{"paper_id":"27a98e65-a862-4d29-a21a-aee1f874314d","body_text":"Clin. Exp. Obstet. Gynecol. 2026; 53(9): 50521\nhttps://doi.org/10.31083/CEOG50521\nCopyright: © 2026 The Author(s). Published by IMR Press.\nThis is an open access article under the CC BY 4.0 license .\nPublisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nSystematic Review\nEffectiveness and Safety of Emerging Therapies Versus Conventional\nTreatments or Placebo for Chronic Gynecologic Pelvic Pain in Adult\nWomen: A Systematic Review\nMaría Camila Pérez Bonilla 1\n , Laura Natalia Peña Gutiérrez 1\n ,\nJuan Esteban Arismendi Muñoz 2\n , César David Rojas Pinzón 3\n ,\nJuan Pablo Alzate Granados 4,*\n , Gloria Ibis Tirado Romero 5\n1Faculty of Medicine, Universidad del Rosario, 111711 Bogotá DC, Colombia\n2Faculty of Medicine, Institución Universitaria Visión de las Américas, 660003 Pereira, Risaralda, Colombia\n3Faculty of Health Sciences, Universidad Autónoma de Bucaramanga, 680003 Bucaramanga, Santander, Colombia\n4Clinical Epidemiology, Universidad Nacional de Colombia, 111321 Bogotá DC, Colombia\n5Clinical Epidemiology, Fundación Universitaria Ciencias de la Salud Colombia, 111321 Bogotá DC, Colombia\n*Correspondence: juanpabloalzategranados@gmail.com (Juan Pablo Alzate Granados)\nAcademic Editor: Maria Grazia Porpora\nSubmitted: 29 January 2026 Revised: 3 April 2026 Accepted: 28 April 2026 Published: 8 September 2026\nAbstract\nBackground: Chronic gynecologic pelvic pain (CGPP) is a multifactorial condition associated with functional impairment and heteroge-\nneous treatment responses. Emerging therapies are increasingly being used. However, their comparative effectiveness and safety remain\nuncertain. Methods: We conducted a systematic review of comparative studies in adult women ( ≥18 years) with CGPP lasting ≥6\nmonths. Interventions included pelvic floor rehabilitation, botulinum toxin type A (BoNT-A), psychological and behavioral therapies,\nnutraceuticals, and oral gonadotropin-releasing hormone (GnRH) antagonists. MEDLINE, EMBASE, and CENTRAL were searched\nfrom inception without language restrictions. Study selection and data extraction were performed independently by two reviewers. Risk\nof bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. Due to substantial heterogeneity across study populations, interven-\ntions, comparators, outcomes, and follow-up durations, a meta-analysis was not performed. Findings were synthesized narratively and\nstratified according to predefined pain phenotypes based on the primary clinical diagnosis reported in each study, including endometriosis-\nassociated pain, pelvic floor myofascial pain, and vulvodynia. Certainty of evidence was assessed using the Grading of Recommendations\nAssessment, Development and Evaluation (GRADE) framework. Results: 21 studies were included. Pelvic floor training was associated\nwith modest reductions in current pelvic pain at 4 and 12 months. Evidence for BoNT-A was inconsistent across studies of pelvic floor\nmyalgia and vestibulodynia. Psychological interventions demonstrated more consistent improvements in functional and psychosocial\noutcomes than in pain intensity. GnRH antagonists produced dose-dependent reductions in endometriosis-associated pain, with higher\nresponder rates than placebo, but were associated with hypoestrogenic adverse effects. Conclusions: Emerging therapies may offer\nbenefits in specific CGPP phenotypes; however, the available evidence remains heterogeneous. A phenotype-informed, multimodal\ntreatment approach may be considered, with careful attention to potential safety trade-offs. Registration: This systematic review was\nregistered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420261302453.\nRegistration record: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261302453.\nKeywords: chronic pelvic pain; endometriosis; pelvic floor disorders; gonadotropin-releasing hormone antagonists; cognitive behavioral\ntherapy\n1. Introduction\nChronic gynecologic pelvic pain (CGPP) affects a\nsubstantial proportion of women of reproductive age and\nrepresents a significant clinical and public health burden\ndue to its impact on quality of life, functional status, and\nhealthcare utilization [ 1]. Current management strategies\nencompass hormonal suppression, surgical intervention,\nanalgesics, and multidisciplinary approaches [2]. Although\nthese interventions may provide benefit for some patients,\nmany women continue to experience persistent symptoms\nor treatment-related adverse effects. Consequently, there\nhas been growing interest in therapies targeting distinct\ncomponents of the pain pathway.