Current and emerging therapies for endometriosis-associated pain: a review

Background Endometriosis is a severe gynaecological disease marked by the formation of endometrial-like growth beyond the uterus, which causes severe pelvic pain, infertility, and a reduced standard of life. Despite the progress that has been made in understanding its aetiology, the treatment remains difficult due to the disease’s complicated structure and diversity in different patient responses. Main body. This narrative review examines both present and emerging therapeutics for endometriosis-related pain, focusing on pharmaceutical, surgical, and complementary treatment options. Current pharmacological treatments, such as nonsteroidal anti-inflammatory medications (NSAIDs), hormone therapy, and analgesics, provide symptom alle- viation but are frequently limited due to side effects and long-term effectiveness issues. Surgical procedures, such as laparoscopy and nerve ablation, provide alternatives, although recurrence rates remain high. Additionally, complementary therapies such as acupuncture and physical therapy are gaining recognition for their role in pain management. The review also explores emerging therapies, including novel pharmacological approaches like selective progesterone receptor modulators (SPRMs), aromatase inhibitors, and gene-based therapies. Advances in minimally invasive surgical techniques and regenerative medicine, such as stem cell therapies, are also discussed.

An essential comparison of these methods of therapy highlights the need for personalised approaches and further research to address variation of the disease. The review concludes with recommendations for subse- quent studies, emphasising the need for long-term studies, real-world data, and innovations in pain management that integrate multifaceted therapies. This analysis aims to provide healthcare providers with a clearer understanding of the changing landscape of endometriosis treatment.

Endometriosis, Pain management, Pharmaceutical therapies, Deep infiltrating endometriosis, Surgical treatments, Complementary therapies *Correspondence: Ayodeji Folorunsho Ajayi [email protected] Full list of author information is available at the end of the article Page 2 of 14Tijani et al. Middle East Fertility Society Journal (2025) 30:9

Background on endometriosis Endometriosis is described by Chauhan et  al., [15], as a chronic gynecological disorder marked by the formation of endometrial-like growth beyond the uterus, resulting in symptoms that include pain in the pelvis, dysmenor - rhea, dyspareunia, and, in severe cases, fertility problems. This disorder, which affects 10% of women of reproduc - tive age worldwide, is a leading cause of death and can significantly reduce women’s standard of living [68]. Endometriosis results from a mix of hereditary, immuno- logical, and environmental factors [15]. Despite existing substantial research, the pathophysiology of endometrio - sis remains incompletely understood, making it a difficult condition to adequately manage. Pathophysiology of endometriosis‑associated pain Maddern et  al., [51], documented that one of the most debilitating aspects of endometriosis is the persis - tent discomfort and pain  associated with the disease. Endometriosis-associated pain (EAP) is primarily due to the endometrium lesions which trigger a response of inflammation, leading to the release of prostaglandins, cytokines, and other inflammatory mediators [47, 48, 51]. This inflammatory environment not only causes direct irritation of the pelvic organs and surrounding tissues, but it also sensitizes the peripheral and central nervous systems, resulting in enhanced pain perception and, in certain circumstances, the development of syndromes of persistent pain [15, 47, 48, 51] (Fig. 1). The prevalence of EAP is alarmingly high among women with endometriosis. Falcone and Flyckt [32], reported that about 70% to 90% of females with endometriosis suffer from persistent pain in their pel - vis, which can persist even after surgical intervention or medical treatment. The pain associated with endometrio- sis is often cyclical [67], worsening during menstruation, but many women also report non-cyclical pain that can be continuous and severe, affecting daily activities and overall well-being [26, 32]. The chronic pain experienced by women with endo - metriosis has quite a lot of implications for their qual - ity of life. Physical, emotional, and social aspects of life are often compromised, with many women reporting feelings of frustration, despair, and anxiety as a result of their chronic discomfort and pain [51, 67]. The impact on sexual function is also significant, with dyspareunia being a common complaint [49], leading to difficulties in inti - mate relationships and a decreased quality of life. Significance and objectives Managing pain caused by endometriosis remains a signif- icant challenge due to the variability of the condition and the limitations of current treatment options. While the primary goal of treatment is to alleviate pain, preserve fertility, and prevent disease recurrence, many available therapies offer only partial relief and are associated with significant side effects. Given these limitations, there is a pressing need to explore new and emerging approaches that may provide more effective and long-term pain relief for women with endometriosis. This narrative review aims to provide a comprehen - sive assessment of both established and developing treatments for endometriosis-related pain, emphasizing their potential benefits and limitations. By examining pharmacological and non-pharmacological approaches, Fig. 1 The primary factors involved in the pathophysiology of endometriosis-associated pain Page 3 of 14 Tijani et al. Middle East Fertility Society Journal (2025) 30:9 including surgical