Effectiveness and Safety of Emerging Therapies Versus Conventional Treatments or Placebo for Chronic Gynecologic Pelvic Pain in Adult Women: A Systematic Review

Background: Chronic gynecologic pelvic pain (CGPP) is a multifactorial condition associated with functional impairment and heteroge- neous treatment responses. Emerging therapies are increasingly being used. However, their comparative effectiveness and safety remain uncertain. Methods: We conducted a systematic review of comparative studies in adult women ( ≥18 years) with CGPP lasting ≥6 months. Interventions included pelvic floor rehabilitation, botulinum toxin type A (BoNT-A), psychological and behavioral therapies, nutraceuticals, and oral gonadotropin-releasing hormone (GnRH) antagonists. MEDLINE, EMBASE, and CENTRAL were searched from inception without language restrictions. Study selection and data extraction were performed independently by two reviewers. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. Due to substantial heterogeneity across study populations, interven- tions, comparators, outcomes, and follow-up durations, a meta-analysis was not performed. Findings were synthesized narratively and stratified according to predefined pain phenotypes based on the primary clinical diagnosis reported in each study, including endometriosis- associated pain, pelvic floor myofascial pain, and vulvodynia. Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. Results: 21 studies were included. Pelvic floor training was associated with modest reductions in current pelvic pain at 4 and 12 months. Evidence for BoNT-A was inconsistent across studies of pelvic floor myalgia and vestibulodynia. Psychological interventions demonstrated more consistent improvements in functional and psychosocial outcomes than in pain intensity. GnRH antagonists produced dose-dependent reductions in endometriosis-associated pain, with higher responder rates than placebo, but were associated with hypoestrogenic adverse effects. Conclusions: Emerging therapies may offer benefits in specific CGPP phenotypes; however, the available evidence remains heterogeneous. A phenotype-informed, multimodal treatment approach may be considered, with careful attention to potential safety trade-offs. Registration: This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD420261302453. Registration record: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261302453.

chronic pelvic pain; endometriosis; pelvic floor disorders; gonadotropin-releasing hormone antagonists; cognitive behavioral therapy 1. Introduction Chronic gynecologic pelvic pain (CGPP) affects a substantial proportion of women of reproductive age and represents a significant clinical and public health burden due to its impact on quality of life, functional status, and healthcare utilization [ 1]. Current management strategies encompass hormonal suppression, surgical intervention, analgesics, and multidisciplinary approaches [2]. Although these interventions may provide benefit for some patients, many women continue to experience persistent symptoms or treatment-related adverse effects. Consequently, there has been growing interest in therapies targeting distinct components of the pain pathway. The pathophysiology of CGPP is complex, involving interactions among peripheral drivers, including endometri- otic lesions and pelvic floor dysfunction, central sensitiza- tion processes, as well as psychosocial factors that modulate pain perception and disability [ 3]. Importantly, multiple pelvic pain syndromes frequently coexist, including neuro- pathic conditions such as pudendal neuralgia, which may influence symptom presentation and treatment response. CGPP encompasses a spectrum of overlapping conditions, including endometriosis-associated pain, pelvic floor my- ofascial pain, and vulvodynia, with contributions from no- ciceptive, neuropathic, and nociplastic mechanisms [ 3,4]. Botulinum toxin type A (BoNT-A) has been evaluated for pelvic floor hypertonicity, although results remain in- consistent [ 3,4,5]. Pelvic floor rehabilitation is included as part of multidisciplinary management approaches for chronic pelvic pain [ 6,7]. Psychological and behavioral in- terventions aim to address central pain processing and cop- ing strategies, which are increasingly recognized as key contributors to chronic pain states [ 8]. Additionally, oral gonadotropin-releasing hormone (GnRH) antagonists have emerged as pharmacological options for endometriosis- associated pain [ 9]. Multimodal physical therapy has also been evaluated as a treatment option for provoked vestibu- lodynia [10]. Consensus classification frameworks have also stan- dardized