{"paper_id":"c6f9ae37-bc47-4a51-bbbb-b0323394e233","body_text":"REVIEW | OPEN ACCESS   \n \nMedical Science 29, e127ms3666 (2025)                                                                                                                                                                1 of 12 \n \n Endometriosis treatment in the 21st  \ncentury: current trends and clinical \nperspectives \n \nPaulina Wasilewska ⃰, Olga Wojtczak, Kacper Zagaja, Justyna \nWróblewska, Hubert Ziembicki, Natalia Skrzypska \n \n \nABSTRACT \nChronic pelvic pain, infertility, and severe menstrual symptoms are part of \neveryday life for millions of women around the world. These issues often remain \nundiagnosed, especially when it comes to endometriosis.  Endometrioisis is a \nmultifaceted disease that might be caused by hormonal imbalance, immune \ndysfunction, microbiome alterations and gene transformation. Managing \nendometriosis symptoms effectively is essential for patients' quality of life, fertility, \nand long -term health. In this review, we brought together current ideas on the \ntreatment, considering both long-standing methods and novel approaches.  \n \nKeywords: endometriosis, hormonal therapy, microbiome, chronic pelvic pain, \nestrogen dependence \n \n \n1. INTRODUCTION  \nEndometriosis is a chronic condition in which endometrial-like tissue grows outside \nof the uterus.    Improper placement of the uterus lining cells leads to inflammation \nand the formation of scar tissue mostly in the pelvis region, which can cause severe \nchronic pelvis pain and infertility (Chapron et al., 2019).  \nThe pathogenesis of endometriosis involves a variety of different factors, which \nproves the complexity of its treatment. The most conventional hypothesis is \nretrograde menstruation, which assumes that the endometrial fragments travel \nthrough the fallopian tubes (Vercellini et al., 2014). Some research highlighted that \nendometriosis is an estrogen -dependent and progesterone -resistant disease (Zhang \n& Wang, 2023), while other research points out the angiogenesis and neurogenesis \ndysregulation (Hey -Cunningham et al., 2013). A holistic approach is also gaining \nattention with recent studies about gut microbiota involved in pathogenesis (Guo & \nZhang, 2024). \nAccording to the data from the World Health Organization (WHO), \nendometriosis affects approximately 5 -10% of women of reproductive age. It is \nessential to note that the true prevalence of endometriosis remains unknown, \nmainly due to the absence of a non -invasive diagnostic method (Shafrir et al., 2018).  \nLate diagnosis remains a significant issue in the effective treatment of endometriosis \nand negatively impacts patients' quality of life. This review aims to raise awareness \nMedical Science \n \n \nTo Cite: \nWasilewska P, Wojtczak O, Zagaja K, Wróblewska J, Ziembicki H, \nSkrzypska N. Endometriosis treatment in the 21st century: current \ntrends and clinical perspectives. Medical Science 2025; 29: e127ms3666  \ndoi: https://doi.org/10.54905/disssi.v29i162.e127ms3666  \n \nAuthors’ Affiliation: \nUniversity Clinical Hospital, 49 Przybyszewskiego St, 60-355 Poznań, Poland \n \n⃰ Corresponding author: \nPaulina Wasilewska \nUniversity Clinical Hospital, 49 Przybyszewskiego St, 60-355 Poznań, \nPoland \nEmail: wasilewska123paula@gmail.com \n \nContact List: \nPaulina Wasilewska  wasilewska123paula@gmail.com \nOlga Wojtczak  olg.wojtczak@gmail.com \nKacper Zagaja  kacper.zagaja@gmail.com \nJustyna Wróblewska wroblewska.ju@gmail.com \nHubert Ziembicki hubert.ziembicki@gmail.com \nNatalia Skrzypska natalia.skrzypska@onet.eu \n \nORCID List:  \nPaulina Wasilewska 0009-0000-9943-7541  \nOlga Wojtczak   0009-0009-3726-437X \nKacper Zagaja   0009-0003-9678-1162  \nJustyna Wróblewska 0009-0003-5586-3938   \nHubert Ziembicki 0000-0003-4298-7213  \nNatalia Skrzypska 0009-0006-0712-7495 \n \nPeer-Review History \nReceived: 27 April 2025 \nReviewed & Revised: 16/May/2025 to 27/July/2025 \nAccepted: 01 August 2025 \nPublished: 07 August 2025 \n \nPeer-review Method \nExternal peer-review was done through double-blind method. \n \nMedical Science \npISSN 2321–7359; eISSN 2321–7367 \n \n \n© The Author(s) 2025. Open Access. This article is licensed under a Creative \nCommons Attribution License 4.0 (CC BY 4.0)., which permits use, sharing, \nadaptation, distribution and reproduction in any medium or format, as long \nas you give appropriate credit to the original author(s) and the source, \nprovide a link to the Creative Commons license, and indicate if changes were \nmade. To view a copy of this license, visit \nhttp://creativecommons.org/licenses/by/4.0/. \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \nDISCOVERY \nSCIENTIFIC SOCIETY \n \n\n \nREVIEW | OPEN ACCESS   \n \nMedical Science 29, e127ms3666 (2025)                                                                                                                                                                2 of 12 \nabout the complexity of endometriosis and present current treatment approaches. The increasing public and scientific recognit ion of \nendometriosis has sparked a new wave of research focused on developing more personalized strategies for patients with \nendometriosis. \n \n \nFigure 1: PRISMA flowchart \n \n2. REVIEW METHODS \nWe reviewed studies from major scientific databases, including PubMed and Google Scholar, with a focus on endometriosis treat ment. \nA total of 237 articles were identified through searches in selected databases. After removing 48 duplicates, 189 articles re mained. After \nscreening the titles and abstracts, we excluded 106 articles. The full text of 83 studies was sought for retrieval, and 20 of  them were not \nretrieved. The full texts of 63 articles were then assessed for eligibility. Of these, 31 were excluded – 12 of this lack of specific data on \nendometriosis diagnosis or treatment outcomes, 8 of these had inappropriate study design, such as case reports, reviews witho ut \noriginal data, or editorials, 6 of these were studies focused on populations not relevant to endometriosis and 5 of these wer e in \nlanguages other than English. Ultimately, 32 articles were included in this review  (Figure 1). These selected articles were analyzed and \n\n\n \nREVIEW | OPEN ACCESS   \n \nMedical Science 29, e127ms3666 (2025)                                                                                                                                                                3 of 12 \nsummarized in this review. We searched the databases using terms such as endometriosis, hormonal therapy, microbiome, chronic  \npelvic pain and estrogen dependence. We set the time range of published articles to January 2010 - March 2025 and included some older \npublications if we considered them valuable for understanding the issue. All publications used in this review were written in English. \n \n3. RESULTS AND DISCUSSION \nPathogenesis of Endometriosis \nThe cause of endometriosis is heterogeneous, as many different factors can contribute to its development. According to the most widely \naccepted model —the retrograde menstruation hypothesis —endometrial fragments travel through the fallopian tubes into the pelvic \ncavity, where they implant on the peritoneum and abdominal organs. There, they proliferate and trigger chronic inflammation, leading \nto the formation of adhesions (Vercellini et al., 2014).  Elevated levels of pro -inflammatory cytokines (e.g., IL -1β, IL -6, TNF -α) and \nincreased presence of activated macrophages and neutrophils have been identified in the peritoneal fluid of affected individu als (Yang \net al., 2017; Zhang & Wang, 2023). \nAnother key feature of endometriosis is estrogen dependence and resistance to progesterone. Numerous studies have shown that \nthe expression level of progesterone receptors, PR -A and PR -B, is generally lower in ectopic endometrial lesions (table 1). \nSimultaneously, high expression of estrogen receptors, especially Erβ, leads to the upregulation of aromatase activity and in creased \nestrogen production within ectopic lesions (Zhang & Wang, 2023). \nOne of the key components of endometriosis pathogenesis is the dysregulation of angiogenesis and neurogenesis. Neurogenesis \npromotes nerve fiber growth around endometriosis lesions. It appears to play a central role in symptom manifestation as it is associated \nwith chronic pelvic pain (Hey-Cunningham et al., 2013). \nRecent studies suggest that the gut microbiota may be involved in the pathogenesis of endometriosis. Dysbiosis may contribute  to \nsystemic inflammation and immune dysregulation; however, the clinical significance of these findings requires confirmation th rough \nwell-designed clinical studies (Guo & Zhang, 2024). \n \nTable 1. Key Mechanisms Involved in the Pathogenesis of Endometriosis \nPathogenic \nMechanism Description Key Molecules / Factors Clinical Implication \nRetrograde \nMenstruation \nBackflow of menstrual blood carrying \nendometrial cells into the pelvic \ncavity \n– Initiates ectopic \nimplantation \nInflammation \nActivation of immune cells and \nproduction of pro-inflammatory \ncytokines \nIL-1β, IL-6, TNF-α, \nmacrophages, neutrophils \nPromotes lesion survival \nand adhesion \nEstrogen \nDependence \nIncreased local estrogen production \nvia aromatase upregulation ERβ, Aromatase Sustains lesion growth \nProgesterone \nResistance \nDecreased response to progesterone \ndue to reduced PR expression PR-A, PR-B \nHinders anti-\nproliferative hormonal \ncontrol \nAngiogenesis Formation of new blood vessels \naround lesions VEGF Supports lesion \nnourishment and growth \nNeurogenesis Growth of nerve fibers into \nendometrial lesions Nerve growth factors Contributes to chronic \npelvic pain \nGut Microbiota \nDysbiosis \nAltered microbiome contributing to \nsystemic inflammation and immune \ndysregulation \nLPS, microbial imbalance \nEmerging target; \nrequires further \ninvestigation \n \n \n \n \n\n \nREVIEW | OPEN ACCESS   \n \nMedical Science 29, e127ms3666 (2025)                                                                                                                                                                4 of 12 \nTraditional Treatment Approaches \nThe traditional endometriosis treatment methods we are familiar with today primarily consist of pharmacological therapy and surgical \ninterventions. The main goals of these methods are reducing the severity of the symptoms, slowing disease progression, and improving \npatients’ quality of life.  \n \nPharmacological Therapy   \nNonsteroidal Anti-Inflammatory Drugs (NSAIDs) \nPain management is one of the most important goals of endometriosis treatment when trying to improve patients’ quality of life. \nNSAIDs tend to be used as therapy of first choice due to their accessibility; however, some small research found minimal and low-\nquality evidence regarding their efficacy for this specific pain. Based on the available data from one small study, the review's authors \ncould not definitively conclude if NSAIDs, specifically naproxen, effectively relieve endometriosis-related pain (Brown et al., 2017). \n \nHormonal Therapy \nDue to the limited efficacy of NSAIDs in some patients, hormonal therapies remain the most effective way of symptom management. \nThe primary focus of all hormonal treatments is to suppress or lower systemic estrogen levels by inhibiting the hypothalamic-pituitary-\novarian axis or by inducing pseudo-decidualization, leading to amenorrhea (Vannuccini et al., 2022). \nProgestin-only pills and combined oral contraceptives (COCs) are typically used as first-line hormonal treatment as they are well-\ntolerated by patients and can be used for a long time. Progestins act through multiple mechanisms: anti-estrogenic, pro-apoptotic, anti-\ninflammatory, and anti-proliferative effects. Progestins suppress endometrial growth and exert antimitotic activity in endometriotic \nlesions. That mechanism ultimately leads to decidualization and atrophy of these lesions (Quaas et al., 2015; Gezer & Oral, 2015). All \nsynthetic progestins achieve symptomatic improvement as they reduce endometriosis-associated pain in approximately 90% of the \npatients (Gezer & Oral, 2015). \nDespite their efficacy, progestins are associated with several side effects. These are mainly due to their androgenic actions and \ninclude weight gain, acne, and menstrual irregularities. Long-term administration of progestin (depot medroxyprogesterone acetate; \nDMPA, also known as Depo-Provera) can be associated with a decrease in bone mineral density (Quaas et al., 2015). Levonorgestrel \nmay cause side effects such as spotting, breakthrough bleeding, bloating, weight gain, and headache in up to one-third of patients. \nLynestrenol was responsible for hot flushes, acne, and sweating, which were the main problems reported by up to 59% of patients. \n(Gezer & Oral, 2015). \n \nGnRH Agonists and Antagonists \nGiven that endometriosis is an estrogen-dependent disease, gonadotropin-releasing hormone (GnRH) agonists have become an \nestablished option in its treatment. GnRH agonists, such as leuprolide acetate and gosereline, work by reducing GnRH pulsatility, \nwhich in turn suppresses the gonadotropic axis and prevents estrogen stimulation of ectopic glands. This mechanism leads to estrogen \nlevels like those seen post-menopause, which avoid stimulation of the uterus lining. This significant reduction in estrogen can lead to \nprogressive bone loss and severe vasomotor symptoms (Brichant et al., 2021). \nTo overcome some of the limitations associated with GnRH agonists, GnRH antagonists have been developed as an alternative \napproach with a more favorable side effect profile. These agents, such as cetrorelix and elagolix, primarily work by completely blocking \nthe GnRH receptor, thereby suppressing GnRH-mediated signal transduction. As a result, they reduce gonadotropin secretion \n(Ortmann et al., 2002). Due to their direct antagonist action, they avoid triggering the flare-up effect that would cause a rapid \nsuppression of gonadotropin secretion (Capezzuoli et al., 2022).  \n \nSurgical Treatment \nSurgical excision is the only cytoreductive approach with promising symptom -relief rates. The basic principles of endometriosis \nexcisional operation involve the uncomplicated resection of visualized endometriotic lesions, performing adhesiolysis, and re storing \nthe normal pelvic anatomy. Surgical intervention is often necessary when organ damage is suspected or has already been detect ed \n(Ferrari et al., 2024).  \nMinimally invasive surgery (MIS), particularly laparoscopy, is currently the approach of choice for endometriosis surgery. Th is \ntechnique offers variety of advantages that it became a gold standard in treatment. Clinicals observe benefits such as smaller blood loss, \n\n \nREVIEW | OPEN ACCESS   \n \nMedical Science 29, e127ms3666 (2025)                                                                                                                                                                5 of 12 \ndecreased pain after the surgery, and shorter duration of hospitalization (Ferrari et al., 2024).  