procedures, alternative therapies, and lifestyle changes, this review seeks to identify the strengths and weaknesses of current treatments and the potential of future therapies to address unmet needs in managing pain caused by endometriosis. Key questions to be addressed include: the effective - ness of current therapies, their limitations and side effects, emerging therapy options, potential challenges to implementation, and directions for future research and clinical practice. By answering these questions, this review aims to be a valuable resource for healthcare pro - viders, researchers, and patients seeking to understand the evolving landscape of endometriosis treatment. Search method An extensive search was undertaken through numer - ous academic search engines, including Scopus, Pub Med, and Google Scholar, to gather relevant literature on current and emerging therapies for endometriosis- associated pain. The search terms used were "endometri - osis-associated pain," "treatment," "therapy," "emerging therapies," “deep infiltrating endometriosis” , and "pain management." Boolean operators were applied to refine the search, combining terms such as " AND" and "OR" to include studies focused on both pharmacological and non-phar - macological treatments. Research studies were selected for inclusion if they were published in English, peer-reviewed, and provided useful information about endometriosis-related pain treatment techniques. To ensure that the most current advances were included, the review focused on articles published within the last decade. Conditions for exclu - sion included research that did not specifically address endometriosis-related pain, case reports, and non-peer- reviewed literature. The data from the selected studies were combined using a narrative technique, to summarize and interpret the findings in light of the study’s existing understanding. Main body Current therapies for endometriosis‑associated pain Pharmacological treatments Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely regarded as the first-line therapy for endome - triosis-associated pain, primarily because they inhibit cyclooxygenase (COX) enzymes (COX-1 and COX-2), which are essential in the production of prostaglandins, a key contributor to pain and inflammation [50, 76]. Machairiotis et  al. [50], emphasize that reducing pros - taglandin synthesis effectively mitigates the pain caused by the inflammatory reaction due to endometrial lesions. However, Smith [72] noted that despite the efficacy of NSAIDs in alleviating menstrual pain, their utility is less impressive in managing chronic pelvic pain. There are also concerns about the side effects of NSAIDs, which include gastrointestinal discomfort, ulcers, and increased cardiovascular risks with prolonged use [37] (Table 1). Hormonal therapies are another avenue for manag - ing endometriosis-associated pain, with oral contracep - tives (OCs) being one of the most commonly prescribed options. OCs suppress ovulation and regulate estrogen levels, which reduces the cyclical changes that trigger endometrial tissue growth [75]. However, Ciarcia and Huckins [19] established that the effectiveness of OCs is limited to their duration of use, and symptoms frequently return upon discontinuation. Szubert et  al. [73], further argue that OCs may not work well for patients with deep infiltrating endometriosis and could lead to side effects like weight gain, mood changes, and an increased risk of thromboembolism, which limits their utility in long-term management. Gonadotropin-releasing hormone (GnRH) agonists and antagonists offer another class of hormonal therapy. These medications work by suppressing estrogen pro - duction, a hormone crucial for the proliferation of endo - metrial lesions [66]. Zhang et al. [88], explain that while GnRH agonists first generate a preliminary boost in lute - inizing hormone (LH) and follicle-stimulating hormone (FSH) before downregulating GnRH receptors, GnRH antagonists directly inhibit these receptors, thus reducing estrogen production immediately. Despite the positive outcomes observed with GnRH therapies, these treat - ments induce hypoestrogenic states, leading to meno - pausal signs, which include flashes of heat, dryness of the vagina, and diminished density of the bones [36, 43]. These side effects often necessitate add-back treatments include providing low amounts of oestrogen or progestin [43]. However, add-back therapy may reduce the effec - tiveness of GnRH therapy [29]. Progestins, synthetic hormones that mimic progester - one, are widely used to induce atrophy in endometrial lesions and alleviate associated pain [65]. Dienogest, for instance, has gained traction due to its favorable side effect profile and its ability to reduce pain more effec - tively than other progestins [22]. Nevertheless, Reis et al. [65], stated that progestins can lead to side effects like breakthrough bleeding, weight gain, and mood changes. Some women also experience recurrence of symptoms after discontinuation of therapy [82, 83]. For patients experiencing severe pain that is not ade - quately controlled by NSAIDs or hormonal therapies, analgesics, opioids, may be prescribed. Opioids act on the central nervous system to alter pain perception, pro - viding relief for more intense pain [4]. However, opioids are controversial in treating endometriosis-associated Page 4 of 14Tijani et al. Middle East Fertility Society Journal (2025) 30:9 Table 1 A comparative overview of the most used treatment modalities for managing endometriosis-associated pain Treatment Modality Subcategory Mechanism of Action Effectiveness Limitations Cost‑Effectiveness Pharmacological NSAIDs [50, 76] Inhibit COX enzymes to reduce inflammation; [76] Moderately effective in pain relief [50] Limited efficacy for chronic pain [37] It has a low cost and is suitable for