{"paper_id":"811971aa-3aaa-442c-9af4-e5e34cd288aa","body_text":"Tijani et al. \nMiddle East Fertility Society Journal            (2025) 30:9  \nhttps://doi.org/10.1186/s43043-025-00221-0\nREVIEW Open Access\n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which \npermits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line \nto the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory \nregulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this \nlicence, visit http://creativecommons.org/licenses/by/4.0/.\nMiddle East Fertility\nSociety Journal\nCurrent and emerging therapies \nfor endometriosis-associated pain: a review\nEbunoluwa Oluwatimileyin Tijani1, Lydia Oluwatoyin Ajayi2, Oladimeji Samson Tijani2, \nOyedayo Phillips Akano3 and Ayodeji Folorunsho Ajayi1,4,5* \nAbstract \nBackground Endometriosis is a severe gynaecological disease marked by the formation of endometrial-like growth \nbeyond the uterus, which causes severe pelvic pain, infertility, and a reduced standard of life. Despite the progress \nthat has been made in understanding its aetiology, the treatment remains difficult due to the disease’s complicated \nstructure and diversity in different patient responses.\nMain body.\nThis narrative review examines both present and emerging therapeutics for endometriosis-related pain, focusing \non pharmaceutical, surgical, and complementary treatment options. Current pharmacological treatments, such \nas nonsteroidal anti-inflammatory medications (NSAIDs), hormone therapy, and analgesics, provide symptom alle-\nviation but are frequently limited due to side effects and long-term effectiveness issues. Surgical procedures, such \nas laparoscopy and nerve ablation, provide alternatives, although recurrence rates remain high.\nAdditionally, complementary therapies such as acupuncture and physical therapy are gaining recognition for their \nrole in pain management. The review also explores emerging therapies, including novel pharmacological approaches \nlike selective progesterone receptor modulators (SPRMs), aromatase inhibitors, and gene-based therapies. Advances \nin minimally invasive surgical techniques and regenerative medicine, such as stem cell therapies, are also discussed.\nConclusion An essential comparison of these methods of therapy highlights the need for personalised approaches \nand further research to address variation of the disease. The review concludes with recommendations for subse-\nquent studies, emphasising the need for long-term studies, real-world data, and innovations in pain management \nthat integrate multifaceted therapies. This analysis aims to provide healthcare providers with a clearer understanding \nof the changing landscape of endometriosis treatment.\nKeywords Endometriosis, Pain management, Pharmaceutical therapies, Deep infiltrating endometriosis, Surgical \ntreatments, Complementary therapies\n*Correspondence:\nAyodeji Folorunsho Ajayi\naajayi22@lautech.edu.ng\nFull list of author information is available at the end of the article\n\nPage 2 of 14Tijani et al. Middle East Fertility Society Journal            (2025) 30:9 \nIntroduction\nBackground on endometriosis\nEndometriosis is described by Chauhan et  al., [15], as a \nchronic gynecological disorder marked by the formation \nof endometrial-like growth beyond the uterus, resulting \nin symptoms that include pain in the pelvis, dysmenor -\nrhea, dyspareunia, and, in severe cases, fertility problems. \nThis disorder, which affects 10% of women of reproduc -\ntive age worldwide, is a leading cause of death and can \nsignificantly reduce women’s standard of living [68]. \nEndometriosis results from a mix of hereditary, immuno-\nlogical, and environmental factors [15]. Despite existing \nsubstantial research, the pathophysiology of endometrio -\nsis remains incompletely understood, making it a difficult \ncondition to adequately manage.\nPathophysiology of endometriosis‑associated pain\nMaddern et  al., [51], documented that one of the most \ndebilitating aspects of endometriosis is the persis -\ntent discomfort and pain  associated with the disease. \nEndometriosis-associated pain (EAP) is primarily due \nto the endometrium lesions which trigger a response of \ninflammation, leading to the release of prostaglandins, \ncytokines, and other inflammatory mediators [47, 48, 51]. \nThis inflammatory environment not only causes direct \nirritation of the pelvic organs and surrounding tissues, \nbut it also sensitizes the peripheral and central nervous \nsystems, resulting in enhanced pain perception and, in \ncertain circumstances, the development of syndromes of \npersistent pain [15, 47, 48, 51] (Fig. 1).\nThe prevalence of EAP is alarmingly high among \nwomen with endometriosis. Falcone and Flyckt [32], \nreported that about 70% to 90% of females with \nendometriosis suffer from persistent pain in their pel -\nvis, which can persist even after surgical intervention or \nmedical treatment. The pain associated with endometrio-\nsis is often cyclical [67], worsening during menstruation, \nbut many women also report non-cyclical pain that can \nbe continuous and severe, affecting daily activities and \noverall well-being [26, 32].\nThe chronic pain experienced by women with endo -\nmetriosis has quite a lot of implications for their qual -\nity of life. Physical, emotional, and social aspects of life \nare often compromised, with many women reporting \nfeelings of frustration, despair, and anxiety as a result of \ntheir chronic discomfort and pain [51, 67]. The impact on \nsexual function is also significant, with dyspareunia being \na common complaint [49], leading to difficulties in inti -\nmate relationships and a decreased quality of life.