Laparoscopic technique of endometriosis \nsurgery is beneficial for better postoperative pain sensation and fertility (table 2). It is also considered safe and efficie nt for treating \ndeep endometriosis with visceral localization, such as in the urinary tract and colon or rectum (Ferrari et al., 2024). \n \nTable 2. Traditional Endometriosis Treatment Approaches \nTreatment Type Method Mechanism of \nAction Advantages Disadvantages / \nSide Effects \nPharmacological \nNSAIDs \nInhibition of \nprostaglandin \nsynthesis (anti-\ninflammatory and \nanalgesic effects) \nWidely \naccessible, rapid \nsymptom relief \nLimited evidence of \nefficacy in \nendometriosis-\nspecific pain \nProgestins / COCs \nEstrogen \nsuppression, anti-\ninflammatory and \nantiproliferative \neffects \nEffective in \nreducing pain \nand controlling \nmenstruation \nAndrogenic effects \n(acne, weight gain), \nmenstrual \nirregularities \nGnRH Agonists \nSuppress HPO axis \n→ reduce estrogen \nlevels \nEffective in \nmoderate to \nsevere cases \nMenopausal-like \nsymptoms, bone \ndensity loss \nGnRH \nAntagonists \nDirect GnRH \nreceptor blockade \nwithout initial “flare-\nup” effect \nFewer side effects \nthan agonists, \nfaster onset \nPossible \nhypoestrogenic \nsymptoms with \nlong-term use \nSurgical \nLaparoscopy \n(MIS) \nLesion excision, \nadhesiolysis, pelvic \nanatomy restoration \nImproves \nfertility, reduces \npain, short \nrecovery time \nRisk of recurrence, \nrequires surgical \nexpertise \nAdvanced Surgery \n(e.g., Laparotomy) \nResection of deeply \ninfiltrating \nendometriosis, organ \nreconstruction \nEffective in \ncomplex cases \ninvolving bowel \nor urinary tract \nHigher risk of \ncomplications, \nlonger \nhospitalization \n \nEmerging and Experimental Therapies \nModern Hormonal Therapies \nOral gonadotropin-releasing hormone (GnRH) receptor antagonists represent a significant improvement in managing endometriosis-\nassociated pain. The main disadvantage of elagolix, particularly at higher effective doses, is its association with hypoestrogenic side \neffects, such as hot flushes and a clinically significant reduction in bone mineral density (BMD). These adverse effects mean a \nmaximum treatment duration limit, typically 6 months for the high-dose regimen and up to 24 months overall, due to concerns about \nbone density loss (Ortmann et al., 2002).  \n\n \nREVIEW | OPEN ACCESS   \n \nMedical Science 29, e127ms3666 (2025)                                                                                                                                                                6 of 12 \nRelugolix combination therapy (relugolix 40 mg, estradiol 1 mg, and norethisterone acetate 0.5 mg) was explicitly developed as a \ntreatment to overcome these long-standing challenges. While relugolix monotherapy, like other GnRH antagonists, leads to dose-\ndependent decreases in BMD and increases in vasomotor symptoms (Osuga et al., 2021; Giudice et al., 2022), the combination therapy \nwas developed to reduce the effects of hypoestrogenism. Clinicians observed that relugolix could maintain estradiol concentrations \nwithin a therapeutic range, thereby providing pain relief while minimizing side effects. This approach allows for the potential for long-\nterm use (Osuga et al., 2021). \nAnother novel gonadotropin-releasing hormone (GnRH) receptor antagonist that has shown promising results in endometriosis-\nassociated pain treatment is Linzagolix. The main advantage of this agent is precise control over estrogen levels, as it allows to keep the \nrange of 20–60 pg/mL. It is beneficial because this range allows for the reduction of symptoms associated with endometriosis while \nminimizing side effects, such as loss of bone mineral density (BMD) (Donnez et al., 2023). Furthermore, linzagolix shows a rapid onset \nof therapeutic effects. It quickly reduces estradiol concentrations, resulting in fast symptom relief. The response was defined as at least \na 30% reduction in menstrual dysmenorrhea and non-menstrual pelvic pain severity combined. Specifically, response rates were 61.5% \nwith 75 mg linzagolix and 56.3% with 200 mg linzagolix, compared to 34.5% with placebo (Donnez et al., 2023). Aside from pain \nreduction, linzagolix was also proven to reduce difficulty associated with defecation and improve overall patient well-being, which \nwas measured by quality-of-life scales. These benefits are maintained or further improved through 52 weeks of continuous \nadministration.  