short-term use [7] Oral Contraceptives [75] Suppress ovulation and stabi- lize hormone levels [75] Effective in managing mild cases [19] May not be sufficient for severe cases [73] Affordable and widely accessible; cost-effective for long-term management of mild cases [83] GnRH Agonists and Antago- nists Reduce the production of oestrogen by suppressing the pituitary gland. Zhang et al., [88] Beneficial in lowering pain [66] It can cause menopausal symptoms with long-term use [36, 43] Expensive but highly effective for short-term relief; less sustain- able for extended use [83] Progestins [65] Inhibit the growth of endo- metrial tissue by modifying hormonal balance [22] Effective pain management [65] Risk of irregular bleeding, weight gain [82, 83] Moderately priced; and cost- effective for chronic cases [24] Opioids [4] Bind to brain opioid receptors to inhibit pain signals [4] Effective for short-term use [4] High potential for addiction and tolerance [12] High cost with significant risks; limited cost-effectiveness for long-term pain relief [86] Surgical Laparoscopy [40] Minimally invasive removal of endometrial lesions [77] Effective symptom relief [31] High recurrence rates, require skilled surgeons [21] High upfront cost; cost-effective if performed by experienced surgeons [71] Laparotomy [85] Open surgery to remove large or deep endometrial lesions [85] Effective for extensive endo- metriosis [85] Longer recovery time, more invasive [87] Expensive with prolonged recovery costs; less favorable compared to laparoscopy [71] Nerve Ablation and Resection [60] Surgical destruction of nerves responsible for transmitting pain [60] Some success in reducing pain [60] Effectiveness varies, not widely practiced [81] Moderate cost: effectiveness varies [55], making sustainability uncertain Complementary and Alterna- tive Acupuncture [47, 48] Stimulates nerves and muscles to promote natural pain relief [47, 48] Some evidence of effective- ness Mira et al., [57] Lack of large-scale clinical trials Mira et al., [57] Moderate per-session cost; effec- tiveness varies [86], impacting cost-effectiveness Dietary Interventions/Herbal Supplements [80] Anti-inflammatory diets to reduce systemic inflamma- tion [61] Limited but emerging evi- dence [80] Lack of regulation in sup- plements, variable patient response [80] Low to moderate cost; effec- tiveness depends on patient adherence and supplement quality [39] Physical Therapy [23] Targeted exercises to strengthen pelvic muscles and reduce pain [23] Effective in improving mobility [23] Requires patient adherence to be effective [23] Moderate cost with high long-term value for compliant patients [3] Page 5 of 14 Tijani et al. Middle East Fertility Society Journal (2025) 30:9 pain because of the risks of dependence, tolerance, and side effects such as constipation and nausea [12]. Long- term use of opioids is not recommended for chronic pain, given the high addiction potential and lack of evidence supporting their effectiveness in chronic conditions. Preuss et al. [64], suggest that alternatives like tramadol might be useful for moderate to severe pain, although these too are loaded with restrictions and potential hazards. Surgical interventions for endometriosis‑associated pain Surgical interventions are often reserved for cases where pharmacological treatments fail to provide sufficient relief from endometriosis-associated pain [40]. Taylor et al. [77], stated that laparoscopy is the standard of excel- lence for identifying and managing endometriosis. Endo - metrial abnormalities, adhesions, and ovarian cysts are all removed with this minimally invasive surgery. Evans et al. [31], noted that laparoscopy has generally positive outcomes, with many women experiencing significant pain relief following the procedure. However, recurrence rates remain a concern, with Conroy et al., [21], reporting that within the first five years of surgery, up to half of all women report symptom recurrence. Laparotomy, a more invasive open surgical procedure, is reserved for more severe cases, such as those with extensive disease or large endometriomas [85]. While surgical management offers relief, its comparative effec - tiveness to medical management remains debated [40, 82, 83, 87] suggest that combining surgery with postopera - tive hormonal therapy may provide the best results. This combined approach appears to address both the physi - cal removal of endometrial tissue and the suppression of hormonal triggers that cause lesion growth. Another surgical technique, nerve ablation, focuses on interrupting the neural pathways responsible for transmitting pain signals from the pelvic region to the brain [60]. Ugurlucan and Yasa [81], discuss procedures like presacral neurectomy and laparoscopic uterosacral nerve ablation (LUNA), which have shown some success in reducing pain. However, the evidence is mixed, with complications such as urinary dysfunction, constipation, and pelvic organ prolapse being reported in some cases [81, 87]. Complementary and alternative therapies for endometriosis‑associated pain Complementary therapies are becoming recognised as complements to conventional treatments for controlling the pain associated with endometriosis. Acupuncture, a traditional Chinese medicine technique [47, 48], is one such therapy that has gained attention. It is believed to work by stimulating specific points on the body to release endogenous opioids and modulate neurotransmitters like serotonin and dopamine [47, 48]. Mira et  al. [57], con - ducted a systematic review and found that acupuncture was comparable to conventional medical treatments in pain relief, with fewer side effects. However, the evidence supporting acupuncture remains inconclusive, and more randomized controlled trials are needed to verify its efficacy. Dietary interventions and herbal supplements are