Efficacy of Elagolix and Relugolix for the Treatment of Pelvic Pain in Patients With Endometriosis: A Systematic Review

Endometriosis is a chronic gynecological condition commonly associated with pelvic pain, dysmenorrhea, dyspareunia, and infertility. Owing to the limitations and adverse effects of traditional hormonal therapies, this study aimed to evaluate the efficacy and safety of elagolix and relugolix for the management of endometriosis-related pain, in comparison with other therapeutic alternatives. A systematic search was conducted in PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), Cochrane, SciELO, ScienceDirect, and Google Scholar, including randomized clinical trials (RCTs) published between 2014 and 2025. Methodological quality was assessed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, together with the GRADE and Jadad tools. Nine clinical trials met the inclusion criteria. The findings suggest that both relugolix and elagolix, whether administered as monotherapy or in combination with estrogens and progestins, effectively reduce endometriosis-associated pain, improve the quality of life, and decrease the need for opioid use. Reported adverse events were generally mild, with minimal loss of bone mineral density (BMD). Importantly, the strongest and most consistent evidence supports the use of relugolix in combination with add-back therapy, which appears to provide sustained efficacy and a more favorable long-term safety profile than monotherapy. Thus, relugolix with hormonal add-back therapy emerges as a safe and effective long-term treatment option for endometriosis-related symptoms, offering significant clinical benefits while mitigating hypoestrogenic side effects. Categories: Family/General Practice, Obstetrics/Gynecology, Internal Medicine

dysmenorrhea, elagolix, endometriosis pain, ob-gyn, pelvic pain, relugolix

And Background Endometriosis is a chronic inflammatory gynecological condition characterized by the ectopic presence of functional endometrial tissue outside the uterine cavity, which responds to hormonal stimuli similarly to eutopic endometrium [1-3] . The most common clinical manifestation is chronic pelvic pain, considered the cardinal symptom, although it may also present with dysmenorrhea, dyspareunia, dyschezia, dysuria, and infertility [1] . This pathology affects approximately 6%-10% of women of reproductive age worldwide, with significantly higher rates in specific subgroups, such as those experiencing infertility (up to 50%) or chronic pelvic pain (up to 70%) [4,5] . According to the World Health Organization, around 190 million women globally live with endometriosis, making it one of the leading causes of noninfectious gynecological disability and having a substantial impact on the quality of life [6] . In Latin America, particularly in countries such as Ecuador, the true burden of the disease remains poorly characterized due to a scarcity of epidemiological studies, limited diagnostic capacity, and a lack of population registries. Hospital-based research in cities such as Quito, Guayaquil, and Cuenca has estimated that between 10% and 12% of women presenting with pelvic pain may suffer from endometriosis, with a reported diagnostic delay ranging from five to 10 years from the initial onset of symptoms [7,8] . This delay is exacerbated by sociocultural factors, including the stigma associated with severe menstrual pain, the normalization of symptoms, and barriers to accessing specialized gynecological care, disproportionately affecting women from rural areas, indigenous populations, and low-income groups [9-11] . Conventional therapeutic approaches are based on three main strategies: analgesic treatment, combined hormonal contraceptives, and gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide, which induce a transient hypoestrogenic state to reduce lesion activity and alleviate pain [12,13] . However, the prolonged use of GnRH agonists is limited by significant adverse effects, such as severe climacteric symptoms, the loss of bone mineral density (BMD), and symptomatic recurrence after treatment cessation, while conventional analgesics provide incomplete relief in most cases [14,15] . In this context, GnRH antagonists represent a significant advancement over existing therapies. Unlike agonists, which initially 1 2 3 1 1 1 1 4 1 5 6 Open Access Review Article How to cite this article Quishpe M, Endara-Mina J, Caizapanta J, et al. (September 12, 2025) Efficacy of Elagolix and Relugolix for the Treatment of Pelvic Pain in Patients With Endometriosis: A Systematic Review. Cureus 17(9): e92149. DOI 10.7759/cureus.92149 stimulate a surge in gonadotropins before downregulating the receptor, antagonists act directly and immediately to suppress gonadotropin release without the initial flare effect. Relugolix and elagolix, both oral GnRH receptor antagonists, have emerged as innovative therapeutic alternatives with potential for managing moderate to severe pain in patients with endometriosis. Their mechanisms of action directly and reversibly block the binding of GnRH to its pituitary receptors, thereby preventing the initial increase in gonadotropin characteristic of agonists and favoring a more favorable safety profile [16,17] . Given the need for effective and safe therapeutic options, this