In the Phase 3 EDELWEISS 3 clinical trial, testing two regimens—75 mg without hormonal add-back therapy (ABT) \nand 200 mg with hormonal ABT—the 200 mg regimen with hormonal ABT successfully alleviated menstrual dysmenorrhea and non-\nmenstrual pelvic pain within 3 months of therapy. Notably, by 52 weeks, both the 200 mg dose with ABT and the 75 mg dose reduced \nboth types of pain, making linzagolix a promising agent for managing endometriosis pain (Donnez et al., 2023). \nSelective Estrogen Receptor Modulators (SERMs) represent a new group of agents that have recently gained attention in the \nendometriosis treatment as they can modulate estrogen activity without reducing estrogen levels. SR-16234 is a novel SERM that is \nstructurally different from previously approved SERMs. It has been reported to have estrogen receptor α antagonistic activity and \nweak partial agonistic activity to the β receptor (Harada et al., 2018).  \nA study conducted by Harada et al., (2018) evaluated SR-16234 in ten patients with dysmenorrhea and pelvic pain related to \nendometriosis and adenomyosis, who received 40 mg of SR-16234 once a day for 12 weeks. The trial results indicated statistically \nsignificant improvements, as pelvic pain VAS significantly decreased at 4, 8, and 12 weeks compared to baseline. Objective \nobservations, such as stiffness of Douglas' pouch and restricted uterine mobility, showed reduced severity after treatment. In one \npatient, a chocolate cyst with a volume of 13,305 mm³ decreased to 1,914 mm³ by 8 weeks and disappeared at 12 weeks. Moreover, \nmean endometrial thickness decreased from 9.75 mm at baseline to 6.87 mm at 12 weeks in 8 patients. The sources highlight that SR-\n16234 appears to have a more favorable side effect profile compared to other common endometriosis treatments due to its \"purer ERα \nantagonist tendencies\".  \nA small study conducted by Kulak et al., (2011) evaluated the administration of 3 mg/kg·d of the SERM Bazedoxifene (BZA) to mice \nwith experimental endometriosis for 8 weeks. The study showed that BZA blocked estrogen-induced stimulation of the endometrial \ntissue while preserving its effects on bone and the central nervous system (Table 3). \n \nTable 3. Novel Hormonal Therapies for Endometriosis \nTherapy Mechanism Benefits Limitations / Notes \nElagolix Oral GnRH antagonist → \nlowers estrogen Effective pain relief Hypoestrogenic effects; BMD \nloss; limited long-term use \nRelugolix \ncombination therapy \nGnRH antagonist + \nestrogen + progestin \nMaintains therapeutic \nestrogen window; fewer \nvasomotor & bone effects \nLong-term safety still under \nevaluation \nLinzagolix Dose-dependent estrogen \nsuppression \nRapid symptom relief; \npreserves BMD; long-term \nefficacy (up to 52 weeks) \nPhase 3 data promising but \nstill under regulatory \nassessment \nSR-16234 (SERM) ERα antagonist, weak \nERβ agonist \nPain reduction, endometrial \nthinning, fewer side effects Early-stage clinical data \nBazedoxifene (BZA) SERM blocking estrogen Maintains bone/CNS health in Preclinical stage \n\n \nREVIEW | OPEN ACCESS   \n \nMedical Science 29, e127ms3666 (2025)                                                                                                                                                                7 of 12 \nstimulation in \nendometrium \nanimal models \n \nModern Endometriosis-Associated Pain Management \nConventional pharmacological treatments are associated with limited effectiveness and adverse side effects. Clinical studies have \nshown that Sacral Neuromodulation (SNM) can significantly reduce chronic pelvic pain. A systematic review and meta-analysis of 20 \nstudies conducted by Greig et al., (2023) found a weighted mean difference in pain scores on a 10-point scale of -4.64 (95% confidence \ninterval [CI] = -5.32 to -3.95, p < 0.00001). This difference indicates a substantial improvement in pain scores, with reported \nimprovements ranging from 40% to 53% in patients who received a complete implant. All studies that assessed quality of life reported \nimprovements in various QoL domains following SNM treatment. Specifically, areas like bodily pain, physical function, social function, \nphysical role, general health, mental health, and vitality showed improvement. The significant benefit of SNM in pain reduction is \nmaintained at 6, 12, and 24 months, with some studies reporting continued considerable decrease in pain scores up to 5 years (Greig et \nal., 2023). \nTranscranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation technique that utilizes electrodes placed on the \nscalp to deliver a weak electric current, thereby modulating neuronal activity (Thair et al., 2017). A randomized controlled clinical trial \nconducted by Mechsner et al., (2023) demonstrated that this technique significantly decreased pain severity in patients with \nendometriosis and chronic pelvic pain. The group using tDCS showed a pain level reduction of approximately 41.3% on the NRS \ncompared to the placebo group (table 4). Moreover, pain perception remains lower even after 1 week after stimulation. This suggests \nthat the tDCS technique may be beneficial for long-term use. \n \nTable 4. Modern