also being explored as adjunctive therapies for manag - ing endometriosis. The theory is that diet and nutrition can modulate inflammation, which plays a critical role in endometriosis-associated pain [80]. Oszajca and Ada - mus [ 61], propose that anti-inflammatory diets rich in omega-3 fatty acids, antioxidants, and phytoestrogens may reduce inflammation and alleviate pain. Herbal sup - plements like curcumin, resveratrol, and pycnogenol have also been studied for their anti-inflammatory properties. Clower, et al. [20], reported that curcumin supplementa - tion can reduce endometriosis-related pain and inflam - matory markers, but these findings should be approached with caution due to limited evidence and potential inter - actions with conventional treatments. Physical therapy, particularly pelvic floor therapy, is another promising complementary approach. Pelvic floor therapy aims to improve the function of pelvic muscles, which may become tense or dysfunctional in women with endometriosis [23]. Techniques include muscle relaxation, biofeedback, and manual therapy to alleviate spasms and improve pelvic alignment [38]. da Silva et al. [23], found that pelvic floor physical therapy substantially decreased discomfort and enhanced their standard of life in people with endometriosis. The therapy is especially beneficial for addressing urinary and bowel dysfunction, a frequent concurrent medical condition in women with endometriosis [62]. Although pelvic floor therapy offers long-term benefits, da Silva et al. [23], also noted that the effectiveness varies based on individual symptoms and therapist expertise. Deep Infiltrating Endometriosis (DIE) Diniz et  al. [28], explain deep infiltrating endometrio - sis as one of the most severe forms of endometriosis, characterized by lesions that penetrate more than 5 mm beneath the peritoneal surface, often involving organs such as the bowel, bladder, and ureters. DIE is a sig - nificant contributor to chronic pelvic pain, dysmenor - rhea, and dyspareunia, with pain often being refractory to standard pharmacological treatments [5, 82, 83]. The complexity and severity of DIE necessitate specialized therapeutic approaches, particularly surgical interven - tions, to address its profound impact on quality of life [28]. Page 6 of 14Tijani et al. Middle East Fertility Society Journal (2025) 30:9 Chamié et  al. [13], document that surgical manage - ment is considered the cornerstone of DIE treatment due to the limited efficacy of medical therapies in resolving deeply infiltrating lesions. Techniques such as excision of endometriotic lesions, bowel resections, and ureterolysis have been commonly employed to alleviate symptoms and restore organ function [13]. However, Perrone et al. [63], note that recurrence rates remain high, showing the need for more advanced sur - gical techniques. Also, Peritonectomy as explained by Brown and Koh [9] as a procedure involving the removal of affected peri - toneal tissue, is an emerging trend in the radical surgi - cal treatment of DIE. By targeting the complete excision of visible and microscopic lesions, peritonectomy has shown promise in reducing pain and improving fertil - ity outcomes in selected patients [9]. Patient selection is critical for peritonectomy and other advanced surgi - cal options for DIE [14]. Candidates are typically those with severe symptoms unresponsive to other treatments, extensive disease involving critical organs, or infertility linked to DIE. However, these procedures are technically demand - ing, requiring highly skilled surgeons with expertise in minimally invasive and radical techniques [9]. Risks associated with peritonectomy include prolonged opera - tive times, higher likelihood of postoperative complica - tions such as bowel perforation or infection, and a longer recovery period compared to standard laparoscopy [41, 45]. These risks must be carefully balanced against the potential benefits when considering surgical options for DIE. Emerging therapies for endometriosis‑associated pain Novel pharmacological approaches Selective Progesterone Receptor Modulators (SPRMs), SPRMs offer a unique mechanism by modulating pro - gesterone receptors, targeting tissue growth and inflam - mation [65]. Unlike traditional progestins, SPRMs act as both agonists and antagonists [65]. Ulipristal acetate, originally for emergency contraception, has been promis- ing in reducing endometriosis-associated pain by inhib - iting cell proliferation and reducing inflammation [54]. Clinical trials show SPRMs are effective in managing pain and controlling lesions, but safety concerns about endo - metrial hyperplasia require further study [54, 70]. Also, Aromatase inhibitors, traditionally used in breast cancer treatment, are developing as an endometriosis treatment due to their ability to reduce local estrogen production [34]. Unusual expression of aromatase contributes to dis- ease development, and blocking this enzyme can lead to pain alleviation [34]. Tosti et al. [79], demonstrated that clinical studies show positive outcomes, especially when combined with hormonal therapies like progestins. How- ever, [34] stated that it has side effects such as bone loss limit long-term use (Fig. 2). Gonadotropin-releasing hormone (GnRH) antago - nists, such as elagolix, provide a more rapid reduction of oestrogen than GnRH agonists, effectively reducing Fig. 2 Emerging therapies for endometriosis-associated pain Page 7 of 14 Tijani et al. Middle East Fertility Society Journal (2025) 30:9 pain with fewer hypoestrogogenic effects [46, 78]. Oral formulations offer a convenient alternative to injections [46], but concerns about bone health remain [1]. Simi - larly, anti-angiogenic therapies target the vascularization of endometriotic lesions, which are dependent on new blood vessel formation for growth [44]. Bevacizumab, an