study aims to evaluate the efficacy of both relugolix and elagolix in reducing pain in patients with endometriosis, considering clinical benefits and the incidence of adverse effects. This will be achieved through a systematic review of recent randomized clinical trials (RCTs), providing updated and high-quality evidence to support clinical decision-making. Review Methodology The research question was structured using the participants, intervention, comparison, and outcome (PICO) framework, where the population consisted of adult women with a confirmed diagnosis of endometriosis; the intervention involved the administration of relugolix or elagolix, either as monotherapy or in combination with other therapies; the comparator was placebo or alternative medical treatment; and the primary outcome was the reduction in pain intensity. Secondary outcomes included improvement in the quality of life and the incidence of adverse effects. This review was conducted following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [18] . This study was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the identification number CRD420251118244, with registration completed on August 2, 2025. The registration was performed retrospectively, after the initiation of the systematic review process. Search Strategy A comprehensive and systematic literature search was conducted in the databases PubMed/Medical Literature Analysis and Retrieval System Online (MEDLINE), ScienceDirect, Cochrane Library, SciELO, and Google Scholar. The search strategy incorporated Medical Subject Headings (MeSH) terms, free-text terms, and synonyms to ensure a thorough retrieval of relevant studies. Boolean operators were used to combine the following concepts: efficacy, endometriosis, relugolix or elagolix, benefits, and adverse effects. The search string included both controlled vocabulary and open terms, for example, (efficacy OR effectiveness) AND (endometriosis) AND (relugolix OR elagolix OR GnRH antagonists) AND (benefits OR outcomes) AND (adverse effects OR side effects). The search was limited to publications in Spanish or English, published between January 2014 and June 2025. Additionally, a manual search was conducted by reviewing the

lists of relevant articles. All retrieved references were manually reviewed to eliminate duplicates. The complete search strings are provided in the Appendices. Inclusion and Exclusion Criteria Randomized clinical trials (RCTs) with double masking that evaluated relugolix or elagolix for the management of pain associated with endometriosis, with a minimum follow-up of three months, were included. Studies that did not report pain outcomes, presented conflicts of interest that compromised the interpretation of results, or did not clearly specify the treatment regimen were excluded. Non-randomized trials, observational studies, reviews, editorials, and letters to the editor were also excluded. Study Selection The review of titles and abstracts was conducted independently by two reviewers (MQ and DT) to determine the eligibility of the studies. In cases of doubt, the full text was obtained for evaluation. Discrepancies were resolved by consensus or with the intervention of a third reviewer (HSV). After applying the selection criteria, a total of nine studies were included in the qualitative synthesis. Data Extraction and Management Data extraction was performed using a standardized form adapted from the model proposed by the Cochrane Consumers and Communication Review Group. The variables collected included author, the year of publication, journal, country and study setting, total sample size and by group, details of the intervention, the duration of follow-up, primary and secondary outcomes, adverse events, and ethical considerations (approval by an ethics committee and the inclusion of informed consent). Two reviewers conducted the extraction independently (JC and AG), resolving discrepancies by consensus or, if necessary, through a third reviewer (JEM). 2025 Quishpe et al. Cureus 17(9): e92149. DOI 10.7759/cureus.92149 2 of 12 Data Analysis and Synthesis Due to the clinical and methodological heterogeneity of the included studies, particularly regarding treatment duration, pain measurement scales, and population characteristics, a meta-analysis was not performed. Instead, a qualitative narrative synthesis was conducted, grouping results by sample, follow-up time, intervention, and the type of outcome (pain reduction, quality of life improvement, and adverse effects). Assessment of Methodological Quality The quality of the included trials was assessed using the Jadad scale [19] and the GRADE approach [20] to evaluate the certainty of the evidence. Only studies with a score of ≥3 on the Jadad scale and at least a moderate level of certainty according to GRADE were included in the final synthesis. The risk of bias was analyzed based on the domains established by GRADE (selection bias, performance bias, detection bias, attrition bias, and reporting bias). Additionally, the Risk of Bias (RoB) II screening tool by Cochrane was used to assess risk of bias. To ensure transparency and reproducibility, a checklist based on the PRISMA 2020 guidelines was applied at all stages of the process. The details of the RoB II assessment are provided in the Appendices.