\nSignificance and objectives\nManaging pain caused by endometriosis remains a signif-\nicant challenge due to the variability of the condition and \nthe limitations of current treatment options. While the \nprimary goal of treatment is to alleviate pain, preserve \nfertility, and prevent disease recurrence, many available \ntherapies offer only partial relief and are associated with \nsignificant side effects. Given these limitations, there is a \npressing need to explore new and emerging approaches \nthat may provide more effective and long-term pain relief \nfor women with endometriosis.\nThis narrative review aims to provide a comprehen -\nsive assessment of both established and developing \ntreatments for endometriosis-related pain, emphasizing \ntheir potential benefits and limitations. By examining \npharmacological and non-pharmacological approaches, \nFig. 1 The primary factors involved in the pathophysiology of endometriosis-associated pain\n\nPage 3 of 14\nTijani et al. Middle East Fertility Society Journal            (2025) 30:9 \n \nincluding surgical procedures, alternative therapies, \nand lifestyle changes, this review seeks to identify the \nstrengths and weaknesses of current treatments and the \npotential of future therapies to address unmet needs in \nmanaging pain caused by endometriosis.\nKey questions to be addressed include: the effective -\nness of current therapies, their limitations and side \neffects, emerging therapy options, potential challenges \nto implementation, and directions for future research \nand clinical practice. By answering these questions, this \nreview aims to be a valuable resource for healthcare pro -\nviders, researchers, and patients seeking to understand \nthe evolving landscape of endometriosis treatment.\nSearch method\nAn extensive search was undertaken through numer -\nous academic search engines, including Scopus, Pub \nMed, and Google Scholar, to gather relevant literature \non current and emerging therapies for endometriosis-\nassociated pain. The search terms used were \"endometri -\nosis-associated pain,\" \"treatment,\" \"therapy,\" \"emerging \ntherapies,\" “deep infiltrating endometriosis” , and \"pain \nmanagement.\"\nBoolean operators were applied to refine the search, \ncombining terms such as \" AND\" and \"OR\" to include \nstudies focused on both pharmacological and non-phar -\nmacological treatments.\nResearch studies were selected for inclusion if they \nwere published in English, peer-reviewed, and provided \nuseful information about endometriosis-related pain \ntreatment techniques. To ensure that the most current \nadvances were included, the review focused on articles \npublished within the last decade. Conditions for exclu -\nsion included research that did not specifically address \nendometriosis-related pain, case reports, and non-peer-\nreviewed literature.\nThe data from the selected studies were combined \nusing a narrative technique, to summarize and interpret \nthe findings in light of the study’s existing understanding.\nMain body\nCurrent therapies for endometriosis‑associated pain\nPharmacological treatments\nNonsteroidal anti-inflammatory drugs (NSAIDs) are \nwidely regarded as the first-line therapy for endome -\ntriosis-associated pain, primarily because they inhibit \ncyclooxygenase (COX) enzymes (COX-1 and COX-2), \nwhich are essential in the production of prostaglandins, \na key contributor to pain and inflammation [50, 76]. \nMachairiotis et  al. [50], emphasize that reducing pros -\ntaglandin synthesis effectively mitigates the pain caused \nby the inflammatory reaction due to endometrial lesions. \nHowever, Smith [72] noted that despite the efficacy of \nNSAIDs in alleviating menstrual pain, their utility is less \nimpressive in managing chronic pelvic pain. There are \nalso concerns about the side effects of NSAIDs, which \ninclude gastrointestinal discomfort, ulcers, and increased \ncardiovascular risks with prolonged use [37] (Table 1).\nHormonal therapies are another avenue for manag -\ning endometriosis-associated pain, with oral contracep -\ntives (OCs) being one of the most commonly prescribed \noptions. OCs suppress ovulation and regulate estrogen \nlevels, which reduces the cyclical changes that trigger \nendometrial tissue growth [75]. However, Ciarcia and \nHuckins [19] established that the effectiveness of OCs is \nlimited to their duration of use, and symptoms frequently \nreturn upon discontinuation. Szubert et  al. [73], further \nargue that OCs may not work well for patients with deep \ninfiltrating endometriosis and could lead to side effects \nlike weight gain, mood changes, and an increased risk of \nthromboembolism, which limits their utility in long-term \nmanagement.\nGonadotropin-releasing hormone (GnRH) agonists \nand antagonists offer another class of hormonal therapy. \nThese medications work by suppressing estrogen pro -\nduction, a hormone crucial for the proliferation of endo -\nmetrial lesions [66]. Zhang et al. [88], explain that while \nGnRH agonists first generate a preliminary boost in lute -\ninizing hormone (LH) and follicle-stimulating hormone \n(FSH) before downregulating GnRH receptors, GnRH \nantagonists directly inhibit these receptors, thus reducing \nestrogen production immediately. Despite the positive \noutcomes observed with GnRH therapies, these treat -\nments induce hypoestrogenic states, leading to meno -\npausal signs, which include flashes of heat, dryness of \nthe vagina, and diminished density of the bones [36, 43]. \nThese side effects often necessitate add-back treatments \ninclude providing low amounts of oestrogen or progestin \n[43]. However, add-back therapy may reduce the effec -\ntiveness of GnRH therapy [29].\nProgestins, synthetic hormones that mimic progester -\none, are widely used to induce atrophy in endometrial \nlesions and alleviate associated pain [65]. Dienogest, for \ninstance, has gained traction due to its favorable side \neffect profile and its ability to reduce pain more effec -\ntively than other progestins [22]. Nevertheless, Reis et al. \n[65], stated that progestins can lead to side effects like \nbreakthrough bleeding, weight gain, and mood changes. \nSome women also experience recurrence of symptoms \nafter discontinuation of therapy [82, 83].