anti-VEGF antibody, has shown promise in reduc - ing lesion size and pain in early trials [33]. While clinical application is still in its infancy, anti-angiogenic agents may become valuable for cases resistant to conventional therapies. Cannabinoids, particularly tetrahydrocannabinol (THC) and cannabidiol (CBD), have gained attention as potential treatments for chronic pain, including endome- triosis-associated pain [35, 58]. Preclinical studies dem - onstrate cannabinoids can reduce pain and inflammation in animal models [58]. Although clinical data is limited, cannabinoids offer potential for patients unresponsive to standard therapies. However, legal challenges and the need for rigorous trials are obstacles to widespread use [69]. Advances in surgical techniques Robotic-assisted surgery improves precision, dexterity, and visualisation, making it excellent for complicated cases of deep spreading endometriosis [11]. It is asso - ciated with better surgical outcomes, such as reduced blood loss and shorter recovery times, and more thor - ough excision of lesions [2]. However, the high cost and need for specialized training limit its availability [11]. On the other hand, minimally invasive techniques like single-port laparoscopy and NOTES (natural orifice transluminal endoscopic surgery) are evolving. Single- port laparoscopy uses a single incision, offering reduced postoperative pain and faster recovery but requiring advanced surgical skills [8]. Although still experimen - tal, the need for external incisions can be eliminated by accessing the abdominal cavity through natural orifices [8]. These advancements represent the future of less inva- sive endometriosis surgery. Gene and molecular therapies Więcek et  al. [84], acknowledged that the etiology of endometriosis is closely linked to irregular epigenetic modifications, making it a promising area for thera - peutic innovation. Among these, DNA methylation and histone acetylation have emerged as important targets. Epigenetic therapies such as histone deacetylase inhibi - tors (HDACis) and DNA methyltransferase inhibitors (DNMTis) have shown potential in preclinical stud - ies [25]. These agents work by modulating gene expres - sion to inhibit the growth of endometriotic lesions and reduce associated pain [25]. For instance, HDACis have demonstrated efficacy in preventing lesion proliferation, while DNMTis can disrupt the pathological processes underpinning the disease [89]. Although these thera - pies are still in the experimental phase, they represent a promising direction for novel, non-invasive treatments. Gene editing technologies, particularly CRISPR-Cas9, have further expanded the therapeutic innovations for endometriosis [16,  30]. CRISPR-Cas9 enables precise genome modifications by targeting specific genes impli - cated in the inflammatory and proliferative pathways of the disease [30]. For example, Chen et al., [ 16] identified genes such as HOXA10 and PTEN as key regulators of cellular growth and inflammation in endometriosis. By using CRISPR-Cas9 to selectively modify these genes, the aim to address the root causes of endometriotic lesion formation. However, Taha et al. [74], noted and explains that several challenges, including the need for reliable delivery mechanisms such as viral vectors or lipid nano - particles, hinder the clinical application of gene editing technologies. A significant hurdle is ensuring targeted delivery to endometriotic tissues while avoiding systemic effects. Ethical considerations are another important aspect of advancing gene-based therapies. Niazi [59] explains that the concerns about off-target effects, where unintended genetic modifications occur, have raised safety questions. Additionally, the long-term consequences of genome editing in humans remain poorly understood, necessitat - ing rigorous preclinical testing and ethical oversight [30, 59]. Beyond technical challenges, societal acceptance of gene editing, particularly for non-life-threatening condi - tions like endometriosis, may influence its adoption. Stem cell therapies and regenerative medicine Stem cell therapies offer promise in regenerating dam - aged tissues. Mesenchymal stem cells (MSCs) can regu - late immune system responses, decrease inflammatory processes, and promote the regeneration of tissues [42, 53]. Stem cell-derived exosomes, containing bioactive molecules, are also being explored for their therapeutic potential [42, 53]. Though experimental, these therapies could revolutionize the treatment of endometriosis-asso - ciated pain. Immunotherapy Immunotherapy targets the altered immune environment in endometriosis, characterized by pro-inflammatory cytokines and impaired immune surveillance [17]. Ther - apies that modulate regulatory T cells or macrophages have shown promise in preclinical studies [27]. Immune checkpoint inhibitors, while groundbreaking in cancer treatment, are still in early stages for endometriosis [17, 27]. Conversely, research into endometriosis vaccines Page 8 of 14Tijani et al. Middle East Fertility Society Journal (2025) 30:9 aims to prevent or treat the disease by stimulating the immune system identifies and removes endometrial cells that have migrated beyond the uterus. [42, 52]. Early studies are exploring proteins involved in cell adhesion and invasion as potential vaccine targets [42, 52]. While promising, vaccine development faces challenges in iden- tifying effective antigens and ensuring long-term immu - nity [42, 52]. Non‑pharmacological interventions Lifestyle modifications, including dietary changes and exercise, play an essential part in controlling endometri - osis-related pain. Mińko et al., [56], Oszajca and Adamus [61] suggests that eating nutrients that reduce inflamma - tion like omega-3 fatty acids might help alleviate symp - toms, while exercise can lower stress and enhance