Through the application of specific search strategies and selection criteria detailed in Figure 1 , a total of 140 articles were initially identified, with 90 duplicate records removed, resulting in 50 records for screening. Ten were excluded due to article type, and seven records were excluded for incomplete access. A total of 33 full-text articles were evaluated according to the inclusion criteria. Ultimately, nine randomized clinical trials were included in the qualitative synthesis, published in both Spanish and English (Figure 1 ). 2025 Quishpe et al. Cureus 17(9): e92149. DOI 10.7759/cureus.92149 3 of 12 FIGURE 1: PRISMA flowchart for the identification and selection of included studies PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; MEDLINE, Medical Literature Analysis and Retrieval System Online Synthesis of Results The studies included in this systematic review were published between 2014 and 2024, comprising a total of nine randomized clinical trials (RCTs), with a global sample of over 8,000 women diagnosed with endometriosis. The research was conducted in countries such as the United States, Japan, Canada, Brazil, the United Kingdom, Poland, Switzerland, Ukraine, Australia, and South Africa. The largest proportion of publications came from the United States and Japan, followed by collaborative trials in Europe and Latin America. The variables frequently evaluated in each of the RCTs included dysmenorrhea, non-menstrual pelvic pain (NMPP), dyspareunia, opioid use, analgesic use, bone mineral density (BMD), adverse effects, and the quality of life through Endometriosis Health Profile-30 items (EHP-30) [21] and Uterine Fibroid Symptom and Quality of Life Questionnaire (UFS-QOL) [22] questionnaires. Specifically, eight studies evaluated parameters related to pelvic pain (dysmenorrhea, non-menstrual pain, and dyspareunia) using validated scales such as the visual analog scale (VAS) [23] and numeric rating scale (NRS) [24] . Six trials included quality of life questionnaires, highlighting the EHP-30 and UFS-QOL, which showed clinically significant improvements in the domains of pain, emotional well-being, and control. Seven of the nine studies employed combination therapy with relugolix, while two explored its comparison with GnRH analogs such as leuprolide. Additionally, five studies analyzed the use of both opioids and analgesics, demonstrating a sustained reduction in their consumption during and after treatment. On the other hand, four trials assessed the effect of treatment on bone mineral density, with only mild loss observed, especially when relugolix was used in combination with estrogens and progestogens. Finally, 2025 Quishpe et al. Cureus 17(9): e92149. DOI 10.7759/cureus.92149 4 of 12 seven studies reported adverse events, primarily hot flashes, nausea, and headaches, with no major clinical compromise or frequent need for treatment discontinuation. The methodological quality criteria (Jadad scale) were adequate in all studies (≥3 points), and the certainty of evidence, according to the GRADE system, was classified as high in seven studies and moderate in two. Table 1 presents the main characteristics of the included primary studies, specifying relevant information such as author, the year of publication, the country of conduct, trial title, methodological design, sample size, the duration of follow-up, the type of intervention, and main findings obtained [25-33] . 2025 Quishpe et al. Cureus 17(9): e92149. DOI 10.7759/cureus.92149 5 of 12 Number Author, Year, and Country Trial Title Design Sample and Follow-Up Intervention Variables

Analysis GRADE/Jadad 1 Carr et al., 2014 (United States) [25] Elagolix, an Oral GnRH Antagonist, Versus Subcutaneous Depot Medroxyprogesterone Acetate for the Treatment of Endometriosis: Effects on Bone Mineral Density Phase 2, randomized, double-blind, placebo- controlled trial 252 patients (elagolix, 126; placebo, 126). Follow- up: 24 weeks Elagolix 150 mg QD or 75 mg BID versus DMPA-SC Bone mineral density (lumbar spine and hip); non-menstrual pelvic pain Minimal, nonsignificant BMD loss across groups. Sustained pelvic pain improvement; 86% clinical response with elagolix 150 mg versus 76.5% with DMPA-SC (NS) Comparable efficacy with minimal skeletal impact High; 5/5 2 Taylor et al., 2017 (multinational) [26] Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist Phase 3, randomized, double-blind, placebo- controlled, multicenter trial 1689 patients (elagolix, 872; placebo, 817). Follow- up: 6-12 months Elagolix 150 mg QD or 200 mg BID versus placebo Dysmenorrhea, pelvic pain, dyspareunia, and opioid use Significant reduction in dysmenorrhea (RR, 2.4-3.9; p<0.001) and pelvic pain (RR, 1.3-1.5; p<0.001). Dyspareunia improved with 200 mg BID. Opioid use decreased modestly High-dose elagolix demonstrated superior clinical efficacy High; 5/5 3 Surrey et al., 2018 (multinational) [27] Long-Term Outcomes of Elagolix in Women With Endometriosis: Results From Two Extension Studies Phase 3, randomized, double-blind, placebo- controlled trial (extension EM- I/II) 569 patients (elagolix, 282; placebo, 287). Follow- up: 12 months Elagolix 150 mg QD or 200 mg BID versus placebo Dysmenorrhea, pelvic pain, dyspareunia, and analgesic use Sustained reduction in dysmenorrhea (>75% responders at 12 months). Consistent effect on pelvic pain. Dyspareunia and analgesic use also improved Sustained efficacy with reduced need for concomitant medication Moderate; 4/5 4 Osuga et al., 2021 (Japan) [28] Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain in a dose– response manner: a randomized, double- blind, placebo-controlled study Phase 3, randomized, double-blind, placebo- controlled trial 487 patients (relugolix, 243; placebo, 244). Follow- up: 12+4 weeks Relugolix 20 or 40 mg QD versus placebo Pelvic pain (VAS), QoL (EHP-30), BMD, and analgesic use Dose-dependent pain reduction: -6.2 mm (20 mg) and -4.3 mm (40 mg) versus placebo (p<0.05). QoL improved. Minimal BMD loss Comparable to leuprorelin, with a faster onset and no flare-up High; 5/5 5 Harada et al., 2022 (Japan) [29] Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain compared with leuprorelin in Japanese women: a phase 3, randomized, double-blind, noninferiority study Phase 3, randomized, double-blind, non-inferiority trial 335 patients (relugolix, 167; leuprorelin, 168). Follow- up: 24+4 weeks Relugolix 40 mg QD versus leuprorelin injections Pelvic pain, dysmenorrhea, analgesic use, QoL, and menstruation recovery Relugolix was non-inferior for pain relief. Faster menstruation recovery (38 versus 68 days). QoL improved. Mild BMD reduction, comparable across groups Effective alternative, especially for women with reproductive goals High; 5/5 6 Giudice et al., 2022 (multinational) [30] Once daily oral relugolix combination therapy versus placebo in patients with endometriosis-associated pain: two replicate phase 3, randomised, double-blind, studies (SPIRIT 1 and 2) Phase 3, randomized, double-blind, placebo- controlled trial 1261 patients (relugolix CT, 424; placebo, 425). Follow- up: 24 weeks Relugolix 40 mg+estradiol 1 mg+norethisterone acetate 0.5 mg QD versus placebo Dysmenorrhea, pelvic pain, opioid use, and adverse events Significant reductions in dysmenorrhea (≥45%) and pelvic pain (18%-23%) versus placebo (p<0.0001). Opioid use substantially reduced. Adverse events similar to placebo; BMD loss of <1% Robust efficacy with favorable long-term safety High; 5/5 7 As-Sanie et al., 2024 (United States and multinational) [31] Impact of relugolix combination therapy on functioning and quality of life in women with endometriosis-associated pain Phase 3, randomized, double-blind, placebo- controlled, multicenter trial 802 patients (relugolix CT, 401; Placebo, 401). Follow- up: 104 weeks Relugolix CT (40 mg relugolix, 1 mg estradiol, and 0.5 mg norethisterone acetate) versus placebo QoL (EHP-30), dysmenorrhea, pelvic pain, and BMD Significant and sustained QoL improvement (EHP-30 pain, -32.8 to - 41.3; p<0.0001); ≥20-point pain reduction in 88.6% at 104 weeks. BMD loss of <1% Long-term efficacy with durable safety High; 5/5 TABLE 1: Randomized clinical trials used in the systematic review GnRH, gonadotropin-releasing hormone; QD, once daily; BID, twice daily; DMPA-SC, subcutaneous depot medroxyprogesterone acetate; BMD, bone mineral density; NS, not significant; RR, relative risk; VAS, visual analog scale; QoL, quality of life; EHP-30, Endometriosis Health Profile-30 items; CT, combination therapy The detailed extensions of the SPIRIT 1 and 2 trials, as well as the ELARIS EM-I and EM-II studies, are provided in the Appendices to allow the comprehensive consultation of their long-term efficacy and safety data.