\nFor patients experiencing severe pain that is not ade -\nquately controlled by NSAIDs or hormonal therapies, \nanalgesics, opioids, may be prescribed. Opioids act on \nthe central nervous system to alter pain perception, pro -\nviding relief for more intense pain [4]. However, opioids \nare controversial in treating endometriosis-associated \n\nPage 4 of 14Tijani et al. Middle East Fertility Society Journal            (2025) 30:9 \nTable 1 A comparative overview of the most used treatment modalities for managing endometriosis-associated pain\nTreatment Modality Subcategory Mechanism of Action Effectiveness Limitations Cost‑Effectiveness\nPharmacological NSAIDs [50, 76] Inhibit COX enzymes to reduce \ninflammation; [76]\nModerately effective in pain \nrelief [50]\nLimited efficacy for chronic \npain [37]\nIt has a low cost and is suitable \nfor short-term use [7]\nOral Contraceptives [75] Suppress ovulation and stabi-\nlize hormone levels [75]\nEffective in managing mild \ncases [19]\nMay not be sufficient for severe \ncases [73]\nAffordable and widely accessible; \ncost-effective for long-term \nmanagement of mild cases [83]\nGnRH Agonists and Antago-\nnists\nReduce the production \nof oestrogen by suppressing \nthe pituitary gland. Zhang \net al., [88]\nBeneficial in lowering pain [66] It can cause menopausal \nsymptoms with long-term use \n[36, 43]\nExpensive but highly effective \nfor short-term relief; less sustain-\nable for extended use [83]\nProgestins [65] Inhibit the growth of endo-\nmetrial tissue by modifying \nhormonal balance [22]\nEffective pain management \n[65]\nRisk of irregular bleeding, \nweight gain [82, 83]\nModerately priced; and cost-\neffective for chronic cases [24]\nOpioids [4] Bind to brain opioid receptors \nto inhibit pain signals [4]\nEffective for short-term use [4] High potential for addiction \nand tolerance [12]\nHigh cost with significant risks; \nlimited cost-effectiveness \nfor long-term pain relief [86]\nSurgical Laparoscopy\n[40]\nMinimally invasive removal \nof endometrial lesions [77]\nEffective symptom relief [31] High recurrence rates, require \nskilled surgeons [21]\nHigh upfront cost; cost-effective \nif performed by experienced \nsurgeons [71]\nLaparotomy [85] Open surgery to remove large \nor deep endometrial lesions \n[85]\nEffective for extensive endo-\nmetriosis [85]\nLonger recovery time, more \ninvasive [87]\nExpensive with prolonged \nrecovery costs; less favorable \ncompared to laparoscopy [71]\nNerve Ablation and Resection \n[60]\nSurgical destruction of nerves \nresponsible for transmitting \npain [60]\nSome success in reducing \npain [60]\nEffectiveness varies, not widely \npracticed [81]\nModerate cost: effectiveness \nvaries [55], making sustainability \nuncertain\nComplementary and Alterna-\ntive\nAcupuncture\n[47, 48]\nStimulates nerves and muscles \nto promote natural pain relief \n[47, 48]\nSome evidence of effective-\nness Mira et al., [57]\nLack of large-scale clinical trials \nMira et al., [57]\nModerate per-session cost; effec-\ntiveness varies [86], impacting \ncost-effectiveness\nDietary Interventions/Herbal \nSupplements\n[80]\nAnti-inflammatory diets \nto reduce systemic inflamma-\ntion [61]\nLimited but emerging evi-\ndence [80]\nLack of regulation in sup-\nplements, variable patient \nresponse [80]\nLow to moderate cost; effec-\ntiveness depends on patient \nadherence and supplement \nquality [39]\nPhysical Therapy [23] Targeted exercises \nto strengthen pelvic muscles \nand reduce pain [23]\nEffective in improving mobility \n[23]\nRequires patient adherence \nto be effective [23]\nModerate cost with high \nlong-term value for compliant \npatients [3]\n\nPage 5 of 14\nTijani et al. Middle East Fertility Society Journal            (2025) 30:9 \n \npain because of the risks of dependence, tolerance, and \nside effects such as constipation and nausea [12]. Long-\nterm use of opioids is not recommended for chronic pain, \ngiven the high addiction potential and lack of evidence \nsupporting their effectiveness in chronic conditions. \nPreuss et al. [64], suggest that alternatives like tramadol \nmight be useful for moderate to severe pain, although \nthese too are loaded with restrictions and potential \nhazards.\nSurgical interventions for endometriosis‑associated pain\nSurgical interventions are often reserved for cases where \npharmacological treatments fail to provide sufficient \nrelief from endometriosis-associated pain [40]. Taylor \net al. [77], stated that laparoscopy is the standard of excel-\nlence for identifying and managing endometriosis. Endo -\nmetrial abnormalities, adhesions, and ovarian cysts are \nall removed with this minimally invasive surgery. Evans \net al. [31], noted that laparoscopy has generally positive \noutcomes, with many women experiencing significant \npain relief following the procedure. However, recurrence \nrates remain a concern, with Conroy et al., [21], reporting \nthat within the first five years of surgery, up to half of all \nwomen report symptom recurrence.\nLaparotomy, a more invasive open surgical procedure, \nis reserved for more severe cases, such as those with \nextensive disease or large endometriomas [85]. While \nsurgical management offers relief, its comparative effec -\ntiveness to medical management remains debated [40, 82, \n83, 87] suggest that combining surgery with postopera -\ntive hormonal therapy may provide the best results. This \ncombined approach appears to address both the physi -\ncal removal of endometrial tissue and the suppression of \nhormonal triggers that cause lesion growth.