\nThe pathophysiology of CGPP is complex, involving\ninteractions among peripheral drivers, including endometri-\notic lesions and pelvic floor dysfunction, central sensitiza-\ntion processes, as well as psychosocial factors that modulate\npain perception and disability [ 3]. Importantly, multiple\npelvic pain syndromes frequently coexist, including neuro-\npathic conditions such as pudendal neuralgia, which may\ninfluence symptom presentation and treatment response.\nCGPP encompasses a spectrum of overlapping conditions,\nincluding endometriosis-associated pain, pelvic floor my-\nofascial pain, and vulvodynia, with contributions from no-\nciceptive, neuropathic, and nociplastic mechanisms [ 3,4].\n\nBotulinum toxin type A (BoNT-A) has been evaluated\nfor pelvic floor hypertonicity, although results remain in-\nconsistent [ 3,4,5]. Pelvic floor rehabilitation is included\nas part of multidisciplinary management approaches for\nchronic pelvic pain [ 6,7]. Psychological and behavioral in-\nterventions aim to address central pain processing and cop-\ning strategies, which are increasingly recognized as key\ncontributors to chronic pain states [ 8]. Additionally, oral\ngonadotropin-releasing hormone (GnRH) antagonists have\nemerged as pharmacological options for endometriosis-\nassociated pain [ 9]. Multimodal physical therapy has also\nbeen evaluated as a treatment option for provoked vestibu-\nlodynia [10].\nConsensus classification frameworks have also stan-\ndardized the terminology for persistent vulvar pain and\nvulvodynia [ 11], while clinical guidelines have provided\nrecommendations for the management of endometriosis\n[12]. Longer-term evidence has further evaluated the ef-\nficacy and safety of relugolix combination therapy for\nendometriosis-associated pain [13].\nDespite increasing clinical use, the evidence base for\nthese interventions remains heterogeneous and fragmented.\nDifferences in pain phenotypes, intervention protocols, out-\ncome measures, and study designs complicate interpreta-\ntion and limit the ability to draw definitive conclusions.\nTherefore, a structured synthesis stratified by pain pheno-\ntype and intervention class is warranted.\nThe objective of this systematic review was to eval-\nuate the effectiveness and safety of emerging therapies for\nCGPP in adult women, with a focus on phenotype-specific\noutcomes and variability in treatment response.\n2. Methods\n2.1 Study Design and Eligibility\nWe conducted a systematic review of comparative\nclinical studies, prioritizing RCTs. Eligible studies in-\ncluded adult women aged 18 years or older with a diagno-\nsis of CGPP of at least six months. Inclusion criteria were\nas follows: endometriosis-associated pain, pelvic floor my-\nofascial pain, and vulvodynia. Exclusion criteria were as\nfollows: acute pain, malignancy, pregnancy-related condi-\ntions, or non-gynecologic pain syndromes.\n2.2 Interventions and Comparators\nInterventions of interest included pelvic floor physi-\ncal therapy, BoNT-A injections, psychological and behav-\nioral therapies, nutraceutical interventions, and oral GnRH\nantagonists. Comparators comprised placebo, usual care,\nwait-list controls, or active treatments. Given the distinct\npathophysiology underlying endometriosis, studies evalu-\nating GnRH antagonists were analyzed as a separate sub-\ngroup and interpreted independently from those addressing\nother CGPP phenotypes.\n2.3 Outcomes\nPrimary outcomes included pain intensity and safety\nparameters, such as adverse events and treatment discontin-\nuation rates. Secondary outcomes included quality of life,\nfunctional status, psychological outcomes, and global im-\nprovement. Safety data were evaluated across all included\nstudies. Reported adverse events and other treatment-\nrelated safety outcomes were summarized when available,\nwhile studies with absent or insufficient safety reporting\nwere explicitly identified.