the terminology for persistent vulvar pain and vulvodynia [ 11], while clinical guidelines have provided recommendations for the management of endometriosis [12]. Longer-term evidence has further evaluated the ef- ficacy and safety of relugolix combination therapy for endometriosis-associated pain [13]. Despite increasing clinical use, the evidence base for these interventions remains heterogeneous and fragmented. Differences in pain phenotypes, intervention protocols, out- come measures, and study designs complicate interpreta- tion and limit the ability to draw definitive conclusions. Therefore, a structured synthesis stratified by pain pheno- type and intervention class is warranted. The objective of this systematic review was to eval- uate the effectiveness and safety of emerging therapies for CGPP in adult women, with a focus on phenotype-specific outcomes and variability in treatment response. 2. Methods 2.1 Study Design and Eligibility We conducted a systematic review of comparative clinical studies, prioritizing RCTs. Eligible studies in- cluded adult women aged 18 years or older with a diagno- sis of CGPP of at least six months. Inclusion criteria were as follows: endometriosis-associated pain, pelvic floor my- ofascial pain, and vulvodynia. Exclusion criteria were as follows: acute pain, malignancy, pregnancy-related condi- tions, or non-gynecologic pain syndromes. 2.2 Interventions and Comparators Interventions of interest included pelvic floor physi- cal therapy, BoNT-A injections, psychological and behav- ioral therapies, nutraceutical interventions, and oral GnRH antagonists. Comparators comprised placebo, usual care, wait-list controls, or active treatments. Given the distinct pathophysiology underlying endometriosis, studies evalu- ating GnRH antagonists were analyzed as a separate sub- group and interpreted independently from those addressing other CGPP phenotypes. 2.3 Outcomes Primary outcomes included pain intensity and safety parameters, such as adverse events and treatment discontin- uation rates. Secondary outcomes included quality of life, functional status, psychological outcomes, and global im- provement. Safety data were evaluated across all included studies. Reported adverse events and other treatment- related safety outcomes were summarized when available, while studies with absent or insufficient safety reporting were explicitly identified. 2.4 Search Strategy and Study Selection MEDLINE, EMBASE, and CENTRAL were searched from inception without language restrictions. Two review- ers independently screened titles and abstracts and per- formed full-text review and data extraction. Disagree- ments were resolved through discussion or, when consen- sus could not be reached, by adjudication from a third re- viewer. Study selection was documented in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Fig. 1). 2.5 Risk of Bias and Certainty of Evidence Risk of bias was assessed using the RoB 2 tool for ran- domized controlled trials. Certainty of evidence was eval- uated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework, con- sidering risk of bias, inconsistency, indirectness, and im- precision. 2.6 Data Synthesis A meta-analysis was not performed due to substantial clinical and methodological heterogeneity, including dif- ferences in pain phenotypes, intervention characteristics, comparator types, outcome measures, and follow-up dura- tions. Therefore, a structured narrative synthesis was con- ducted, stratified by pain phenotype and intervention class. Pain phenotypes were categorized a priori based on the primary clinical condition reported in each study, includ- ing endometriosis-associated pain, pelvic floor myofascial pain, and vulvodynia. 3. Results 3.1 Study Characteristics Included studies evaluated emerging interventions across heterogeneous CGPP phenotypes (Table 1, Ref. [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31, 32,33,34]), encompassing endometriosis-associated pain [14,27,31], pelvic floor myofascial pain [ 16,17], and pro- voked vestibulodynia [ 15]. The distribution of interven- tions varied across phenotypes. Pelvic floor–directed in- terventions were primarily assessed in populations with endometriosis and pelvic floor myalgia, whereas BoNT- A studies focused on vestibulodynia and pelvic floor dys- function. Psychological and behavioral interventions were 2 Fig. 1. PRISMA 2020 flow diagram of study selection . evaluated predominantly in endometriosis-associated pain cohorts, often within broader multidisciplinary treatment frameworks. Interventions included pelvic floor training [ 14], botulinum toxin injections [ 15,16,17], nutraceutical adjuncts [ 18], psychological and behavioral ther- apies [ 19,20,21,22], and oral GnRH antagonists, such as elagolix, linzagolix, relugolix, and ASP1707 [23,24,25,26,27,28,29,30,31,32,33,34]. GnRH antagonist trials were conducted exclusively in endometriosis cohorts and were generally larger and more standardized in design than trials evaluating other intervention classes. 