\nAnother surgical technique, nerve ablation, focuses \non interrupting the neural pathways responsible for \ntransmitting pain signals from the pelvic region to the \nbrain [60]. Ugurlucan and Yasa [81], discuss procedures \nlike presacral neurectomy and laparoscopic uterosacral \nnerve ablation (LUNA), which have shown some success \nin reducing pain. However, the evidence is mixed, with \ncomplications such as urinary dysfunction, constipation, \nand pelvic organ prolapse being reported in some cases \n[81, 87].\nComplementary and alternative therapies \nfor endometriosis‑associated pain\nComplementary therapies are becoming recognised as \ncomplements to conventional treatments for controlling \nthe pain associated with endometriosis. Acupuncture, a \ntraditional Chinese medicine technique [47, 48], is one \nsuch therapy that has gained attention. It is believed to \nwork by stimulating specific points on the body to release \nendogenous opioids and modulate neurotransmitters like \nserotonin and dopamine [47, 48]. Mira et  al. [57], con -\nducted a systematic review and found that acupuncture \nwas comparable to conventional medical treatments in \npain relief, with fewer side effects. However, the evidence \nsupporting acupuncture remains inconclusive, and more \nrandomized controlled trials are needed to verify its \nefficacy.\nDietary interventions and herbal supplements are \nalso being explored as adjunctive therapies for manag -\ning endometriosis. The theory is that diet and nutrition \ncan modulate inflammation, which plays a critical role \nin endometriosis-associated pain [80]. Oszajca and Ada -\nmus [ 61], propose that anti-inflammatory diets rich in \nomega-3 fatty acids, antioxidants, and phytoestrogens \nmay reduce inflammation and alleviate pain. Herbal sup -\nplements like curcumin, resveratrol, and pycnogenol have \nalso been studied for their anti-inflammatory properties. \nClower, et al. [20], reported that curcumin supplementa -\ntion can reduce endometriosis-related pain and inflam -\nmatory markers, but these findings should be approached \nwith caution due to limited evidence and potential inter -\nactions with conventional treatments.\nPhysical therapy, particularly pelvic floor therapy, is \nanother promising complementary approach. Pelvic floor \ntherapy aims to improve the function of pelvic muscles, \nwhich may become tense or dysfunctional in women \nwith endometriosis [23]. Techniques include muscle \nrelaxation, biofeedback, and manual therapy to alleviate \nspasms and improve pelvic alignment [38]. da Silva et al. \n[23], found that pelvic floor physical therapy substantially \ndecreased discomfort and enhanced their standard of life \nin people with endometriosis. The therapy is especially \nbeneficial for addressing urinary and bowel dysfunction, \na frequent concurrent medical condition in women with \nendometriosis [62]. Although pelvic floor therapy offers \nlong-term benefits, da Silva et al. [23], also noted that the \neffectiveness varies based on individual symptoms and \ntherapist expertise.\nDeep Infiltrating Endometriosis (DIE)\nDiniz et  al. [28], explain deep infiltrating endometrio -\nsis as one of the most severe forms of endometriosis, \ncharacterized by lesions that penetrate more than 5 mm \nbeneath the peritoneal surface, often involving organs \nsuch as the bowel, bladder, and ureters. DIE is a sig -\nnificant contributor to chronic pelvic pain, dysmenor -\nrhea, and dyspareunia, with pain often being refractory \nto standard pharmacological treatments [5, 82, 83]. The \ncomplexity and severity of DIE necessitate specialized \ntherapeutic approaches, particularly surgical interven -\ntions, to address its profound impact on quality of life \n[28].\n\nPage 6 of 14Tijani et al. Middle East Fertility Society Journal            (2025) 30:9 \nChamié et  al. [13], document that surgical manage -\nment is considered the cornerstone of DIE treatment \ndue to the limited efficacy of medical therapies in \nresolving deeply infiltrating lesions. Techniques such \nas excision of endometriotic lesions, bowel resections, \nand ureterolysis have been commonly employed to \nalleviate symptoms and restore organ function [13]. \nHowever, Perrone et al. [63], note that recurrence rates \nremain high, showing the need for more advanced sur -\ngical techniques.\nAlso, Peritonectomy as explained by Brown and Koh \n[9] as a procedure involving the removal of affected peri -\ntoneal tissue, is an emerging trend in the radical surgi -\ncal treatment of DIE. By targeting the complete excision \nof visible and microscopic lesions, peritonectomy has \nshown promise in reducing pain and improving fertil -\nity outcomes in selected patients [9]. Patient selection \nis critical for peritonectomy and other advanced surgi -\ncal options for DIE [14]. Candidates are typically those \nwith severe symptoms unresponsive to other treatments, \nextensive disease involving critical organs, or infertility \nlinked to DIE.\nHowever, these procedures are technically demand -\ning, requiring highly skilled surgeons with expertise \nin minimally invasive and radical techniques [9]. Risks \nassociated with peritonectomy include prolonged opera -\ntive times, higher likelihood of postoperative complica -\ntions such as bowel perforation or infection, and a longer \nrecovery period compared to standard laparoscopy [41, \n45]. These risks must be carefully balanced against the \npotential benefits when considering surgical options for \nDIE.