This systematic review, which integrates evidence from nine randomized clinical trials with a large sample of women diagnosed with endometriosis, provides a comprehensive assessment of the clinical efficacy, 2025 Quishpe et al. Cureus 17(9): e92149. DOI 10.7759/cureus.92149 6 of 12 safety, impact on quality of life, and reduction in analgesic use of treatment with relugolix and elagolix, both as monotherapy and in combination with hormonal therapy. The findings confirm that relugolix, whether administered alone or in conjunction with estrogens and progestogens, represents an effective and well-tolerated therapeutic alternative for the treatment of pain associated with endometriosis. Across the included clinical trials [25-31] , between 70% and 88.6% of patients achieved clinically significant improvement in pelvic pain control, as measured using validated tools such as the EHP-30 [22] and NRS [24] , over follow-up periods ranging from 24 to 104 weeks. In SPIRIT 1 and 2, a 75% reduction in dysmenorrhea and a 59%-66% reduction in non-menstrual pelvic pain (NMPP) were observed, with an absolute difference of 47.6% (95% CI: 39.3-56.0; p<0.0001) compared to placebo [30] . Opioid use decreased by up to 15.9% in the treatment group, without clinically relevant changes in bone mineral density (BMD) or serious adverse events. Dyspareunia also improved in several trials, with Taylor et al. (2017) [26] and Surrey et al. (2018) [27] reporting up to a 60% reduction, compared to 36.5% with placebo (p<0.001), and relative risks ranging from 1.4 to 1.6. Bone safety outcomes were favorable, with combination therapy maintaining BMD loss under 1% even at 104 weeks, according to As-Sanie et al. (2024) [31] and Osuga et al. (2021) [28] . Mild but significant reductions in lumbar spine BMD (-2.1% versus -0.1% with placebo; p<0.005) were observed but without the increased incidence of hot flashes or flare-up phenomena commonly associated with GnRH agonists [25-31] . These findings are consistent with previous meta-analyses. For example, Sobral et al. (2025) demonstrated an 84% reduction in dysmenorrhea and a 68.9% reduction in non-menstrual pain after two years of treatment, with sustained long-term benefits [32] . These results support the hypothesis that the analgesic effect may be mediated by the stable modulation of the hypothalamic-pituitary-ovarian axis, leading to suppressed estradiol levels without inducing severe hypoestrogenism [33] . Similarly, Xin et al. (2023) found that GnRH antagonists significantly reduced pelvic pain (relative risk {RR}, 0.48; 95% CI, 0.35-0.65), with less bone loss compared to GnRH agonists such as leuprolide [34] . On the other hand, the Cochrane meta- analysis by Veth et al. (2023), which included 15 randomized trials and over 1,800 women, concluded that while GnRH agonists (e.g., leuprolide and nafarelin) are effective for pain relief, they are limited by adverse effects such as hypoestrogenism-induced BMD loss, severe hot flashes, mood disturbances, and vaginal dryness [35] . These effects restrict their use to six months or require co-treatment with hormone replacement therapy [35,36] . Overall, the studies included in this review, especially SPIRIT 1 and 2, suggest that relugolix combination therapy can be administered for up to 24 months without significant bone loss (<1%) while maintaining efficacy in dysmenorrhea, NMPP, and reduction in opioid use [30] . This could represent a potential shift in the therapeutic paradigm, enabling longer-term treatment for women with endometriosis who require sustained pain control, particularly those of reproductive age. Regarding non-menstrual pelvic pain, the SPIRIT 2 trial, with 623 participants, reported improvement in 66% of treated patients compared to 43% with placebo, with an absolute difference of 23.4% (95% CI, 14.0- 32.8; p<0.0001) [30] . Studies by Harada et al. (2022) [29] and As-Sanie et al. (2024) [31] confirm that, although NMPP has a more complex pathophysiology, relugolix maintains a sustained effect, particularly in combination therapy, with VAS differences ranging from -4.3 to -6.2 mm compared to placebo. In terms of dyspareunia, while Vercellini et al. (2016) [37] noted that this symptom tends to be less responsive to hormonal treatment, Taylor et al. (2017) [26] and Surrey et al. (2018) [27] demonstrated notable improvements with relugolix, suggesting that its therapeutic effects may extend beyond general pelvic pain to symptoms that directly impact sexual quality of life. Regarding bone mineral density, a common concern in estrogen-suppressive therapies, the analyzed studies demonstrate that the combination of relugolix with hormonal therapy offers adequate protection, with losses of <1% even at 104 weeks [38] . This contrasts with the accelerated bone loss typically seen with GnRH agonists and supports the long-term safety profile of relugolix-based regimens [35,36] .

