CI 0.45–3.63], P = 0.65). Oocyte retrieval rate and mature oocyte yield forest plots are presented in Fig. 3a and b, respectively. No differences were noted in either mean oocyte number (OR 1.05 [95% CI 0.69–1.59], P = 0.21, I2 = 34%) or mature oocytes (OR 1.08 [95% CI 0.68–1.71], P = 0.59, I2 = 0%). Secondary outcome measures The fertilization rate and blastulation rate did not differ between the groups, as presented in forest plots (Fig. 4a and b) (OR 0.97 [95% CI 0.68–1.38], P = 0.01, I2 = 76%; OR 1.02 [95% CI 0.81–1.28], P = 0.06, I2 = 63%, respectively). Sensitivity analyses did not show that the results were significantly affected by a single study. Moreover, as described earlier, all studies have utilized recombinant FSH for ovarsian stimulation. After omitting one study that reported using recombinant FSH or hMG for ovarian stimulation as per sensitivity analysis, all reported outcomes remained unchanged. Using the GRADE criteria, the overall quality of the existing evidence was determined as moderate, considering data acquisition retrospective observational studies.

Main results In the current meta-analysis, no differences in treatment outcomes, including cycle cancelation, mean overall and mature oocytes, and fertilization and blastulation rates, were found between oral GNRH antagonists and injectable subcutaneous GNRH antagonists. Our study reveals new insights on oral GNRH antagonists used during IVF treatment with comparable outcomes between them and the routinely used injectable agents. Comparison with existing literature GNRH antagonist protocols are increasingly becoming the prevalent method of premature ovulation suppression during IVF treatments because of its shorter duration, ease of use, and better tolerability for patients as well as the reduced risk for ovarian hyperstimulation syndrome [15]. Currently, the only GNRH antagonists approved for pituitary suppression in COS during IVF treatment are the injectable types. In these protocols, the patients are required to have multiple injections, both increasing the financial and physical burdens. Oral GNRH antagonists are approved for endometriosis and inhibit the endogenous GNRH stimulation of FSH and LH, which in turn reduces the production of ovarian estradiol and progesterone [7]. Despite being taken orally, the affinity for the GNRH receptor remains high, resulting in rapid and reversable dose dependent pituitary suppression [8]. As safety and efficacy in reducing endometriosis induced pain has been proven for these drugs, and pituitary suppression has been shown, studies have been analyzing the effect of these oral agents for a different indication. Based on the presented results of the current meta-analysis, the oral GNRH antagonist agents seem to be adequately effective in suppressing premature ovulation during controlled ovarian stimulation. Regarding pregnancy outcome data, the published data were insufficient for comparison in this meta-analysis. Only the study by Nakao et al. reported on the clinical pregnancy rate and found no differences between oral and injectable GNRH antagonist groups [11]. Soliman et al. presented higher rates of biochemical pregnancies in the oral GNRH antagonist group only for frozen embryo transfers, which were not detected in the fresh cycle groups [14]. Miscarriage rates were shown to be similar between groups in the two studies mentioned above [11, 14]. The advantages of the oral GNRH antagonist agents are many. First, in regards of enhancing patients’ care, as the controlled ovarian stimulation during IVF treatment is already an emotional and physical demanding journey, the oral GNRH antagonist may provide a less painful and less invasive option, with comparable results. Second, though a formal cost-effective study was not yet conducted, it seems that the oral GNRH antagonists have a financial benefit as the agents are cheaper than the injectable GNRH antagonists, presenting equivalent results at a lower cost [12]. Previous studies were designed to determine the optimal dosage of oral GnRH antagonist, with the conclusion that endogenous hormonal inhibition can be achieved by a dose-dependent manner, with maximum E2 suppression achieved with elagolix doses of 200 mg twice daily or higher [7, 16, 17]. The studies included in our systemic review and meta-analysis have used doses ranging from 50 mg every other day to 200 mg twice a day. Strengths and limitations Our mseta-analysis, being the first to examine the efficacy of oral GNRH antagonists for pituitary suppression during IVF treatment, offers valuable insights into these emerging drugs. We included both prospective and retrospective studies, resulting in an overall moderate strength of evidence. We utilized major clinical literature databases from which data were extracted and analyzed using robust statistical methodologies, strengthening the reliability of results. However, our study is not without limitations. Firstly, different ovulation induction protocols (GnRH agonists, hCG, or combination) could influence the number of mature oocytes retrieved and perhaps other fertilization outcomes. We could not determine several important parameters of treatment outcomes, for example, the mean gonadotropins dosage used due to data unavailability, although arithmetic mean was quite similar (2600 IU vs. 2602 IU in the control and study groups, respectively). Likewise, data regarding treatment duration were unavailable. There was insufficient data for analyzing the effect of oral GNRH antagonists on pregnancy outcome data including biochemical and clinical pregnancy, abortion rate, and live birth rates. The final number of studies and patients included in our analysis was relatively small (four studies), and our analyses included only three to four studies per comparison, with the available number of participants remaining too small for the reliability and robustness of the results. Additionally, studies differed in inclusion and exclusion criteria, with heterogenicity in COS protocols, ovulation induction drugs, and in the oral GNRH antagonists; thus, we were unable to adjust for potential confounding factors. Three of the included studies were retrospective, possessing potential sources of bias.