\n2.4 Search Strategy and Study Selection\nMEDLINE, EMBASE, and CENTRAL were searched\nfrom inception without language restrictions. Two review-\ners independently screened titles and abstracts and per-\nformed full-text review and data extraction. Disagree-\nments were resolved through discussion or, when consen-\nsus could not be reached, by adjudication from a third re-\nviewer. Study selection was documented in accordance\nwith the Preferred Reporting Items for Systematic Reviews\nand Meta-Analyses (PRISMA) guidelines (Fig. 1).\n2.5 Risk of Bias and Certainty of Evidence\nRisk of bias was assessed using the RoB 2 tool for ran-\ndomized controlled trials. Certainty of evidence was eval-\nuated using the Grading of Recommendations Assessment,\nDevelopment and Evaluation (GRADE) framework, con-\nsidering risk of bias, inconsistency, indirectness, and im-\nprecision.\n2.6 Data Synthesis\nA meta-analysis was not performed due to substantial\nclinical and methodological heterogeneity, including dif-\nferences in pain phenotypes, intervention characteristics,\ncomparator types, outcome measures, and follow-up dura-\ntions. Therefore, a structured narrative synthesis was con-\nducted, stratified by pain phenotype and intervention class.\nPain phenotypes were categorized a priori based on the\nprimary clinical condition reported in each study, includ-\ning endometriosis-associated pain, pelvic floor myofascial\npain, and vulvodynia.\n3. Results\n3.1 Study Characteristics\nIncluded studies evaluated emerging interventions\nacross heterogeneous CGPP phenotypes (Table 1, Ref.\n[14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,\n32,33,34]), encompassing endometriosis-associated pain\n[14,27,31], pelvic floor myofascial pain [ 16,17], and pro-\nvoked vestibulodynia [ 15]. The distribution of interven-\ntions varied across phenotypes. Pelvic floor–directed in-\nterventions were primarily assessed in populations with\nendometriosis and pelvic floor myalgia, whereas BoNT-\nA studies focused on vestibulodynia and pelvic floor dys-\nfunction. Psychological and behavioral interventions were\n2\n\n\nFig. 1. PRISMA 2020 flow diagram of study selection .\nevaluated predominantly in endometriosis-associated pain\ncohorts, often within broader multidisciplinary treatment\nframeworks.\nInterventions included pelvic floor training [ 14],\nbotulinum toxin injections [ 15,16,17], nutraceutical\nadjuncts [ 18], psychological and behavioral ther-\napies [ 19,20,21,22], and oral GnRH antagonists,\nsuch as elagolix, linzagolix, relugolix, and ASP1707\n[23,24,25,26,27,28,29,30,31,32,33,34]. GnRH antagonist\ntrials were conducted exclusively in endometriosis cohorts\nand were generally larger and more standardized in design\nthan trials evaluating other intervention classes.\n3.2 Efficacy\nPain outcomes are summarized in Table 2 (Ref.\n[14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,\n32,33,34]) and are presented by intervention class and un-\nderlying pain phenotype. Pelvic floor training was associ-\nated with modest reductions in current pelvic pain at 4 and\n12 months in women with endometriosis-associated pain\n[14]. Nonetheless, these effects were not consistently ob-\nserved across all pain domains.\nBotulinum toxin studies reported heterogeneous find-\nings across populations with pelvic floor myalgia and\nvestibulodynia. Several trials demonstrated short-term im-\nprovements in pain-related outcomes; however, between-\ngroup differences were inconsistent, and results varied ac-\ncording to study design, injection protocols, and outcome\nmeasures [15,16,17].\n3\n\nTable 1. Characteristics of included studies .