3.2 Efficacy Pain outcomes are summarized in Table 2 (Ref. [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31, 32,33,34]) and are presented by intervention class and un- derlying pain phenotype. Pelvic floor training was associ- ated with modest reductions in current pelvic pain at 4 and 12 months in women with endometriosis-associated pain [14]. Nonetheless, these effects were not consistently ob- served across all pain domains. Botulinum toxin studies reported heterogeneous find- ings across populations with pelvic floor myalgia and vestibulodynia. Several trials demonstrated short-term im- provements in pain-related outcomes; however, between- group differences were inconsistent, and results varied ac- cording to study design, injection protocols, and outcome measures [15,16,17]. 3 Table 1. Characteristics of included studies . Intervention Study Population Intervention details Comparator Follow-up PFMT Gabrielsen et al. (2025) [ 14] Women aged 18–45 years with surgically confirmed endometriosis; NRS ≥4 PFMT + supervised exercise + home program Pain education 4, 12 months BoNT-A (vestibulodynia) Diomande et al. (2019) [ 15] Provoked vestibulodynia BoNT-A 50–100 U (subcutaneous) Placebo 3 months BoNT-A (PF myalgia) Dessie et al. (2019) [ 16] Chronic pelvic pain with pelvic floor myalgia BoNT-A + PFPT Placebo + PFPT 2–12 weeks BoNT-A (PF spasm) Abbott et al. (2006) [ 17] Chronic pelvic pain >2 years with pelvic floor spasm/myalgia BoNT-A (80–100 U) Placebo 3–6 months Nutraceutical Cobellis et al. (2011) [ 18] Endometriosis (rASRM stage I–II) PEA + transpolydatin Placebo or celecoxib 3 months CBT (online) Chandra et al. (2026) [ 19] Endometriosis-associated chronic pelvic pain Internet-based CBT Usual care or wait-list 8–12 weeks ACT/mindfulness Hansen et al. (2023) [ 20] Endometriosis; NRS ≥5 ACT-based group program Wait-list Not reported Psychotherapy Beissner et al. (2018) [ 21] Laparoscopically confirmed endometriosis CBT + somatosensory therapy Wait-list 3 months CBT (in-person) Donatti et al. (2025) [ 22] Endometriosis; V AS≥5 Individual CBT Usual care 4 months GnRH antagonist Carr et al. (2013) [ 23] Endometriosis Elagolix 150 mg once daily Placebo 8 weeks GnRH antagonist Diamond et al. (2014) [ 24] Endometriosis Elagolix 150–250 mg once daily Placebo 12–24 weeks GnRH antagonist Carr et al. (2014) [ 25] Endometriosis Elagolix (once or twice daily) (DMPA-SC) 24 weeks GnRH antagonist Taylor et al. (2017) [ 26] Endometriosis Elagolix 150–200 mg Placebo 3–6 months GnRH antagonist Abrao et al. (2021) [ 27] Surgically confirmed endometriosis Elagolix Placebo 3–6 months GnRH antagonist Ács et al. (2015) [ 28] Endometriosis Elagolix Placebo or leuprorelin Not reported GnRH antagonist Donnez et al. (2020) [ 29] Endometriosis-associated pain Linzagolix 50–200 mg Placebo 12–24 weeks GnRH antagonist Donnez et al. (2024) [ 30] Surgically confirmed endometriosis Linzagolix ± add-back therapy Placebo 3–6 months GnRH antagonist Osuga et al. (2021) [ 31] Endometriosis Relugolix 10–40 mg Placebo or leuprorelin 12 weeks GnRH antagonist Osuga et al. (2021) [ 32] Endometriosis (extension study) Relugolix Placebo or leuprorelin 24 weeks GnRH antagonist Harada et al. (2022) [ 33] Endometriosis Relugolix 40 mg Leuprorelin 24 weeks GnRH antagonist D’Hooghe et al. (2019) [ 34] Surgically confirmed endometriosis ASP1707 3–15 mg Placebo or leuprorelin 12–24 weeks PFMT, 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, numeric rating scale; V AS, visual analog scale; rASRM, revised American Society for Reproductive Medicine classification; DMPA-SC, depot medroxyprogesterone acetate (subcutaneous); QD, once daily; GnRH, gonadotropin-releasing hormone; PEA, palmitoylethanolamide; U, units. 