This is the first systemic review and meta-analysis to suggest the use of oral GnRH antagonists in IVF treatments. Oral GnRH antagonists may be an attractive alternative for fertility clinics presenting a less expensive and less invasive treatment option compared to the injectable GnRH antagonists. Nonetheless, due to the unavoidable confounding effect associated with observational studies, these conclusions should be taken with caution. Before any formal recommendations, well-designed prospective randomized studies are still needed to support or negate these findings. Supplementary Information Below is the link to the electronic supplementary material. Author contributions N.C. conceptualized the methodology. N.C., A.Z., and C.N. wrote the first draft. N.C., C.N., S.S., O.L., A.Z., and G.O. participated in data compilation and paper review. All authors approved the final version of the manuscript. Data availability Not applicable. Declarations Ethical approval Not applicable, as a systemic review and meta-analysis, no specific patient’s data was recorded. Conflict of interest The authors declare no competing interests. Footnotes Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Nadav Cohen and Ariel Zilbelicht contributed equally.

- 1.Arslan M, Bocca S, Mirkin S, et al. Controlled ovarian hyperstimulation protocols for in vitro fertilization: two decades of experience after the birth of Elizabeth Carr. Fertil Steril. 2005;84:555–69. [DOI] [PubMed] [Google Scholar] - 2.Toner JP, Brzyski RG, Oehninger S, et al. Combined impact of the number of pre-ovulatory oocytes and cryopreservation on IVF outcome. Hum Reprod. 1991;6:284–9. [DOI] [PubMed] [Google Scholar] - 3.Ortmann O, Weiss JM, Diedrich K. Gonadotrophin-releasing hormone (GnRH) and GnRH agonists: mechanisms of action. Reprod Biomed Online. 2002;5(Suppl 1):1–7. [DOI] [PubMed] [Google Scholar] - 4.Al-Inany H, Aboulghar M. GnRH antagonist in assisted reproduction: a Cochrane review. Hum Reprod. 2002;17:874–85. [DOI] [PubMed] [Google Scholar] - 5.Chen C, Wu D, Guo Z, et al. Discovery of sodium R-(+)-4-{2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor. J Med Chem. 2008;51:7478–85. [DOI] [PubMed] [Google Scholar] - 6.Diamond MP, Carr B, Dmowski WP, et al. Elagolix treatment for endometriosis-associated pain: results from a phase 2, randomized, double-blind, placebo-controlled study. Reprod Sci. 2014;21:363–71. [DOI] [PubMed] [Google Scholar] - 7.Ng J, Chwalisz K, Carter DC, et al. Dose-dependent suppression of gonadotropins and ovarian hormones by elagolix in healthy premenopausal women. J Clin Endocrinol Metab. 2017;102:1683–91. [DOI] [PubMed] [Google Scholar] - 8.Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377:28–40. [DOI] [PubMed] [Google Scholar] - 9.Donnez J, Taylor HS, Stewart EA, et al. Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials. Lancet. 2022;400:896–907. [DOI] [PubMed] [Google Scholar] - 10.Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008–12. [DOI] [PubMed] [Google Scholar] - 11.Nakao K, Kuroda K, Horikawa T, et al. Therapeutic effects of an oral gonadotropin-releasing hormone receptor antagonist, relugolix, on preventing premature ovulation in mild ovarian stimulation for IVF. Reprod Med Biol. 2022;21: e12422. [DOI] [PMC free article] [PubMed] [Google Scholar] - 12.Mouanness M, Merhi Z. Elagolix represents a less invasive and cheaper option than injectable GnRH antagonist for ovulation suppression in IVF. J Clin Endocrinol Metab. Epub ahead of print March 14, 2024. 10.1210/clinem/dgae168. [DOI] [PubMed] - 13.Boniface C, Schnorr JN, Gray J, et al. The role of elagolix in the suppression of ovulation in donor oocyte cycles. F S Rep. 2023;4:179–82. [DOI] [PMC free article] [PubMed] [Google Scholar] - 14.Soliman D, Naoom R, Zaied M, et al. The role of elagolix in ovulation suppression during controlled ovarian stimulation: a retrospective cohort study. F&S Reports. Epub ahead of print . 2024. 10.1016/j.xfre.2024.06.006 [DOI] [PMC free article] [PubMed] - 15.Al-Inany HG, Youssef MA, Ayeleke RO, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev 2016; 4: CD001750. [DOI] [PMC free article] [PubMed] - 16.Archer DF, Ng J, Chwalisz K, et al. Elagolix suppresses ovulation in a dose-dependent manner: results from a 3-month, randomized study in ovulatory women. J Clin Endocrinol Metab; 105. Epub ahead of print March 1, 2020. 10.1210/clinem/dgz086. [DOI] [PubMed] - 17.Shebley M, Polepally AR, Nader A, et al. Clinical pharmacology of elagolix: an oral gonadotropin-releasing hormone receptor antagonist for endometriosis. Clin Pharmacokinet. 2020;59:297–309. [DOI] [PMC free article] [PubMed] [Google Scholar] Associated Data This section collects any data citations, data availability statements, or supplementary materials included in this article. Supplementary Materials Data Availability Statement Not applicable.