\nIntervention Study Population Intervention details Comparator Follow-up\nPFMT Gabrielsen et al. (2025) [ 14] Women aged 18–45 years with surgically\nconfirmed endometriosis; NRS ≥4\nPFMT + supervised exercise + home\nprogram\nPain education 4, 12 months\nBoNT-A (vestibulodynia) Diomande et al. (2019) [ 15] Provoked vestibulodynia BoNT-A 50–100 U (subcutaneous) Placebo 3 months\nBoNT-A (PF myalgia) Dessie et al. (2019) [ 16] Chronic pelvic pain with pelvic floor\nmyalgia\nBoNT-A + PFPT Placebo + PFPT 2–12 weeks\nBoNT-A (PF spasm) Abbott et al. (2006) [ 17] Chronic pelvic pain >2 years with pelvic\nfloor spasm/myalgia\nBoNT-A (80–100 U) Placebo 3–6 months\nNutraceutical Cobellis et al. (2011) [ 18] Endometriosis (rASRM stage I–II) PEA + transpolydatin Placebo or celecoxib 3 months\nCBT (online) Chandra et al. (2026) [ 19] Endometriosis-associated chronic pelvic\npain\nInternet-based CBT Usual care or wait-list 8–12 weeks\nACT/mindfulness Hansen et al. (2023) [ 20] Endometriosis; NRS ≥5 ACT-based group program Wait-list Not reported\nPsychotherapy Beissner et al. (2018) [ 21] Laparoscopically confirmed\nendometriosis\nCBT + somatosensory therapy Wait-list 3 months\nCBT (in-person) Donatti et al. (2025) [ 22] Endometriosis; V AS≥5 Individual CBT Usual care 4 months\nGnRH antagonist Carr et al. (2013) [ 23] Endometriosis Elagolix 150 mg once daily Placebo 8 weeks\nGnRH antagonist Diamond et al. (2014) [ 24] Endometriosis Elagolix 150–250 mg once daily Placebo 12–24 weeks\nGnRH antagonist Carr et al. (2014) [ 25] Endometriosis Elagolix (once or twice daily) (DMPA-SC) 24 weeks\nGnRH antagonist Taylor et al. (2017) [ 26] Endometriosis Elagolix 150–200 mg Placebo 3–6 months\nGnRH antagonist Abrao et al. (2021) [ 27] Surgically confirmed endometriosis Elagolix Placebo 3–6 months\nGnRH antagonist Ács et al. (2015) [ 28] Endometriosis Elagolix Placebo or leuprorelin Not reported\nGnRH antagonist Donnez et al. (2020) [ 29] Endometriosis-associated pain Linzagolix 50–200 mg Placebo 12–24 weeks\nGnRH antagonist Donnez et al. (2024) [ 30] Surgically confirmed endometriosis Linzagolix ± add-back therapy Placebo 3–6 months\nGnRH antagonist Osuga et al. (2021) [ 31] Endometriosis Relugolix 10–40 mg Placebo or leuprorelin 12 weeks\nGnRH antagonist Osuga et al. (2021) [ 32] Endometriosis (extension study) Relugolix Placebo or leuprorelin 24 weeks\nGnRH antagonist Harada et al. (2022) [ 33] Endometriosis Relugolix 40 mg Leuprorelin 24 weeks\nGnRH antagonist D’Hooghe et al. (2019) [ 34] Surgically confirmed endometriosis ASP1707 3–15 mg Placebo or leuprorelin 12–24 weeks\nPFMT, pelvic floor muscle training; PFPT, pelvic floor physical therapy; BoNT-A, botulinum toxin type A; CBT, cognitive behavioral therapy; ACT, acceptance and commitment therapy; NRS,\nnumeric rating scale; V AS, visual analog scale; rASRM, revised American Society for Reproductive Medicine classification; DMPA-SC, depot medroxyprogesterone acetate (subcutaneous);\nQD, once daily; GnRH, gonadotropin-releasing hormone; PEA, palmitoylethanolamide; U, units.\n4\n\n\nTable 2. Efficacy/effectiveness outcomes of included studies .\nIntervention Study Comparison Outcomes Key findings\nPFMT Gabrielsen et al. (2025) [ 14] PFMT + exercise vs. education Pain (NRS), dyspareunia, urinary\nsymptoms\nModest reduction in current pain at 4 and 12 months;\nno consistent effect on worst pain or dyspareunia\nBoNT-A (vestibulodynia) Diomande et al. (2019) [ 15] 50–100 U vs. placebo Pain (V AS), sensitivity, sexual\nfunction\nNo significant between-group differences across\noutcomes\nBoNT-A (PF myalgia) Dessie et al. (2019) [ 16] BoNT-A + PFPT vs. PFPT Pain, pelvic floor symptoms No consistent between-group differences in pain;\nlimited improvements in pelvic floor scores\nBoNT-A (PF spasm) Abbott et al. (2006) [ 17] BoNT-A vs. placebo Pain, pelvic pressure, global\nimprovement\nMixed results; some improvements in pelvic pressure\nand global outcomes\nNutraceutical Cobellis et al. (2011) [ 18] PEA + transpolydatin vs.\nplacebo/active comparator\nPain (V AS), satisfaction Improvements in pain and satisfaction reported;\neffects were smaller compared with active\ncomparators\nCBT (online) Chandra et al. (2026) [ 19] iCBT vs. usual care Disability, mood, pain Improvements in disability and mood; modest and\nvariable effects on pain intensity\nACT/mindfulness Hansen et al. (2023) [ 20] ACT vs. wait-list Pain, QoL, symptoms Improvements mainly in quality of life; inconsistent\neffects on pain\nPsychotherapy Beissner et al. (2018) [ 21] Therapy vs. wait-list Pain, psychological outcomes Limited between-group differences; small sample size\nCBT (in-person) Donatti et al. (2025) [ 22] Individual CBT vs. usual care Pain perception, coping\nstrategies, depression, stress,\nQoL\nSignificant improvements in pain perception, coping,\npsychological outcomes, and quality of life compared\nwith usual care\nGnRH antagonist (elagolix) Carr et al. (2013) [ 23]; Diamond et al.