\nEmerging therapies for endometriosis‑associated \npain\nNovel pharmacological approaches\nSelective Progesterone Receptor Modulators (SPRMs), \nSPRMs offer a unique mechanism by modulating pro -\ngesterone receptors, targeting tissue growth and inflam -\nmation [65]. Unlike traditional progestins, SPRMs act \nas both agonists and antagonists [65]. Ulipristal acetate, \noriginally for emergency contraception, has been promis-\ning in reducing endometriosis-associated pain by inhib -\niting cell proliferation and reducing inflammation [54]. \nClinical trials show SPRMs are effective in managing pain \nand controlling lesions, but safety concerns about endo -\nmetrial hyperplasia require further study [54, 70]. Also, \nAromatase inhibitors, traditionally used in breast cancer \ntreatment, are developing as an endometriosis treatment \ndue to their ability to reduce local estrogen production \n[34]. Unusual expression of aromatase contributes to dis-\nease development, and blocking this enzyme can lead to \npain alleviation [34]. Tosti et al. [79], demonstrated that \nclinical studies show positive outcomes, especially when \ncombined with hormonal therapies like progestins. How-\never, [34] stated that it has side effects such as bone loss \nlimit long-term use (Fig. 2).\nGonadotropin-releasing hormone (GnRH) antago -\nnists, such as elagolix, provide a more rapid reduction \nof oestrogen than GnRH agonists, effectively reducing \nFig. 2 Emerging therapies for endometriosis-associated pain\n\nPage 7 of 14\nTijani et al. Middle East Fertility Society Journal            (2025) 30:9 \n \npain with fewer hypoestrogogenic effects [46, 78]. Oral \nformulations offer a convenient alternative to injections \n[46], but concerns about bone health remain [1]. Simi -\nlarly, anti-angiogenic therapies target the vascularization \nof endometriotic lesions, which are dependent on new \nblood vessel formation for growth [44]. Bevacizumab, \nan anti-VEGF antibody, has shown promise in reduc -\ning lesion size and pain in early trials [33]. While clinical \napplication is still in its infancy, anti-angiogenic agents \nmay become valuable for cases resistant to conventional \ntherapies.\nCannabinoids, particularly tetrahydrocannabinol \n(THC) and cannabidiol (CBD), have gained attention as \npotential treatments for chronic pain, including endome-\ntriosis-associated pain [35, 58]. Preclinical studies dem -\nonstrate cannabinoids can reduce pain and inflammation \nin animal models [58]. Although clinical data is limited, \ncannabinoids offer potential for patients unresponsive \nto standard therapies. However, legal challenges and the \nneed for rigorous trials are obstacles to widespread use \n[69].\nAdvances in surgical techniques\nRobotic-assisted surgery improves precision, dexterity, \nand visualisation, making it excellent for complicated \ncases of deep spreading endometriosis [11]. It is asso -\nciated with better surgical outcomes, such as reduced \nblood loss and shorter recovery times, and more thor -\nough excision of lesions [2]. However, the high cost and \nneed for specialized training limit its availability [11]. \nOn the other hand, minimally invasive techniques like \nsingle-port laparoscopy and NOTES (natural orifice \ntransluminal endoscopic surgery) are evolving. Single-\nport laparoscopy uses a single incision, offering reduced \npostoperative pain and faster recovery but requiring \nadvanced surgical skills [8]. Although still experimen -\ntal, the need for external incisions can be eliminated by \naccessing the abdominal cavity through natural orifices \n[8]. These advancements represent the future of less inva-\nsive endometriosis surgery.\nGene and molecular therapies\nWięcek et  al. [84], acknowledged that the etiology of \nendometriosis is closely linked to irregular epigenetic \nmodifications, making it a promising area for thera -\npeutic innovation. Among these, DNA methylation and \nhistone acetylation have emerged as important targets. \nEpigenetic therapies such as histone deacetylase inhibi -\ntors (HDACis) and DNA methyltransferase inhibitors \n(DNMTis) have shown potential in preclinical stud -\nies [25]. These agents work by modulating gene expres -\nsion to inhibit the growth of endometriotic lesions and \nreduce associated pain [25]. For instance, HDACis have \ndemonstrated efficacy in preventing lesion proliferation, \nwhile DNMTis can disrupt the pathological processes \nunderpinning the disease [89]. Although these thera -\npies are still in the experimental phase, they represent a \npromising direction for novel, non-invasive treatments.\nGene editing technologies, particularly CRISPR-Cas9, \nhave further expanded the therapeutic innovations for \nendometriosis [16,  30]. CRISPR-Cas9 enables precise \ngenome modifications by targeting specific genes impli -\ncated in the inflammatory and proliferative pathways of \nthe disease [30]. For example, Chen et al., [ 16] identified \ngenes such as HOXA10 and PTEN as key regulators of \ncellular growth and inflammation in endometriosis. By \nusing CRISPR-Cas9 to selectively modify these genes, the \naim to address the root causes of endometriotic lesion \nformation. However, Taha et al. [74], noted and explains \nthat several challenges, including the need for reliable \ndelivery mechanisms such as viral vectors or lipid nano -\nparticles, hinder the clinical application of gene editing \ntechnologies. A significant hurdle is ensuring targeted \ndelivery to endometriotic tissues while avoiding systemic \neffects.\nEthical considerations are another important aspect of \nadvancing gene-based therapies. Niazi [59] explains that \nthe concerns about off-target effects, where unintended \ngenetic modifications occur, have raised safety questions. \nAdditionally, the long-term consequences of genome \nediting in humans remain poorly understood, necessitat -\ning rigorous preclinical testing and ethical oversight [30, \n59]. Beyond technical challenges, societal acceptance of \ngene editing, particularly for non-life-threatening condi -\ntions like endometriosis, may influence its adoption.\nStem cell therapies and regenerative medicine\nStem cell therapies offer promise in regenerating dam -\naged tissues. Mesenchymal stem cells (MSCs) can regu -\nlate immune system responses, decrease inflammatory \nprocesses, and promote the regeneration of tissues [42, \n53]. Stem cell-derived exosomes, containing bioactive \nmolecules, are also being explored for their therapeutic \npotential [42, 53]. Though experimental, these therapies \ncould revolutionize the treatment of endometriosis-asso -\nciated pain.