overall well-being. Mińko et al. [56] found that cognitive-behav - ioral therapy (CBT) effectively manages chronic pain by treating emotional and cognitive elements. New medicines for endometriosis-related pain, such as innovative pharmacological drugs, better surgical proce - dures, gene therapies, and immunotherapies, are excit - ing alternatives to traditional treatments. However, many of these medicines are still in experimental stages, and more study is needed to determine their efficacy, safety, and long-term effects. A multidisciplinary strategy that includes pharmaceutical, surgical, and lifestyle therapies customised to individual patient needs is expected to shape the future of endometriosis management (Table 2). This table highlights the relative efficacy, safety, cost- effectiveness, and accessibility of various treatments. Comparison of current and emerging therapies Current therapies for endometriosis related pain include hormonal treatments, nonsteroidal nonsteroidal pain relievers, and surgical techniques. Hormonal medica - tions, such as contraception pills, gonadotropin-releas - ing hormone (GnRH) agonists, and progestins, focus on decreasing oestrogen levels to reduce endometrial tissue growth. [75]. GnRH agonists are often effective in man - aging moderate to severe pain [66], but prolonged use can lead to adverse effects like reduced bone density and mood changes, limiting patient adherence [36, 43, 73]. While, emerging therapies such as selective progester - one receptor modulators (SPRMs), GnRH antagonists, and aromatase inhibitors show promise with fewer side effects. For instance, ulipristal acetate, an SPRM, reduces pain while minimizing estrogen-related side effects [54]. GnRH antagonists like elagolix offer fewer menopausal symptoms and more flexible dosing [78]. However, the safety of prolonged and continuous usage of these thera - pies is not yet fully understood, warranting more clinical trials and studies. Cost-effectiveness is a critical aspect when compar - ing therapies. Older hormonal treatments, such as oral contraceptives, are generally affordable and widely available, making them accessible to many patients [75]. However, newer treatments like SPRMs and GnRH antagonists are often expensive, which limits their availability, especially in low-income regions [10]. Surgery, particularly advanced laparoscopic techniques, also comes with high costs, and the need for post- surgical therapy increases the financial burden [10]. Cost-effective analyses are essential to ensure that new therapies are accessible and equitable. Patient commitment to treatment is crucial for effectiveness, yet it is frequently compromised by side effects. Hormonal therapy, while helpful, frequently produce menopausal symptoms and lower patient quality of life [73]. Similarly, long-term NSAID use can cause gastrointestinal problems, lowering adher - ence [37]. Although emerging medicines with less side effects may increase patient adherence, the complexity of treatment regimens and the chronic nature of the ail - ment remain hurdles to long-term management. Despite progress in treatment options, variability in patient response to therapies remains a significant chal - lenge. Endometriosis presents diverse clinical manifes - tations, making it difficult to predict the effectiveness of treatments [82, 83]. Factors such as lesion location, patient age, and comorbidities can all influence out - comes [10], necessitating a more personalized approach to care. However, the development of individualized treatments is limited by a lack of reliable biomark - ers and incomplete understanding of endometriosis’ underlying mechanisms [18]. Research limitations also hinder effective treatment. Many studies on endometriosis therapies are limited by minimal amounts of samples along with brief fol - low-up periods., and inconsistent outcome measures. Additionally, reliance on subjective patient-reported outcomes, such as pain scores, complicates the inter - pretation of efficacy.To improve treatment outcomes, more robust trials that include larger, more diverse populations and objective measures are necessary. Socioeconomic and cultural factors further com - plicate treatment access. In low- and middle-income countries, financial limitations and insufficient health - care infrastructure restrict access to advanced therapies [6]. Even in wealthier nations, disparities based on race, socioeconomic status, and geography exist, leading to unequal treatment outcomes [6 ]. Cultural stigmas sur - rounding menstruation and reproductive health can delay diagnosis and treatment, further exacerbating disparities. Page 9 of 14 Tijani et al. Middle East Fertility Society Journal (2025) 30:9 Table 2 Comparative summary of current and emerging therapies for endometriosis-associated pain Therapy Type Efficacy Safety Profiles Cost‑Effectiveness Accessibility Challenges Current Therapies NSAIDs Effective for mild to moderate pain relief; limited in reducing disease progression [66] Although generally safe for immediate usage, prolonged use can induce gastrointestinal as well as renal difficulties [66] Low-cost but may lead to increased long-term costs due to potential side effects requiring further management [73] Widely accessible over the counter or by pre- scription [66] Long-term use associated with risks; doesn’t address the underlying cause of endo- metriosis [10] Hormonal Therapies Reduces pain and suppresses disease activity; GnRH agonists are effective for severe cases [66] Hormonal negative con- sequences include mood changes, weight gain, and reduced bone density. [73] Moderate cost: repeated prescriptions or long-term treatment required, increasing overall cost [73] Widely accessible in most healthcare settings, though GnRH agonists may require specialized prescrip- tion [66] Does not provide a