\n(2014) [24]; Carr et al. (2014) [ 25];\nTaylor et al. (2017) [ 26]; Abrao et al.\n(2021) [27]; Ács et al. (2015) [ 28]\nElagolix vs. placebo/active\ncomparator\nDysmenorrhea, nonmenstrual\npelvic pain, overall pelvic pain,\nresponder rates\nReductions in endometriosis-associated pain and\ngenerally higher responder rates compared with\nplacebo; efficacy findings were broadly consistent\nacross baseline patient subgroups.\nGnRH antagonist (linzagolix) Donnez et al. (2020) [ 29]; Donnez et\nal. (2024) [ 30]\nLinzagolix vs. placebo Dysmenorrhea, nonmenstrual\npelvic pain\nDose-dependent improvements in pain outcomes\nGnRH antagonist (relugolix) Osuga et al. (2021) [ 31]; Osuga et al.\n(2021) [32]; Harada et al. (2022) [ 33]\nRelugolix vs. placebo/active\ncomparator\nPain, symptom scores Significant reductions in pain; dose-response\nrelationship observed\nGnRH antagonist (ASP1707) D’Hooghe et al. (2019) [ 34] ASP1707 vs. placebo/active\ncomparator\nPain scores Modest improvements in pain outcomes compared\nwith placebo\nPFMT, pelvic floor muscle training; PFPT, pelvic floor physical therapy; BoNT-A, botulinum toxin type A; CBT, cognitive behavioral therapy; iCBT, internet-delivered cognitive behavioral therapy;\nACT, acceptance and commitment therapy; QoL, quality of life; NRS, numeric rating scale; V AS, visual analog scale; PEA, palmitoylethanolamide; GnRH, gonadotropin-releasing hormone.\n5\n\nTable 3. Safety outcomes of included studies .\nIntervention Study Comparison Outcomes Key findings\nPFMT Gabrielsen et al. (2025) [ 14] PFMT + exercise vs. education Adverse events No adverse events or symptom worsening\nreported\nBoNT-A (vestibulodynia) Diomande et al. (2019) [ 15] 50–100 U vs. placebo Adverse events No serious adverse events; transient post-injection\npain was commonly reported\nBoNT-A (PF myalgia) Dessie et al. (2019) [ 16] BoNT-A + PFPT vs. PFPT Adverse events No significant between-group differences; mild\nand transient adverse events reported\nBoNT-A (PF spasm) Abbott et al. (2006) [ 17] BoNT-A vs. placebo Adverse events No clear between-group differences; occasional\npelvic and urinary symptoms reported\nNutraceutical Cobellis et al. (2011) [ 18] PEA + transpolydatin vs.\nplacebo/active comparator\nAdverse events No significant adverse events or laboratory\nabnormalities reported\nCBT (online) Chandra et al. (2026) [ 19] iCBT vs. usual care Adverse events Adverse events were not systematically reported\nACT/mindfulness Hansen et al. (2023) [ 20] ACT vs. wait-list Adverse events Safety outcomes not reported\nPsychotherapy Beissner et al. (2018) [ 21] Therapy vs. wait-list Adverse events Safety outcomes not reported\nGnRH antagonist (elagolix) Diamond et al. (2014) [ 24]; Carr et al.\n(2014) [25]; Taylor et al. (2017) [ 26];\nÁcs et al. (2015) [ 28]\nElagolix vs. placebo/active\ncomparator\nTEAEs, BMD Dose-dependent reductions in bone mineral\ndensity; increased vasomotor symptoms; other\nadverse events generally similar across groups\nGnRH antagonist (linzagolix) Donnez et al. (2020) [ 29]; Donnez et al.\n(2024) [30]\nLinzagolix vs. placebo TEAEs, BMD Increased adverse events with higher doses; bone\ndensity changes and vasomotor symptoms\nreported; serious events uncommon\nGnRH antagonist (relugolix) Osuga et al. (2021) [ 31]; Osuga et al.\n(2021) [32]; Harada et al. (2022) [ 33]\nRelugolix vs. placebo/active\ncomparator\nTEAEs, BMD Higher frequency of adverse events with\nincreasing dose; common events included\nvasomotor and menstrual symptoms; reductions\nin BMD observed\nGnRH antagonist (ASP1707) D’Hooghe et al. (2019) [ 34] ASP1707 vs. placebo/active\ncomparator\nTEAEs Adverse events were generally mild to moderate;\nno major safety concerns were identified\nBoNT-A, botulinum toxin type A; PFMT, pelvic floor muscle training; BMD, bone mineral density; TEAEs, treatment-emergent adverse events.\n6\n\n\nGnRH antagonist trials, analyzed as a separate\nsubgroup, demonstrated more consistent findings within\nendometriosis-associated pain. Across multiple random-\nized studies, these agents were associated with higher re-\nsponder rates and greater reductions in dysmenorrhea and\nnonmenstrual pelvic pain than placebo or active compara-\ntors [ 24,25,26,27,30,31,32,33,34]. These trials generally\nemployed standardized endpoints and consistent outcome\ndefinitions.