\nImmunotherapy\nImmunotherapy targets the altered immune environment \nin endometriosis, characterized by pro-inflammatory \ncytokines and impaired immune surveillance [17]. Ther -\napies that modulate regulatory T cells or macrophages \nhave shown promise in preclinical studies [27]. Immune \ncheckpoint inhibitors, while groundbreaking in cancer \ntreatment, are still in early stages for endometriosis [17, \n27]. Conversely, research into endometriosis vaccines \n\nPage 8 of 14Tijani et al. Middle East Fertility Society Journal            (2025) 30:9 \naims to prevent or treat the disease by stimulating the \nimmune system identifies and removes endometrial cells \nthat have migrated beyond the uterus. [42, 52]. Early \nstudies are exploring proteins involved in cell adhesion \nand invasion as potential vaccine targets [42, 52]. While \npromising, vaccine development faces challenges in iden-\ntifying effective antigens and ensuring long-term immu -\nnity [42, 52].\nNon‑pharmacological interventions\nLifestyle modifications, including dietary changes and \nexercise, play an essential part in controlling endometri -\nosis-related pain. Mińko et al., [56], Oszajca and Adamus \n[61] suggests that eating nutrients that reduce inflamma -\ntion like omega-3 fatty acids might help alleviate symp -\ntoms, while exercise can lower stress and enhance overall \nwell-being. Mińko et al. [56] found that cognitive-behav -\nioral therapy (CBT) effectively manages chronic pain by \ntreating emotional and cognitive elements.\nNew medicines for endometriosis-related pain, such as \ninnovative pharmacological drugs, better surgical proce -\ndures, gene therapies, and immunotherapies, are excit -\ning alternatives to traditional treatments. However, many \nof these medicines are still in experimental stages, and \nmore study is needed to determine their efficacy, safety, \nand long-term effects. A multidisciplinary strategy that \nincludes pharmaceutical, surgical, and lifestyle therapies \ncustomised to individual patient needs is expected to \nshape the future of endometriosis management (Table 2).\nThis table highlights the relative efficacy, safety, cost-\neffectiveness, and accessibility of various treatments.\nComparison of current and emerging therapies\nCurrent therapies for endometriosis related pain include \nhormonal treatments, nonsteroidal nonsteroidal pain \nrelievers, and surgical techniques. Hormonal medica -\ntions, such as contraception pills, gonadotropin-releas -\ning hormone (GnRH) agonists, and progestins, focus on \ndecreasing oestrogen levels to reduce endometrial tissue \ngrowth. [75]. GnRH agonists are often effective in man -\naging moderate to severe pain [66], but prolonged use \ncan lead to adverse effects like reduced bone density and \nmood changes, limiting patient adherence [36, 43, 73]. \nWhile, emerging therapies such as selective progester -\none receptor modulators (SPRMs), GnRH antagonists, \nand aromatase inhibitors show promise with fewer side \neffects. For instance, ulipristal acetate, an SPRM, reduces \npain while minimizing estrogen-related side effects [54]. \nGnRH antagonists like elagolix offer fewer menopausal \nsymptoms and more flexible dosing [78]. However, the \nsafety of prolonged and continuous usage of these thera -\npies is not yet fully understood, warranting more clinical \ntrials and studies.\nCost-effectiveness is a critical aspect when compar -\ning therapies. Older hormonal treatments, such as oral \ncontraceptives, are generally affordable and widely \navailable, making them accessible to many patients \n[75]. However, newer treatments like SPRMs and \nGnRH antagonists are often expensive, which limits \ntheir availability, especially in low-income regions [10]. \nSurgery, particularly advanced laparoscopic techniques, \nalso comes with high costs, and the need for post-\nsurgical therapy increases the financial burden [10]. \nCost-effective analyses are essential to ensure that new \ntherapies are accessible and equitable.\nPatient commitment to treatment is crucial for \neffectiveness, yet it is frequently compromised by side \neffects. Hormonal therapy, while helpful, frequently \nproduce menopausal symptoms and lower patient \nquality of life [73]. Similarly, long-term NSAID use \ncan cause gastrointestinal problems, lowering adher -\nence [37]. Although emerging medicines with less side \neffects may increase patient adherence, the complexity \nof treatment regimens and the chronic nature of the ail -\nment remain hurdles to long-term management.\nDespite progress in treatment options, variability in \npatient response to therapies remains a significant chal -\nlenge. Endometriosis presents diverse clinical manifes -\ntations, making it difficult to predict the effectiveness \nof treatments [82, 83]. Factors such as lesion location, \npatient age, and comorbidities can all influence out -\ncomes [10], necessitating a more personalized approach \nto care. However, the development of individualized \ntreatments is limited by a lack of reliable biomark -\ners and incomplete understanding of endometriosis’ \nunderlying mechanisms [18].\nResearch limitations also hinder effective treatment. \nMany studies on endometriosis therapies are limited \nby minimal amounts of samples along with brief fol -\nlow-up periods., and inconsistent outcome measures. \nAdditionally, reliance on subjective patient-reported \noutcomes, such as pain scores, complicates the inter -\npretation of efficacy.To improve treatment outcomes, \nmore robust trials that include larger, more diverse \npopulations and objective measures are necessary.