4 Table 2. Efficacy/effectiveness outcomes of included studies . Intervention Study Comparison Outcomes Key findings PFMT Gabrielsen et al. (2025) [ 14] PFMT + exercise vs. education Pain (NRS), dyspareunia, urinary symptoms Modest reduction in current pain at 4 and 12 months; no consistent effect on worst pain or dyspareunia BoNT-A (vestibulodynia) Diomande et al. (2019) [ 15] 50–100 U vs. placebo Pain (V AS), sensitivity, sexual function No significant between-group differences across outcomes BoNT-A (PF myalgia) Dessie et al. (2019) [ 16] BoNT-A + PFPT vs. PFPT Pain, pelvic floor symptoms No consistent between-group differences in pain; limited improvements in pelvic floor scores BoNT-A (PF spasm) Abbott et al. (2006) [ 17] BoNT-A vs. placebo Pain, pelvic pressure, global improvement Mixed results; some improvements in pelvic pressure and global outcomes Nutraceutical Cobellis et al. (2011) [ 18] PEA + transpolydatin vs. placebo/active comparator Pain (V AS), satisfaction Improvements in pain and satisfaction reported; effects were smaller compared with active comparators CBT (online) Chandra et al. (2026) [ 19] iCBT vs. usual care Disability, mood, pain Improvements in disability and mood; modest and variable effects on pain intensity ACT/mindfulness Hansen et al. (2023) [ 20] ACT vs. wait-list Pain, QoL, symptoms Improvements mainly in quality of life; inconsistent effects on pain Psychotherapy Beissner et al. (2018) [ 21] Therapy vs. wait-list Pain, psychological outcomes Limited between-group differences; small sample size CBT (in-person) Donatti et al. (2025) [ 22] Individual CBT vs. usual care Pain perception, coping strategies, depression, stress, QoL Significant improvements in pain perception, coping, psychological outcomes, and quality of life compared with usual care GnRH antagonist (elagolix) Carr et al. (2013) [ 23]; Diamond et al. (2014) [24]; Carr et al. (2014) [ 25]; Taylor et al. (2017) [ 26]; Abrao et al. (2021) [27]; Ács et al. (2015) [ 28] Elagolix vs. placebo/active comparator Dysmenorrhea, nonmenstrual pelvic pain, overall pelvic pain, responder rates Reductions in endometriosis-associated pain and generally higher responder rates compared with placebo; efficacy findings were broadly consistent across baseline patient subgroups. GnRH antagonist (linzagolix) Donnez et al. (2020) [ 29]; Donnez et al. (2024) [ 30] Linzagolix vs. placebo Dysmenorrhea, nonmenstrual pelvic pain Dose-dependent improvements in pain outcomes GnRH antagonist (relugolix) Osuga et al. (2021) [ 31]; Osuga et al. (2021) [32]; Harada et al. (2022) [ 33] Relugolix vs. placebo/active comparator Pain, symptom scores Significant reductions in pain; dose-response relationship observed GnRH antagonist (ASP1707) D’Hooghe et al. (2019) [ 34] ASP1707 vs. placebo/active comparator Pain scores Modest improvements in pain outcomes compared with placebo PFMT, 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; ACT, acceptance and commitment therapy; QoL, quality of life; NRS, numeric rating scale; V AS, visual analog scale; PEA, palmitoylethanolamide; GnRH, gonadotropin-releasing hormone. 5 Table 3. Safety outcomes of included studies . Intervention Study Comparison Outcomes Key findings PFMT Gabrielsen et al. (2025) [ 14] PFMT + exercise vs. education Adverse events No adverse events or symptom worsening reported BoNT-A (vestibulodynia) Diomande et al. (2019) [ 15] 50–100 U vs. placebo Adverse events No serious adverse events; transient post-injection pain was commonly reported BoNT-A (PF myalgia) Dessie et al. (2019) [ 16] BoNT-A + PFPT vs. PFPT Adverse events No significant between-group differences; mild and transient adverse events reported BoNT-A (PF spasm) Abbott et al. (2006) [ 17] BoNT-A vs. placebo Adverse events No clear between-group differences; occasional pelvic and urinary symptoms reported Nutraceutical Cobellis et al. (2011) [ 18] PEA + transpolydatin vs. placebo/active comparator Adverse events No significant adverse events or laboratory abnormalities reported CBT (online) Chandra et al. (2026) [ 19] iCBT vs. usual care Adverse events Adverse events were not systematically reported ACT/mindfulness Hansen et al. (2023) [ 20] ACT vs. wait-list Adverse events Safety outcomes not reported Psychotherapy Beissner et al. (2018) [ 21] Therapy vs. wait-list Adverse events Safety outcomes not reported GnRH antagonist (elagolix) Diamond et al. (2014) [ 24]; Carr et al. (2014) [25]; Taylor et al. (2017) [ 26]; Ács et al. (2015) [ 28] Elagolix vs. placebo/active comparator TEAEs, BMD Dose-dependent reductions in bone mineral density; increased vasomotor symptoms; other adverse events generally similar across groups GnRH antagonist (linzagolix) Donnez et al. (2020) [ 29]; Donnez et al. (2024) [30] Linzagolix vs. placebo TEAEs, BMD Increased adverse events with higher doses; bone density changes and vasomotor symptoms reported; serious events uncommon GnRH antagonist (relugolix) Osuga et al. (2021) [ 31]; Osuga et al. (2021) [32]; Harada et al. (2022) [ 33] Relugolix vs. placebo/active comparator TEAEs, BMD Higher frequency of adverse events with increasing dose; common events included vasomotor and menstrual symptoms; reductions in BMD observed GnRH antagonist (ASP1707) D’Hooghe et al. (2019) [ 34] ASP1707 vs. placebo/active comparator TEAEs Adverse events were generally mild to moderate; no major safety concerns were identified BoNT-A, botulinum toxin type A; PFMT, pelvic floor muscle training; BMD, bone mineral density; TEAEs, treatment-emergent adverse events. 