Pain Management Techniques for Endometriosis \nTechnique Mechanism Benefits Limitations / Notes \nSacral Neuromodulation \n(SNM) \nElectrical stimulation of \nsacral nerves \nReduces pain (up to 53%); QoL \nimprovements maintained up to \n5 years \nInvasive procedure; \ndevice-dependent \ntDCS \nNon-invasive brain \nstimulation via scalp \nelectrodes \n~41% pain reduction; long-\nlasting analgesic effects \nRequires further clinical \ntrials; access to \ntechnology \n \nImmunomodulatory and Anti-Inflammatory Therapies \nImmunological factors significantly play a significant role in the pathogenesis of endometriosis. Immunotherapy has become a \npromising innovative treatment strategy. \nOne type of the immunotherapy involves targeting the function of immune cells, particularly macrophages. The decrease in \nmacrophage phagocytosis in peritoneal fluid is a significant contributor to immune imbalance in endometriosis patients. High \nexpression of CD47, which provides a \"don't eat me\" signal, is increased in ectopic endometrium, blocking normal macrophage \nphagocytosis. Blocking the CD47-SIRPa signaling pathway reduces CD47 expression and allows macrophages to perform normal \nphagocytosis (Li et al., 2023).  \nImmunotherapy targeting the CD47-SIRPα signaling pathway appears to be effective for treating endometriosis. Another \nimmunotherapy line used in endometriosis treatment is Immune Cytokine Modulators. Interleukins, especially IL-12, take part in the \npathogenesis of endometriosis. IL-12 affects variety of factors regarding immunology. It stimulates the production of another cytokines, \nsupport the migration of inflammatory cells, and boost the cytotoxic activity of natural killer (NK) cells (Li et al., 2023). A study \nperformed by Zhang et al., (2025) revealed that treatment of NK cells with an IL-12 heterodimer reduced the ratio of free p40 to IL-12. \nThis action enhanced the cytotoxicity of NK cells in ectopic endometrial tissue, thereby suppressing the development of the ectopic \nendometrial tissue (table 5). It appears that IL-12 may be a potential target for reducing free p40 levels observed in patients with \nendometriosis. \n \n \n \n\n \nREVIEW | OPEN ACCESS   \n \nMedical Science 29, e127ms3666 (2025)                                                                                                                                                                8 of 12 \nTable 5. Immunomodulatory and Anti-inflammatory Therapies for Endometriosis \nTherapy Mechanism Benefits Limitations / Notes \nCD47 \nblockade \nEnhances macrophage phagocytosis of \nectopic tissue \nTargets immune \ndysfunction underlying \ndisease \nExperimental; \npreclinical models \nIL-12 therapy Enhances NK cell activity & suppresses \nectopic tissue via cytokine modulation \nPromotes immune clearance \nof lesions \nNeeds further human \nstudies \n \nNon-pharmacological and Supportive Therapies \nRecent studies have examined the role of the gut microbiome as a potential new avenue for the treatment of endometriosis. Mod ulating \nthe type and abundance of gut microbiota using probiotics has shown promising effects (Sahin et al., 2018). For instance, the  strain \nLactobacillus gasseri  OLL2809 activates the NK cells, which were proven to suppress the growth of endometriosis lesions in mouse \nmodels. L. Gasseri could reduce chronic pelvic pain and dysmenorrhea in patients with endometriosis, while still being a safe treatment \noption (Sahin et al., 2018; Kobayashi, 2023). \nOmega-3 PUFAs were proven to reduce LPS-producing bacteria (E. coli) and increase LPS-suppressing bacteria (Bifidobacterium). It \nled to a reduction in inflammatory cytokines such as TNF -α, IL-1β, and IL -6. Moreover, premenopausal women taking Omega -3 fatty \nacids were less likely to develop endometriosis. Supplementation with alpha -linolenic acid (ALA), an omega -3 PUFA was proven to \npositively influence gut microbiota - it positively changed gut bacteria composition ( Lactobacillus, Bacteroides, Muribaculum, and \nBifidobacterium). Moreover, ALA reduced abdominal LPS levels and PGE2 concentrations (Guo & Zhang, 2024). \nAnother modern endometriosis treatment line is fecal microbiota transplantation (FMT). It is a procedure that involves \nadministration of a fecal bacteria from a healthy donor into the gastrointestinal tract of a recipient. Experimental studies have shown \nthat fecal microbiota transplantation from mice with endometriosis can increase lesion growth when transferred to the healthy  one \n(Kobayashi, 2023). This experiment result could mean that microbiota of patients with endometriosis can contribute to disease  \nprogression (table 6). However, we still need more data of FTM being used as a treatment line of endometriosis. \n \nTable 6. Microbiome and Nutritional Therapies for Endometriosis \nApproach Mechanism / Agent Benefits Limitations / Notes \nProbiotics (L. \ngasseri) \nActivates NK cells; modifies \ngut microbiota \nPain