\nSocioeconomic and cultural factors further com -\nplicate treatment access. In low- and middle-income \ncountries, financial limitations and insufficient health -\ncare infrastructure restrict access to advanced therapies \n[6]. Even in wealthier nations, disparities based on race, \nsocioeconomic status, and geography exist, leading to \nunequal treatment outcomes [6 ]. Cultural stigmas sur -\nrounding menstruation and reproductive health can \ndelay diagnosis and treatment, further exacerbating \ndisparities.\n\nPage 9 of 14\nTijani et al. Middle East Fertility Society Journal            (2025) 30:9 \n \nTable 2 Comparative summary of current and emerging therapies for endometriosis-associated pain\nTherapy Type Efficacy Safety Profiles Cost‑Effectiveness Accessibility Challenges\nCurrent Therapies\nNSAIDs Effective for mild to moderate \npain relief; limited in reducing \ndisease progression [66]\nAlthough generally safe \nfor immediate usage, \nprolonged use can induce \ngastrointestinal as well as renal \ndifficulties [66]\nLow-cost but may lead \nto increased long-term costs \ndue to potential side effects \nrequiring further management \n[73]\nWidely accessible \nover the counter or by pre-\nscription [66]\nLong-term use associated \nwith risks; doesn’t address \nthe underlying cause of endo-\nmetriosis [10]\nHormonal Therapies Reduces pain and suppresses \ndisease activity; GnRH agonists \nare effective for severe cases \n[66]\nHormonal negative con-\nsequences include mood \nchanges, weight gain, \nand reduced bone density. [73]\nModerate cost: repeated \nprescriptions or long-term \ntreatment required, increasing \noverall cost [73]\nWidely accessible in most \nhealthcare settings, \nthough GnRH agonists may \nrequire specialized prescrip-\ntion [66]\nDoes not provide a permanent \ncure; side effects often limit \nlong-term use [36]\nSurgical Interventions Laparoscopy is effective \nin removing lesions and provid-\ning long-term pain relief [77]\nRisks include infection, scar-\nring, and potential recurrence \nof endometriosis [10]\nHigh upfront costs due to sur-\ngical procedures, though cost-\neffective in the long term \nfor some patients [10]\nAccessible in regions \nwith advanced healthcare \nfacilities but requires special-\nized expertise [77]\nRisk of recurrence, high costs, \nand potential complications \nfrom surgery [21]\nOpioid Analgesics Effective for short-term pain \nrelief but not a long-term solu-\ntion [47, 48]\nHigh risk of addiction, toler-\nance, and opioid-related side \neffects [47, 48]\nCan be costly over time, \nparticularly due to the need \nfor careful management of side \neffects [57]\nAccessible, but there is increas-\ning regulation due to the opi-\noid crisis [47, 48]\nHigh potential for addiction, \ntolerance, and societal concerns \nregarding opioid overuse [47, 48]\nEmerging Therapies\nSelective Progesterone Recep-\ntor Modulators (SPRMs)\nPromising in clinical trials \nwith efficacy in reducing lesion \nsize and associated pain [65]\nEarly evidence suggests fewer \nside effects than traditional hor-\nmonal therapies, though more \ndata is needed [65]\nCost-effectiveness not yet fully \nestablished due to the emerg-\ning nature of the treatment \n[70]\nLimited accessibility as it is still \nin experimental stages or early \nclinical use [70])\nLong-term effects and safety \nare still unknown; further trials \nneeded [54]\nGnRH Antagonists Provides rapid pain relief \nlike agonists but without the \ninitial hormonal flare associated \nwith agonists [54]\nPotential side effects include \nheadache, hot flashes, \nand mood changes [36]\nHigh cost due to the novel \nnature of the drug and need \nfor repeated administration \n[43]\nCurrently available in certain \nregions but less accessible due \nto cost and regulatory approv-\nals [29]\nStill expensive, with potential \nside effects requiring careful \npatient monitoring [29]\nAromatase Inhibitors Reduces estrogen levels, show-\ning promise in managing pain \nand reducing lesion size [34]\nRisks include bone loss \nand increased fracture risk [34]\nModerate to high cost, espe-\ncially considering potential \nlong-term side effects that may \nrequire further treatment [34]\nLimited availability due to its \noff-label use in endome-\ntriosis, more commonly used \nfor breast cancer [34]\nOff-label usage in endometriosis; \nsafety concerns, particularly \nwith long-term use, and higher \ncost compared to other thera-\npies [34]\nStem Cell Therapies Early studies show poten-\ntial in tissue regeneration \nand reducing inflammation \nassociated with endometriosis \n[42, 53]\nStill experimental; long-term \nsafety and efficacy data are \nlacking [42, 53]\nCurrently very expensive due \nto its novel and experimental \nnature [42, 53]\nExtremely limited accessibil-\nity; available only in research \nsettings or specialized clinics \n[42, 53]\nExperimental nature means \nunknown risks, high costs, \nand limited accessibility [42, 53]\nImmunotherapy Promising in targeting immune \nsystem dysfunction that may \ncontribute to endometriosis \npathology [27]\nStill in the early stages \nof research, safety profiles \nremain unclear [27]\nVery high cost due to experi-\nmental and targeted nature \nof treatments [42]\nCurrently only available in clini-\ncal trials or highly specialized \ncenters [42]\nUnknown long-term effects, \nhigh costs, and accessibility \nlimitations [52]\n\nPage 10 of 14Tijani et al. Middle East Fertility Society Journal            (2025) 30:9 \nTable 2 (continued)\nTherapy Type Efficacy Safety Profiles Cost‑Effectiveness Accessibility Challenges\nGene and Molecular Therapies Potential to correct underlying \ngenetic and molecular drivers \nof endometriosis [82, 83]\nEarly-stage research; unknown \nsafety risks and ethical con-\ncerns [82, 83]\nLikely to be expensive due \nto complexity and cutting-\nedge nature [16]\nLimited to experimental \nor clinical trial settings [30]\nHigh cost, ethical concerns \nand unknown long-term effects \n[30]\n\nPage 11 of 14\nTijani et al. Middle East Fertility Society Journal            (2025) 30:9 \n \nFuture directions\nAs the understanding of endometriosis continues to \nevolve, there are several critical areas where further \nresearch and innovation are needed.