Some multinational trials included heterogeneous populations in terms of age, the stage of endometriosis, and prior treatments, which hinder the extrapolation of results to specific groups such as adolescents, perimenopausal women, or individuals with infertility [30] . In addition, some studies applied strict exclusion criteria, omitting patients with gynecological comorbidities such as fibroids and adenomyosis, which are common in clinical practice, thereby limiting the applicability of findings to more complex scenarios. Differences in follow-up duration (ranging from 12 to 104 weeks) may also affect the comparability of outcomes such as bone mineral density, chronic dysmenorrhea, and adverse events. Standardizing study duration and incorporating post-treatment follow-up would be desirable to better assess the persistence of effects. Furthermore, if PROSPERO registration had been performed retrospectively, this could raise concerns about selective reporting bias. Although such bias cannot be entirely excluded, the risk was mitigated by 2025 Quishpe et al. Cureus 17(9): e92149. DOI 10.7759/cureus.92149 7 of 12 maintaining consistency between predefined and reported outcomes and ensuring that all methodological deviations were transparently documented. Finally, articles published in languages other than English or Spanish were excluded due to operational limitations in technical translation, which may have introduced a degree of language bias.

This systematic review highlights that relugolix and elagolix, used either as monotherapy or in combination with add-back therapy, are effective and well-tolerated pharmacological options for the management of endometriosis-associated pain. Evidence from randomized clinical trials consistently demonstrates meaningful improvements in core symptoms, contributing to enhanced daily functioning and quality of life for affected women. Furthermore, these treatments offer advantages beyond symptom control, including a reduced need for concomitant analgesics, which underscores their relevance in long-term pain management strategies. While current findings support their integration into clinical practice, further research is necessary to confirm their long-term safety and effectiveness, ensuring their sustained role in the therapeutic landscape of endometriosis. Appendices Table 2 shows the extent of the SPIRIT and ELARIS EM studies. Number Author, Year, and Country Trial Title Design Sample and Follow-up Intervention Outcomes

Analysis GRADE/Jadad 1 Giudice et al., 2022 (multinational) (SPIRIT 1) [30] Relugolix combination therapy with estradiol and norethisterone acetate in women with endometriosis-associated pain (SPIRIT 1) Phase 3, multicenter, randomized, double-blind, placebo- controlled trial 638 women (RCT, 321; placebo, 317). Follow-up: 24 weeks Relugolix 40 mg+estradiol 1 mg+norethisterone acetate 0.5 mg once daily versus placebo Menstrual pain, non-menstrual pelvic pain, the quality of life, and analgesic use Significant reduction in both menstrual and non-menstrual pain compared to placebo; decreased reliance on analgesics; clinically meaningful improvements in the quality of life Demonstrated high efficacy with a consistent safety profile High; 5/5 2 Giudice et al., 2022 (multinational) (SPIRIT 2) [30] Relugolix combination therapy with estradiol and norethisterone acetate in women with endometriosis-associated pain (SPIRIT 2) Phase 3, multicenter, randomized, double-blind, placebo- controlled trial 623 women (RCT, 312; placebo, 311). Follow-up: 24 weeks Relugolix 40 mg+estradiol 1 mg+norethisterone acetate 0.5 mg once daily versus placebo Menstrual pain, non-menstrual pelvic pain, the quality of life, and analgesic use Findings consistent with SPIRIT 1: significant improvement in pain reduction, reduced need for concomitant analgesics, and favorable safety profile High efficacy with reproducible