6 GnRH antagonist trials, analyzed as a separate subgroup, demonstrated more consistent findings within endometriosis-associated pain. Across multiple random- ized studies, these agents were associated with higher re- sponder rates and greater reductions in dysmenorrhea and nonmenstrual pelvic pain than placebo or active compara- tors [ 24,25,26,27,30,31,32,33,34]. These trials generally employed standardized endpoints and consistent outcome definitions. Psychological and behavioral interventions were as- sociated with improvements in pain-related and psychoso- cial outcomes, particularly in measures of function, cop- ing, and quality of life. However, effects on pain intensity were more heterogeneous, and substantial variation was ob- served across studies in outcome measures and follow-up duration [19,20,21,22]. The nutraceutical intervention (palmi- toylethanolamide plus transpolydatin) was associated with improvements in pain scores and patient-reported satisfaction compared with placebo or baseline; however, greater effects were observed with active comparators, suggesting a relatively limited comparative benefit. 3.3 Safety Safety outcomes were available in a subset of in- cluded studies, as several trials did not report adverse events or provided insufficient detail for data extrac- tion. Safety findings are summarized in Table 3 (Ref. [14,15,16,17,18,19,20,21,24,25,26,28,29,30,31,32,33,34]). Pelvic floor training was generally well tolerated, and no serious adverse events were reported in the included studies [ 14]. Similarly, most botulinum toxin studies did not report serious adverse events. Nevertheless, transient post-injection pain and localized discomfort were com- monly described [ 15,16,17]. Occasional reports of urinary or fecal symptoms were observed, although these were not consistently different between groups. In contrast, GnRH antagonist trials reported a higher frequency of treatment-emergent adverse events. These in- cluded vasomotor symptoms, menstrual changes, and re- ductions in bone mineral density, with some studies also reporting laboratory abnormalities such as alterations in lipid profiles or liver enzyme levels [ 27,30,31,33]. The fre- quency and severity of these events appeared to vary ac- cording to dose and treatment duration. Adverse event reporting was limited or inconsistently described in several psychological and behavioral inter- vention studies, restricting interpretation of their safety profiles. Overall, differences in reporting standards and follow-up duration across studies limit comparability of safety outcomes. 3.4 Risk of Bias Risk of bias assessments are presented in Table4 (Ref. [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31, 32,33,34]). Most studies were judged as having some con- cerns overall, mainly related to missing outcome data and selective reporting. Several trials showed low risk or some concerns across the randomization and outcome measurement do- mains [ 25,31,34], whereas others were rated as high risk due to deviations from intended interventions or limitations in outcome assessment. These methodological limitations, together with inconsistency and imprecision across studies, contributed to low-to-moderate certainty of evidence. 4. Discussion This systematic review provides a structured synthe- sis of emerging therapies for CGPP , highlighting variability in reported outcomes across pain phenotypes and interven- tion classes. The findings reflect the complexity of CGPP as a heterogeneous clinical entity, in which treatment re- sponse may vary according to underlying mechanisms, pa- tient characteristics, and intervention design. Among the included interventions, oral GnRH antag- onists had the most consistent evidence base, particularly for endometriosis-associated pain. These trials were gener- ally larger and employed more standardized outcome mea- sures, which may contribute to consistency across studies [9,10]. Reported improvements in dysmenorrhea and non- menstrual pelvic pain align with hormonal modulation of disease activity described in the previous literature. How- ever, these findings should be interpreted in the context of relatively homogeneous study populations and the occur- rence of hypoestrogenic adverse effects, including reduc- tions in bone mineral density, which remain relevant in clin- ical decision-making. In contrast, the evidence