permanent cure; side effects often limit long-term use [36] Surgical Interventions Laparoscopy is effective in removing lesions and provid- ing long-term pain relief [77] Risks include infection, scar- ring, and potential recurrence of endometriosis [10] High upfront costs due to sur- gical procedures, though cost- effective in the long term for some patients [10] Accessible in regions with advanced healthcare facilities but requires special- ized expertise [77] Risk of recurrence, high costs, and potential complications from surgery [21] Opioid Analgesics Effective for short-term pain relief but not a long-term solu- tion [47, 48] High risk of addiction, toler- ance, and opioid-related side effects [47, 48] Can be costly over time, particularly due to the need for careful management of side effects [57] Accessible, but there is increas- ing regulation due to the opi- oid crisis [47, 48] High potential for addiction, tolerance, and societal concerns regarding opioid overuse [47, 48] Emerging Therapies Selective Progesterone Recep- tor Modulators (SPRMs) Promising in clinical trials with efficacy in reducing lesion size and associated pain [65] Early evidence suggests fewer side effects than traditional hor- monal therapies, though more data is needed [65] Cost-effectiveness not yet fully established due to the emerg- ing nature of the treatment [70] Limited accessibility as it is still in experimental stages or early clinical use [70]) Long-term effects and safety are still unknown; further trials needed [54] GnRH Antagonists Provides rapid pain relief like agonists but without the initial hormonal flare associated with agonists [54] Potential side effects include headache, hot flashes, and mood changes [36] High cost due to the novel nature of the drug and need for repeated administration [43] Currently available in certain regions but less accessible due to cost and regulatory approv- als [29] Still expensive, with potential side effects requiring careful patient monitoring [29] Aromatase Inhibitors Reduces estrogen levels, show- ing promise in managing pain and reducing lesion size [34] Risks include bone loss and increased fracture risk [34] Moderate to high cost, espe- cially considering potential long-term side effects that may require further treatment [34] Limited availability due to its off-label use in endome- triosis, more commonly used for breast cancer [34] Off-label usage in endometriosis; safety concerns, particularly with long-term use, and higher cost compared to other thera- pies [34] Stem Cell Therapies Early studies show poten- tial in tissue regeneration and reducing inflammation associated with endometriosis [42, 53] Still experimental; long-term safety and efficacy data are lacking [42, 53] Currently very expensive due to its novel and experimental nature [42, 53] Extremely limited accessibil- ity; available only in research settings or specialized clinics [42, 53] Experimental nature means unknown risks, high costs, and limited accessibility [42, 53] Immunotherapy Promising in targeting immune system dysfunction that may contribute to endometriosis pathology [27] Still in the early stages of research, safety profiles remain unclear [27] Very high cost due to experi- mental and targeted nature of treatments [42] Currently only available in clini- cal trials or highly specialized centers [42] Unknown long-term effects, high costs, and accessibility

[52] Page 10 of 14Tijani et al. Middle East Fertility Society Journal (2025) 30:9 Table 2 (continued) Therapy Type Efficacy Safety Profiles Cost‑Effectiveness Accessibility Challenges Gene and Molecular Therapies Potential to correct underlying genetic and molecular drivers of endometriosis [82, 83] Early-stage research; unknown safety risks and ethical con- cerns [82, 83] Likely to be expensive due to complexity and cutting- edge nature [16] Limited to experimental or clinical trial settings [30] High cost, ethical concerns and unknown long-term effects [30] Page 11 of 14 Tijani et al. Middle East Fertility Society Journal (2025) 30:9 Future directions As the understanding of endometriosis continues to evolve, there are several critical areas where further research and innovation are needed. One of the major gaps in current endometriosis research is the lack in long-term studies that can pro - vide real-world evidence on the effectiveness and safety of various treatments. Many existing studies are short- term and have limited sample sizes, which limits their generalisability. Additionally, there is a need for greater depth research into the fundamental mechanisms of endometriosis, particularly in areas like immunology, genetics, and the role of environmental factors. Personalised medicine represents a possible route for enhancing endometriosis treatment outcomes. Identi - fying and confirming biomarkers could open the door for more focused medications, allowing physicians to adapt treatments to specific patient profiles. This tech - nique may reduce variability in treatment responses and lead to more effective pain management strategies. Future advances in endometriosis pain management may result from the combination of different tech - niques. This could involve using new pharmaceutical medicines, sophisticated surgical procedures, and com - plementary therapies such as acupuncture and physical therapy. Combining these treatments could result in more comprehensive and long-term pain alleviation. The development of combination therapies, which use numerous treatment modalities at the same time, has the potential to address endometriosis’ complex character. Emerging research disciplines, such as epi - genetics and microbiome, have the potential to provide new insights and therapeutic methods. Understanding how genetic and microbiological factors drive endo - metriosis may help researchers identify new therapy options.