across populations High; 5/5 3 Taylor et al., 2017 (multinational) (ELARIS EM- I) [26] Elagolix for endometriosis-associated pain (ELARIS EM-I) Phase 3, multicenter, randomized, double-blind, placebo- controlled trial 872 women. Follow-up: six months Elagolix 150 mg once daily or 200 mg twice daily versus placebo Menstrual pain, non-menstrual pelvic pain, analgesic use, and the quality of life Both elagolix regimens significantly reduced menstrual and non- menstrual pain versus placebo; decreased analgesic use; dose- dependent hypoestrogenic adverse effects observed Robust efficacy with a manageable safety profile High; 5/5 4 Taylor et al., 2017 (multinational) (ELARIS EM- II) [26] Elagolix for endometriosis-associated pain (ELARIS EM-II) Phase 3, multicenter, randomized, double-blind, placebo- controlled trial 817 women. Follow-up: six months Elagolix 150 mg once daily or 200 mg twice daily versus placebo Menstrual pain, non-menstrual pelvic pain, analgesic use, and the quality of life Consistent with EM-I: significant reductions in both pain domains, lower analgesic use, and a safety profile marked by mild-to-moderate hypoestrogenic effects and bone mineral density loss Confirmed efficacy and reproducibility across study populations High; 5/5 TABLE 2: Extension of SPIRIT and ELARIS EM studies RCT: relugolix combination therapy Table 3 shows the search equations. 2025 Quishpe et al. Cureus 17(9): e92149. DOI 10.7759/cureus.92149 8 of 12 Databases Search Equations PubMed/MEDLINE ("Endometriosis"[Mesh] OR endometriosis) AND ("Pelvic Pain"[Mesh] OR "Dysmenorrhea"[Mesh] OR "Dyspareunia" [Mesh] OR pelvic pain OR pelvic pains OR pelvic-pain OR dysmenorrhea OR dysmenorrhoeas OR dyspareunia OR "nonmenstrual pelvic pain" OR "non-menstrual pelvic pain") AND ("Elagolix" OR "Relugolix" OR "Gonadotropin- Releasing Hormone Antagonists" OR "GnRH antagonist" OR "oral GnRH antagonist") AND ("Treatment Outcome" [Mesh] OR "Patient Reported Outcome Measures"[Mesh] OR "Quality of Life"[Mesh] OR "Visual Analog Scale"[Mesh] OR efficacy OR effectiveness OR benefit OR "pain reduction" OR "pain relief" OR "quality of life" OR "Drug-Related Side Effects and Adverse Reactions"[Mesh] OR safety OR tolerability OR "adverse effect" OR "adverse event") AND ("2014/01/01"[Date - Publication]: "2025/06/30"[Date - Publication]) AND (english[lang] OR spanish[lang]) AND humans[MeSH Terms] Cochrane (MeSH descriptor: [Endometriosis] explode all trees OR endometriosis:ti,ab,kw) AND (MeSH descriptor: [Pelvic Pain] explode all trees OR MeSH descriptor: [Dysmenorrhea] explode all trees OR MeSH descriptor: [Dyspareunia] explode all trees OR pelvic pain OR dysmenorrhea OR dyspareunia OR "nonmenstrual pelvic pain" OR "non-menstrual pelvic pain") AND (MeSH descriptor: [Gonadotropin-Releasing Hormone Antagonists] explode all trees OR elagolix OR relugolix OR "GnRH antagonist" OR "gonadotropin-releasing hormone antagonist" OR "oral GnRH antagonist") AND (MeSH descriptor: [Treatment Outcome] explode all trees OR MeSH descriptor: [Patient Reported Outcome Measures] explode all trees OR MeSH descriptor: [Quality of Life] explode all trees OR MeSH descriptor: [Drug- Related Side Effects and Adverse Reactions] explode all trees OR efficacy OR effectiveness OR benefit OR "pain reduction" OR "pain relief" OR "quality of life" OR safety OR tolerability OR "adverse effect" OR "adverse event") SciELO (endometriosis) AND ("dolor pélvico" OR dismenorrea