\nPsychological and behavioral interventions were as-\nsociated with improvements in pain-related and psychoso-\ncial outcomes, particularly in measures of function, cop-\ning, and quality of life. However, effects on pain intensity\nwere more heterogeneous, and substantial variation was ob-\nserved across studies in outcome measures and follow-up\nduration [19,20,21,22].\nThe nutraceutical intervention (palmi-\ntoylethanolamide plus transpolydatin) was associated\nwith improvements in pain scores and patient-reported\nsatisfaction compared with placebo or baseline; however,\ngreater effects were observed with active comparators,\nsuggesting a relatively limited comparative benefit.\n3.3 Safety\nSafety outcomes were available in a subset of in-\ncluded studies, as several trials did not report adverse\nevents or provided insufficient detail for data extrac-\ntion. Safety findings are summarized in Table 3 (Ref.\n[14,15,16,17,18,19,20,21,24,25,26,28,29,30,31,32,33,34]).\nPelvic floor training was generally well tolerated, and\nno serious adverse events were reported in the included\nstudies [ 14]. Similarly, most botulinum toxin studies did\nnot report serious adverse events. Nevertheless, transient\npost-injection pain and localized discomfort were com-\nmonly described [ 15,16,17]. Occasional reports of urinary\nor fecal symptoms were observed, although these were not\nconsistently different between groups.\nIn contrast, GnRH antagonist trials reported a higher\nfrequency of treatment-emergent adverse events. These in-\ncluded vasomotor symptoms, menstrual changes, and re-\nductions in bone mineral density, with some studies also\nreporting laboratory abnormalities such as alterations in\nlipid profiles or liver enzyme levels [ 27,30,31,33]. The fre-\nquency and severity of these events appeared to vary ac-\ncording to dose and treatment duration.\nAdverse event reporting was limited or inconsistently\ndescribed in several psychological and behavioral inter-\nvention studies, restricting interpretation of their safety\nprofiles. Overall, differences in reporting standards and\nfollow-up duration across studies limit comparability of\nsafety outcomes.\n3.4 Risk of Bias\nRisk of bias assessments are presented in Table4 (Ref.\n[14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,\n32,33,34]). Most studies were judged as having some con-\ncerns overall, mainly related to missing outcome data and\nselective reporting.\nSeveral trials showed low risk or some concerns\nacross the randomization and outcome measurement do-\nmains [ 25,31,34], whereas others were rated as high risk\ndue to deviations from intended interventions or limitations\nin outcome assessment. These methodological limitations,\ntogether with inconsistency and imprecision across studies,\ncontributed to low-to-moderate certainty of evidence.\n4. Discussion\nThis systematic review provides a structured synthe-\nsis of emerging therapies for CGPP , highlighting variability\nin reported outcomes across pain phenotypes and interven-\ntion classes. The findings reflect the complexity of CGPP\nas a heterogeneous clinical entity, in which treatment re-\nsponse may vary according to underlying mechanisms, pa-\ntient characteristics, and intervention design.\nAmong the included interventions, oral GnRH antag-\nonists had the most consistent evidence base, particularly\nfor endometriosis-associated pain. These trials were gener-\nally larger and employed more standardized outcome mea-\nsures, which may contribute to consistency across studies\n[9,10]. Reported improvements in dysmenorrhea and non-\nmenstrual pelvic pain align with hormonal modulation of\ndisease activity described in the previous literature. How-\never, these findings should be interpreted in the context of\nrelatively homogeneous study populations and the occur-\nrence of hypoestrogenic adverse effects, including reduc-\ntions in bone mineral density, which remain relevant in clin-\nical decision-making.