relief; suppresses lesion \ngrowth in mice Human studies ongoing \nOmega-3 PUFAs / \nALA \nAnti-inflammatory; \nmicrobiota modulation \nReduces lesion size, inflammation, \nPGE2; improves gut flora Mostly preclinical data \nFMT Transplantation of healthy \nmicrobiota \nPotential to reset dysbiotic gut \nenvironment \nExperimental; no human \ntrials yet \n \nGene and Cell-Based Therapies \nEndometriosis is considered a complex disease characterized by widespread epigenetic and genetic defects, which makes gene therapy \npromising strategy of treatment (Zhao et al., 2012). Research has identified microRNA expression that is lower in patients with \nendometriosis. In mouse models, treatment with Let-7b, which is a specific microRNA, reduced endometroid lesions which could be a \nsign of its therapeutic potential. The inflammatory marker IL-6 was suppressed in the treated group, proving that Let-7b reduces \ninflammation associated with the disease (Sahin et al., 2018). \nMoreover, endometriosis is an angiogenesis-dependent disease, meaning newly formed blood vessels are necessary for the survival \nand growth of lesions. Pigment epithelium-derived factor (PEDF) is a protein that inhibits angiogenesis (Zhao et al., 2012). In a study \nconducted by Zhao et al., (2012) intravenously administered PEDF was successfully distributed to endometriotic lesions in a rat model \nof peritoneal endometriosis and significantly reduced their size. \nCell-based therapy is an approach that is gaining attention as a potential future treatment for endometriosis. One of the cell therapy \ntreatments that deserves particular attention is the use of adipose tissue-derived stem cells (ASCs). Administration of ASCs reduced \nstromal fibrosis and the proliferation of endometriotic epithelial cells in the endometrial tissues (Table 7). Moreover, ASC \n\n \nREVIEW | OPEN ACCESS   \n \nMedical Science 29, e127ms3666 (2025)                                                                                                                                                                9 of 12 \nadministration decreased the expression of pro-inflammatory cytokines such as Mcp, IL-6, and Lif, as well as the pro-fibrotic cytokine \ntumor growth factor-β1 (Tgfb1) (Hirakawa et al., 2022). \n \nTable 7. Gene and Cell-Based Therapies for Endometriosis \nTherapy Mechanism Benefits Limitations / Notes \nLet-7b microRNA Downregulates ERs, KRAS, IL-6 Reduces lesion size and \ninflammation \nPreclinical; delivery \nsystems still under \ndevelopment \nPEDF (anti-\nangiogenic protein) \nInhibits new blood vessel growth \nin lesions \nReduces lesion size in \nanimal models Requires clinical translation \nASCs (stem cells) \nAnti-fibrotic, anti-inflammatory; \nreduces cytokines like IL-6 and \nTGF-β1 \nInhibits lesion \nprogression; restores \ntissue balance \nExperimental; long-term \neffects unknown \n \nSurgery \nRobotic-assisted laparoscopic surgery has gained increasing attention and is being adopted more frequently for endometriosis surgery. \nRobotic technology provides features like 3D vision, improved ergonomics, and reduced tremor effects (Ferrari et al., 2024; Lee & Kim, \n2024; Ong et al., 2024). Robotic assistance may also be particularly helpful in increasing dissection precision and improving autonomic \nnerve identification and preservation, potentially resulting in better functional outcomes (Ferrari et al., 2024). \nDespite promising possibilities of Robotic-Assisted Laparoscopic Surgery, studies comparing both minimally invasive surgical \ntechniques show mixed results (Ferrari et al., 2024; Ong et al., 2024; Song et al., 2023). Published reports indicate that laparoscopic \nsurgery characterizes a statistically significant lower operation and hospitalization time compared with the robotic technique. \nHowever, for bowel-deep infiltrating endometriosis, some studies strongly suggest that robotic surgery is not a better option. This \ntechnique was associated with longer operating time, but shorter hospital stays and fewer complications compared to the laparoscopic \nsurgery (Ong et al., 2024).  On the other hand, no significant differences were observed between the two techniques in terms of blood \nloss, rehospitalization rates, intraoperative and postoperative complications, or conversion rates (Song et al., 2023). \n \n4. CONCLUSION \nEndometriosis is a chronic and weakening condition that severely impacts patients’ quality of life and requires a complex treatment \napproach. Managing endometriosis remains a challenge due to the variety of symptoms, disease progression, and patient responses to \ntreatments. Traditional treatment strategies, such as NSAIDs, hormonal therapy, and laparoscopic surgery, remain a foundation of \ncare. NSAIDs, while used the most commonly, have limited clinical relevance for managing endometriosis-related pain across studies. \nThe inconsistent effectiveness data underscore the need for more rigorous research in this area. Hormonal