for pelvic floor rehabili- tation was more variable. Pelvic floor physical therapy comprises a range of modalities, including relaxation tech- niques, biofeedback, and strengthening approaches, which are often combined and inconsistently reported across stud- ies. This variability may contribute to the modest and het- erogeneous effects observed in pain outcomes. In addition, pelvic floor interventions are frequently delivered as part of multimodal care, limiting the ability to isolate their specific contribution. The findings for BoNT-A were also inconsistent. Dif- ferences in injection protocols, dosing regimens, targeted muscle groups, and patient selection likely contribute to variability across studies. Furthermore, the coexistence of multiple pain mechanisms within CGPP populations may influence treatment response, particularly in studies includ- ing mixed phenotypes. Although BoNT-A remains of inter- est in selected patients with pelvic floor dysfunction, cur- rent evidence is insufficient to draw definitive conclusions regarding its comparative effectiveness. Psychological and behavioral interventions demon- strated a distinct pattern, with more consistent improve- ments in functional outcomes, coping, and psychological 7 Table 4. Risk of bias assessment (RoB 2) . Study Randomization Deviations Missing data Outcome measurement Selective reporting Overall Abbott et al. (2006) [ 17] Low Low Some concerns Low Some concerns Some concerns Abrao et al. (2021) [ 27] Some concerns Some concerns Some concerns Low Some concerns Some concerns Ács et al. (2015) [ 28] Some concerns Low Some concerns Low High High Carr et al. (2013) [ 23] Low Some concerns High Low Some concerns High Carr et al. (2014) [ 25] Some concerns Low High Low Some concerns High Chandra et al. (2026) [ 19] Low High Some concerns High Some concerns High Cobellis et al. (2011) [ 18] Some concerns Some concerns Low Some concerns Some concerns Some concerns D’Hooghe et al. (2019) [ 34] Low Low Some concerns Low Some concerns Some concerns Dessie et al. (2019) [ 16] Some concerns Some concerns Some concerns Low Some concerns Some concerns Diamond et al. (2014) [ 24] Low Low Some concerns Low Some concerns Some concerns Diomande et al. (2019) [ 15] Some concerns Some concerns Low Low Some concerns Some concerns Donatti et al. (2025) [ 22] High High Some concerns High High High Donnez et al. (2020) [ 29] Some concerns Low Some concerns Low Some concerns Some concerns Donnez et al. (2024) [ 30] Low Low Some concerns Low Some concerns Some concerns Gabrielsen et al. (2025) [ 14] Some concerns Some concerns Some concerns High High High Hansen et al. (2023) [ 20] Some concerns High High High High High Harada et al. (2022) [ 33] Some concerns Low Some concerns Low Some concerns Some concerns Osuga et al. (2021) [ 31] Some concerns Low Some concerns Low Some concerns Some concerns Osuga et al. (2021) [ 32] Some concerns Some concerns High Some concerns Some concerns High Beissner et al. (2018) [ 21] Some concerns High Some concerns High Some concerns High Taylor et al. (2017) [ 26] Low Some concerns Some concerns Some concerns Some concerns Some concerns Low, low risk of bias; High, high risk of bias; Some concerns, some concerns of bias. distress than in pain intensity. This observation aligns with multidimensional models of chronic pain, in which central processing and psychosocial factors play a key role in shap- ing the pain experience. The relatively modest changes in pain intensity across these studies may reflect differences in outcome prioritization rather than a lack of clinical benefit. An important consideration in interpreting these find- ings is the inherent heterogeneity of CGPP . Chronic pelvic pain encompasses overlapping conditions such as en- dometriosis, pelvic floor dysfunction, vulvodynia, and neu- ropathic pain syndromes, which are not always clearly dis- tinguished in clinical trials. In addition, subtypes within these conditions may have distinct mechanisms and treat- ment responses. Limited phenotypic characterization in the included studies may therefore contribute to outcome vari- ability and restrict the identification of patient subgroups more likely to benefit from specific interventions. Methodological factors should also be considered. Al- though all included studies were randomized, several raised concerns related to missing data, deviations from intended interventions, and selective reporting. Sample sizes were often limited outside of GnRH antagonist trials, and follow- up durations varied across studies. Differences in outcome measures and reporting further limited comparability and precluded quantitative synthesis.