OR dispareunia OR "dolor pélvico no menstrual") AND (elagolix OR relugolix OR "antagonista de GnRH" OR "antagonistas de GnRH" OR "antagonista oral de GnRH") AND (eficacia OR efectividad OR beneficios OR "resultado del tratamiento" OR "calidad de vida" OR seguridad OR "eventos adversos" OR tolerabilidad) ScienceDirect TITLE-ABSTR-KEY(endometriosis AND ("pelvic pain" OR dysmenorrhea OR dyspareunia OR "nonmenstrual pelvic pain" OR "non-menstrual pelvic pain") AND (elagolix OR relugolix OR "GnRH antagonist*" OR "gonadotropin- releasing hormone antagonist" OR "oral GnRH antagonist") AND (efficacy OR effectiveness OR benefit OR "treatment outcome" OR "quality of life" OR "pain reduction" OR "pain relief" OR safety OR tolerability OR "adverse effect" OR "adverse event")) Google Scholar ("endometriosis") AND ("pelvic pain" OR dysmenorrhea OR dyspareunia OR "nonmenstrual pelvic pain" OR "non- menstrual pelvic pain") AND (elagolix OR relugolix OR "GnRH antagonist" OR "gonadotropin-releasing hormone antagonist" OR "oral GnRH antagonist") AND (efficacy OR effectiveness OR "treatment outcome" OR "quality of life" OR "pain reduction" OR safety OR tolerability OR "adverse effects" OR "adverse events") TABLE 3: Search equations MEDLINE: Medical Literature Analysis and Retrieval System Online Table 4 shows the analysis of the risk of bias in the randomized studies included with RoB II. 2025 Quishpe et al. Cureus 17(9): e92149. DOI 10.7759/cureus.92149 9 of 12 Study Bias From the Randomization Process Bias Due to Intended Interventions Bias Due to Missing Outcome Data Bias in the Measurement of the Outcomes Bias in the Selection of the Reported Result Overall Risk of Bias Carr et al., 2014 (United States) [25] Low risk Low risk Some concerns Low risk Low risk Some concerns Taylor et al., 2017 (multinational) [26] Low risk Low risk Low risk Low risk Low risk Low risk Surrey et al., 2018 (multinational) [27] Low risk Some concerns Some concerns Low risk Low risk Some concerns Osuga et al., 2021 (Japan) [28] Low risk Low risk Low risk Low risk Low risk Low risk Harada et al., 2022 (Japan) [29] Low risk Low risk Low risk Low risk Low risk Low risk Giudice et al., 2022 (multinational) [30] Low risk Low risk Low risk Low risk Low risk Low risk As-Sanie et al., 2024 (United States and multinational) [31] Low risk Low risk Low risk Low risk Low risk Low risk TABLE 4: Analysis of risk of bias in the randomized studies included with RoB II RoB: Risk of Bias Additional Information Author Contributions All authors have reviewed the final version to be published and agreed to be accountable for all aspects of the work. Concept and design: Jesús Endara-Mina, Mayuri Quishpe, Alisson Guzmán, Dayana Tenesaca, Diana Asto, Odalis Mena, Jorge Avilés, Henry Sarmiento-Vallejo, Noelya Rengel, Josselyn Caizapanta, Genesis Vaca Acquisition, analysis, or interpretation of data: Jesús Endara-Mina, Mayuri Quishpe, Alisson Guzmán, Dayana Tenesaca, Diana Asto, Odalis Mena, Jorge Avilés, Henry Sarmiento-Vallejo, Noelya Rengel, Josselyn Caizapanta, Genesis Vaca Drafting of the manuscript: Jesús Endara-Mina, Mayuri Quishpe, Alisson Guzmán, Dayana Tenesaca, Diana Asto, Odalis Mena, Jorge Avilés, Henry Sarmiento-Vallejo, Noelya Rengel, Josselyn Caizapanta, Genesis Vaca Critical review of the manuscript for important intellectual content: Jesús Endara-Mina, Mayuri Quishpe, Alisson Guzmán, Dayana Tenesaca, Diana Asto, Odalis Mena, Jorge Avilés, Henry Sarmiento- Vallejo, Noelya Rengel, Josselyn Caizapanta, Genesis Vaca Supervision: Jesús Endara-Mina Disclosures Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

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