\nIn contrast, the evidence for pelvic floor rehabili-\ntation was more variable. Pelvic floor physical therapy\ncomprises a range of modalities, including relaxation tech-\nniques, biofeedback, and strengthening approaches, which\nare often combined and inconsistently reported across stud-\nies. This variability may contribute to the modest and het-\nerogeneous effects observed in pain outcomes. In addition,\npelvic floor interventions are frequently delivered as part of\nmultimodal care, limiting the ability to isolate their specific\ncontribution.\nThe findings for BoNT-A were also inconsistent. Dif-\nferences in injection protocols, dosing regimens, targeted\nmuscle groups, and patient selection likely contribute to\nvariability across studies. Furthermore, the coexistence of\nmultiple pain mechanisms within CGPP populations may\ninfluence treatment response, particularly in studies includ-\ning mixed phenotypes. Although BoNT-A remains of inter-\nest in selected patients with pelvic floor dysfunction, cur-\nrent evidence is insufficient to draw definitive conclusions\nregarding its comparative effectiveness.\nPsychological and behavioral interventions demon-\nstrated a distinct pattern, with more consistent improve-\nments in functional outcomes, coping, and psychological\n7\n\nTable 4. Risk of bias assessment (RoB 2) .\nStudy Randomization Deviations Missing data Outcome measurement Selective reporting Overall\nAbbott et al. (2006) [ 17] Low Low Some concerns Low Some concerns Some concerns\nAbrao et al. (2021) [ 27] Some concerns Some concerns Some concerns Low Some concerns Some concerns\nÁcs et al. (2015) [ 28] Some concerns Low Some concerns Low High High\nCarr et al. (2013) [ 23] Low Some concerns High Low Some concerns High\nCarr et al. (2014) [ 25] Some concerns Low High Low Some concerns High\nChandra et al. (2026) [ 19] Low High Some concerns High Some concerns High\nCobellis et al. (2011) [ 18] Some concerns Some concerns Low Some concerns Some concerns Some concerns\nD’Hooghe et al. (2019) [ 34] Low Low Some concerns Low Some concerns Some concerns\nDessie et al. (2019) [ 16] Some concerns Some concerns Some concerns Low Some concerns Some concerns\nDiamond et al. (2014) [ 24] Low Low Some concerns Low Some concerns Some concerns\nDiomande et al. (2019) [ 15] Some concerns Some concerns Low Low Some concerns Some concerns\nDonatti et al. (2025) [ 22] High High Some concerns High High High\nDonnez et al. (2020) [ 29] Some concerns Low Some concerns Low Some concerns Some concerns\nDonnez et al. (2024) [ 30] Low Low Some concerns Low Some concerns Some concerns\nGabrielsen et al. (2025) [ 14] Some concerns Some concerns Some concerns High High High\nHansen et al. (2023) [ 20] Some concerns High High High High High\nHarada et al. (2022) [ 33] Some concerns Low Some concerns Low Some concerns Some concerns\nOsuga et al. (2021) [ 31] Some concerns Low Some concerns Low Some concerns Some concerns\nOsuga et al. (2021) [ 32] Some concerns Some concerns High Some concerns Some concerns High\nBeissner et al. (2018) [ 21] Some concerns High Some concerns High Some concerns High\nTaylor et al. (2017) [ 26] Low Some concerns Some concerns Some concerns Some concerns Some concerns\nLow, low risk of bias; High, high risk of bias; Some concerns, some concerns of bias.\ndistress than in pain intensity. This observation aligns with\nmultidimensional models of chronic pain, in which central\nprocessing and psychosocial factors play a key role in shap-\ning the pain experience. The relatively modest changes in\npain intensity across these studies may reflect differences in\noutcome prioritization rather than a lack of clinical benefit.\nAn important consideration in interpreting these find-\nings is the inherent heterogeneity of CGPP . Chronic pelvic\npain encompasses overlapping conditions such as en-\ndometriosis, pelvic floor dysfunction, vulvodynia, and neu-\nropathic pain syndromes, which are not always clearly dis-\ntinguished in clinical trials. In addition, subtypes within\nthese conditions may have distinct mechanisms and treat-\nment responses. Limited phenotypic characterization in the\nincluded studies may therefore contribute to outcome vari-\nability and restrict the identification of patient subgroups\nmore likely to benefit from specific interventions.