The present and developing treatments for pain related to endometriosis have been reviewed, with an emphasis on the advantages and disadvantages of each strategy. Pharmacological treatments, such as hormone therapy, NSAIDs, and analgesics, continue to be the mainstays; nevertheless, their efficacy is frequently hampered by side effects, insufficient symptom alleviation, and inconsistent patient responses. Though they can sig - nificantly reduce discomfort, surgical techniques like laparoscopy and more complex ones like peritonectomy come with hazards, such as complications and variable long-term effectiveness. While new pharmacological drugs, gene and molecular therapies, and sophisticated surgical methods are examples of emerging medicines, they still mostly involve experimentation and need to be rigorously validated. The results highlight the significance of treating endo - metriosis-related pain using a customised, interdisci - plinary strategy. To meet the demands of each patient, doctors should customise treatment regimens by com - bining pharmacological, surgical, and complementary therapy. Emerging medicines should be approached cautiously, therefore, taking into account both their potential advantages and the dearth of comprehensive clinical evidence currently indicating their widespread application. Furthermore, since they are essential to delivering holistic care, the psychological and social effects of endometriosis cannot be disregarded. Despite progress, there are still many obstacles to overcome in the treatment of pain related to endome - triosis. In order to evaluate the safety, effectiveness, and cost-efficiency of both established and novel treat - ments, future research should concentrate on carrying out long-term, practical trials. Therapeutic results may be improved by looking into how biomarkers and per - sonalised medicine might predict treatment response. Furthermore, knowing the immunological, epigenetic, and genetic processes that underlie endometriosis may help develop more specialised and efficient therapies. Abbreviations NSAIDs Nonsteroidal Anti-inflammatory Drugs EAP Endometriosis-Associated Pain COX Cyclooxygenase OCs Oral Contraceptives GnRH Gonadotropin-Releasing Hormone SPRMs Selective Progesterone Receptor Modulators ESGE European Society for Gynaecological Endoscopy CDC Centers for Disease Control and Prevention IVF In Vitro Fertilization SPRMs Selective Progesterone Receptor Modulators GnRH Gonadotropin-Releasing Hormone THC Tetrahydrocannabinol CBD Cannabidiol VEGF Vascular Endothelial Growth Factor

None. Authors’ contributions A.F.A. conceptualized and outlined the review. O.S.T. prepared the materials. E.O.T. and L.O.A. drafted the manuscript’s first version. O.P .A. and A.F.A. edited the work. All authors reviewed and approved the final manuscript. Funding No funding. Data availability No datasets were generated or analysed during the current study. Declarations Ethics approval and consent to participate Not applicable. Page 12 of 14Tijani et al. Middle East Fertility Society Journal (2025) 30:9 Consent for publication Not applicable. Competing interests The authors declare no competing interests. Author details 1 Anchor Biomed Research Institute, Ogbomoso, Oyo State, Nigeria. 2 Depart- ment of Biochemistry, Ladoke Akintola University of Technology, Ogbomoso, Oyo State, Nigeria. 3 Department of Physiology, School of Basic Medical Sciences, Babcock University, Ilishan Remo, Ogun State, Nigeria. 4 Department of Physiology, Ladoke Akintola University of Technology, PMB 4000, Ogbo- moso, Oyo State, Nigeria. 5 Department of Physiology, Adeleke University, Ede, Osun State, Nigeria. Received: 18 October 2024 Accepted: 4 April 2025

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