This review has several limitations, including hetero- geneity in study design, variability in outcome measures, limited reporting of safety outcomes, and potential risk of bias in the included trials. These factors may affect the com- parability and interpretation of the findings. The certainty of evidence ranged from low to moderate across outcomes, primarily due to inconsistency across studies and impreci- sion in effect estimates, further limiting confidence in the observed findings. In this context, a structured narrative synthesis strati- fied by pain phenotype and intervention class was consid- ered more appropriate than quantitative pooling. This ap- proach enables a more clinically interpretable summary of the evidence while acknowledging heterogeneity. Overall, the findings support a phenotype-informed, multimodal approach to CGPP management, in which inter- ventions may be selected according to the predominant pain mechanism and patient profile. However, the available evi- dence remains heterogeneous, warranting cautious interpre- tation. Future studies incorporating clearer phenotypic defi- nitions, standardized outcome measures, and longer follow- up are needed to improve the understanding of treatment effects in this complex condition. 5. Conclusions The available evidence suggests that emerging ther- apies may provide benefits for specific CGPP pheno- types; however, the findings remain heterogeneous and of variable certainty. Pelvic floor rehabilitation and psy- chological interventions were associated with improve- ments in functional and psychosocial outcomes, whereas GnRH antagonists demonstrated more consistent effects in 8 endometriosis-associated pain, along with relevant safety considerations. These findings support a phenotype-informed, mul- timodal approach to CGPP management. However, clini- cal decisions should be individualized, considering poten- tial risks, patient characteristics, and variability in treatment response. Future research incorporating standardized out- comes, longer follow-up, and improved phenotypic char- acterization is warranted to better define the role of these interventions and to identify subgroups most likely to ben- efit. Availability of Data and Materials The data supporting the conclusions of this review are derived from previously published studies, which are cited in the reference list. No new datasets were generated or analyzed for this study. Therefore, data sharing is not ap- plicable. Author Contributions MCPB and JPAG conceived and designed the study. MCPB, LNPG, and JEAM conducted the literature search and study selection. MCPB, LNPG, and CDRP extracted and synthesized the data. JPAG and GITR supervised the study, provided methodological guidance, and contributed to the interpretation of the study findings and their clini- cal implications. MCPB drafted the initial manuscript. All authors critically revised the manuscript for important in- tellectual content, approved the final version, and agree to be accountable for all aspects of the work. Ethics Approval and Consent to Participate Not applicable. This study is a systematic review of published literature and did not involve direct participation of human subjects or animals. Acknowledgment The authors would like to thank all contributors and collaborators involved in the development of this work. Funding This research received no external funding. Conflicts of Interest The authors declare no conflicts of interest. Declaration of AI and AI-Assisted Technologies in the Writing Process During the preparation of this manuscript, the authors used an artificial intelligence tool (ChatGPT-4o, OpenAI) to assist with language refinement and editorial clarity. The authors reviewed and edited all content generated by the AI tool and take full responsibility for the integrity, accuracy, and originality of the work. Supplementary Material Supplementary material associated with this article can be found, in the online version, at https://doi.org/10. 31083/CEOG50521.

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