\nOne of the major gaps in current endometriosis \nresearch is the lack in long-term studies that can pro -\nvide real-world evidence on the effectiveness and safety \nof various treatments. Many existing studies are short-\nterm and have limited sample sizes, which limits their \ngeneralisability. Additionally, there is a need for greater \ndepth research into the fundamental mechanisms of \nendometriosis, particularly in areas like immunology, \ngenetics, and the role of environmental factors.\nPersonalised medicine represents a possible route for \nenhancing endometriosis treatment outcomes. Identi -\nfying and confirming biomarkers could open the door \nfor more focused medications, allowing physicians to \nadapt treatments to specific patient profiles. This tech -\nnique may reduce variability in treatment responses \nand lead to more effective pain management strategies.\nFuture advances in endometriosis pain management \nmay result from the combination of different tech -\nniques. This could involve using new pharmaceutical \nmedicines, sophisticated surgical procedures, and com -\nplementary therapies such as acupuncture and physical \ntherapy. Combining these treatments could result in \nmore comprehensive and long-term pain alleviation.\nThe development of combination therapies, which \nuse numerous treatment modalities at the same time, \nhas the potential to address endometriosis’ complex \ncharacter. Emerging research disciplines, such as epi -\ngenetics and microbiome, have the potential to provide \nnew insights and therapeutic methods. Understanding \nhow genetic and microbiological factors drive endo -\nmetriosis may help researchers identify new therapy \noptions.\nConclusion\nThe present and developing treatments for pain related \nto endometriosis have been reviewed, with an emphasis \non the advantages and disadvantages of each strategy. \nPharmacological treatments, such as hormone therapy, \nNSAIDs, and analgesics, continue to be the mainstays; \nnevertheless, their efficacy is frequently hampered \nby side effects, insufficient symptom alleviation, and \ninconsistent patient responses. Though they can sig -\nnificantly reduce discomfort, surgical techniques like \nlaparoscopy and more complex ones like peritonectomy \ncome with hazards, such as complications and variable \nlong-term effectiveness. While new pharmacological \ndrugs, gene and molecular therapies, and sophisticated \nsurgical methods are examples of emerging medicines, \nthey still mostly involve experimentation and need to \nbe rigorously validated.\nThe results highlight the significance of treating endo -\nmetriosis-related pain using a customised, interdisci -\nplinary strategy. To meet the demands of each patient, \ndoctors should customise treatment regimens by com -\nbining pharmacological, surgical, and complementary \ntherapy. Emerging medicines should be approached \ncautiously, therefore, taking into account both their \npotential advantages and the dearth of comprehensive \nclinical evidence currently indicating their widespread \napplication. Furthermore, since they are essential to \ndelivering holistic care, the psychological and social \neffects of endometriosis cannot be disregarded.\nDespite progress, there are still many obstacles to \novercome in the treatment of pain related to endome -\ntriosis. In order to evaluate the safety, effectiveness, \nand cost-efficiency of both established and novel treat -\nments, future research should concentrate on carrying \nout long-term, practical trials. Therapeutic results may \nbe improved by looking into how biomarkers and per -\nsonalised medicine might predict treatment response. \nFurthermore, knowing the immunological, epigenetic, \nand genetic processes that underlie endometriosis may \nhelp develop more specialised and efficient therapies.\nAbbreviations\nNSAIDs  Nonsteroidal Anti-inflammatory Drugs\nEAP  Endometriosis-Associated Pain\nCOX  Cyclooxygenase\nOCs  Oral Contraceptives\nGnRH  Gonadotropin-Releasing Hormone\nSPRMs  Selective Progesterone Receptor Modulators\nESGE  European Society for Gynaecological Endoscopy\nCDC  Centers for Disease Control and Prevention\nIVF  In Vitro Fertilization\nSPRMs  Selective Progesterone Receptor Modulators\nGnRH  Gonadotropin-Releasing Hormone\nTHC  Tetrahydrocannabinol\nCBD  Cannabidiol\nVEGF  Vascular Endothelial Growth Factor\nAcknowledgements\nNone.\nAuthors’ contributions\nA.F.A. conceptualized and outlined the review. O.S.T. prepared the materials. \nE.O.T. and L.O.A. drafted the manuscript’s first version. O.P .A. and A.F.A. edited \nthe work. All authors reviewed and approved the final manuscript.\nFunding\nNo funding.\nData availability\nNo datasets were generated or analysed during the current study.\nDeclarations\nEthics approval and consent to participate\nNot applicable.\n\nPage 12 of 14Tijani et al. Middle East Fertility Society Journal            (2025) 30:9 \nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare no competing interests.\nAuthor details\n1 Anchor Biomed Research Institute, Ogbomoso, Oyo State, Nigeria. 2 Depart-\nment of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, \nOyo State, Nigeria. 3 Department of Physiology, School of Basic Medical \nSciences, Babcock University, Ilishan Remo, Ogun State, Nigeria. 4 Department \nof Physiology, Ladoke Akintola University of Technology, PMB 4000, Ogbo-\nmoso, Oyo State, Nigeria. 5 Department of Physiology, Adeleke University, Ede, \nOsun State, Nigeria. \nReceived: 18 October 2024   Accepted: 4 April 2025\nReferences\n 1. Ács N, O’Brien C, Jiang P , Burke J, Jimenez R, Garner E, Chwalisz K (2015) \nTreatment of endometriosis-associated pain with elagolix, an oral GnRH \nantagonist: results from a phase 2, randomized controlled study. 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