\nMethodological factors should also be considered. Al-\nthough all included studies were randomized, several raised\nconcerns related to missing data, deviations from intended\ninterventions, and selective reporting. Sample sizes were\noften limited outside of GnRH antagonist trials, and follow-\nup durations varied across studies. Differences in outcome\nmeasures and reporting further limited comparability and\nprecluded quantitative synthesis.\nLimitations\nThis review has several limitations, including hetero-\ngeneity in study design, variability in outcome measures,\nlimited reporting of safety outcomes, and potential risk of\nbias in the included trials. These factors may affect the com-\nparability and interpretation of the findings. The certainty\nof evidence ranged from low to moderate across outcomes,\nprimarily due to inconsistency across studies and impreci-\nsion in effect estimates, further limiting confidence in the\nobserved findings.\nIn this context, a structured narrative synthesis strati-\nfied by pain phenotype and intervention class was consid-\nered more appropriate than quantitative pooling. This ap-\nproach enables a more clinically interpretable summary of\nthe evidence while acknowledging heterogeneity.\nOverall, the findings support a phenotype-informed,\nmultimodal approach to CGPP management, in which inter-\nventions may be selected according to the predominant pain\nmechanism and patient profile. However, the available evi-\ndence remains heterogeneous, warranting cautious interpre-\ntation. Future studies incorporating clearer phenotypic defi-\nnitions, standardized outcome measures, and longer follow-\nup are needed to improve the understanding of treatment\neffects in this complex condition.\n5. Conclusions\nThe available evidence suggests that emerging ther-\napies may provide benefits for specific CGPP pheno-\ntypes; however, the findings remain heterogeneous and\nof variable certainty. Pelvic floor rehabilitation and psy-\nchological interventions were associated with improve-\nments in functional and psychosocial outcomes, whereas\nGnRH antagonists demonstrated more consistent effects in\n8\n\n\nendometriosis-associated pain, along with relevant safety\nconsiderations.\nThese findings support a phenotype-informed, mul-\ntimodal approach to CGPP management. However, clini-\ncal decisions should be individualized, considering poten-\ntial risks, patient characteristics, and variability in treatment\nresponse. Future research incorporating standardized out-\ncomes, longer follow-up, and improved phenotypic char-\nacterization is warranted to better define the role of these\ninterventions and to identify subgroups most likely to ben-\nefit.\nAvailability of Data and Materials\nThe data supporting the conclusions of this review are\nderived from previously published studies, which are cited\nin the reference list. No new datasets were generated or\nanalyzed for this study. Therefore, data sharing is not ap-\nplicable.\nAuthor Contributions\nMCPB and JPAG conceived and designed the study.\nMCPB, LNPG, and JEAM conducted the literature search\nand study selection. MCPB, LNPG, and CDRP extracted\nand synthesized the data. JPAG and GITR supervised the\nstudy, provided methodological guidance, and contributed\nto the interpretation of the study findings and their clini-\ncal implications. MCPB drafted the initial manuscript. All\nauthors critically revised the manuscript for important in-\ntellectual content, approved the final version, and agree to\nbe accountable for all aspects of the work.\nEthics Approval and Consent to Participate\nNot applicable. This study is a systematic review of\npublished literature and did not involve direct participation\nof human subjects or animals.\nAcknowledgment\nThe authors would like to thank all contributors and\ncollaborators involved in the development of this work.\nFunding\nThis research received no external funding.\nConflicts of Interest\nThe authors declare no conflicts of interest.\nDeclaration of AI and AI-Assisted\nTechnologies in the Writing Process\nDuring the preparation of this manuscript, the authors\nused an artificial intelligence tool (ChatGPT-4o, OpenAI)\nto assist with language refinement and editorial clarity. 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