therapies, particularly \nprogestins and combined oral contraceptives, are the foundation for symptom control. At the same time, they seem beneficial i n \nreducing lesion proliferation. However, side effect associated with their use, especially the androgenic effects and impact o n bone \ndensity, proves the need for developing other treatment options with better tolerability. The GnRH agonists and antagonists a t first \nseemed like ideal hormonal therapy options, providing hypoestrogenism. Unfortunately, they are associated with menopausal -like \nsymptoms and bone loss. These side effect prevents clinicians from using GnRH agonist and antagonist as a long -term treatment \noption. Newer oral GnRH antagonists like relugolix and linzagolix have the ability to keep the estradiol levels within a ther apeutic \nwindow. Their development represents the best of both worlds - combining effectiveness and safety for long-term use. \nSurgical intervention, particularly minimally invasive laparoscopy, are a foundation of endometriosis treatment. They are mos tly \nbeneficial for women with significant organ involvement. Laparoscopy offers quicker recovery and better fertility outcomes, b ut on the \nother hand, it might need more specialized surgical training as it is more technically challenging. The integration of roboti c-assisted \nlaparoscopic surgery offers promising improvements in precision and ergonomics. However, long -term safety data is limited, and \nfurther research is necessary to assess the risk profile over an extended period of use.  \nNovel immunomodulatory therapies targeting the CD47 -SIRPa signaling pathway and NK cells are gaining attention. This \ntreatment approach could complement already existing hormonal strategies. Moreover, the role of microbiome, dietary intervent ions \nand supplementation are becoming essential strategies for controlling chronic pain and inflammation associated with endometri osis. It \n\n \nREVIEW | OPEN ACCESS   \n \nMedical Science 29, e127ms3666 (2025)                                                                                                                                                                10 of 12 \nstarts a new wave of holistic approach to endometriosis management; however, future high -quality RCTs with long follow -up periods \nand standardized supplements formulations are needed to provide more substantial evidence.  Modern pain management techniques, \nsuch as sacral neuromodulation and transcranial direct current stimulation, provide alternative options for patients with chr onic pelvic \npain.  The success in pain relief of these approaches highlights the complex nature of endometriosis -related pain. Novel approaches, \nincluding gene and cell -based therapies, represent a promising but still experimental area. Evidence from several studies strongly \nsuggests that technologies such as microRNA manipulation and adipose tissue -derived stem cells (ASCs) may hold promise for future \nendometriosis management, focusing on targeted treatments. Future research is needed to understand long -term outcomes better and \nintegrate these strategies into clinical practice.  \nEndometriosis remains a challenging condition that requires a complex treatment approach. The shift from traditional to moder n \nand experimental therapies shows a significant shift towards more personalized care. We can see the need for new strategies t hat \naddress both symptoms and pathophysiology of endometriosis. Looking forward, future research should focus on large -scale, long-\nterm clinical trials to validate these new therapies and explore the approaches that integrate pharmacological, surgical, and  lifestyle \ninterventions. A greater emphasis on patient -specific characteristics, including hormonal sensitivity, immune profile, and genetic \nbackground, may also help provide tailored strategies for managing endometriosis. Ultimately, the goal is to change from symp tom \nmanagement toward long-term disease modification and improved quality of life for all patients affected by endometriosis. \n \nAuthor’s Contributions \nPaulina Wasilewska contributed to the study design, coordinated the writing process, and led the development of the final manuscript. \nOlga Wojtczak was responsible for background research, clinical content input and refinement of the discussion section. \nKacper Zagaja supported data interpretation, helped organize the structure of the paper, and reviewed the final draft for consistency. \nJustyna Wróblewska performed the initial literature screening, contributed to the introduction and conclusion sections.  \nHubert Ziembicki assisted with referencing and table preparations. \nNatalia Skrzypska assisted in literature analysis, handled formatting and technical editing and ensured adherence to submission \nguidelines. \n \nAcknowledgments \nThe authors have no acknowledgments to disclose. \n \nInformed consent \nNot applicable. \n \nEthical approval \nNot applicable. \n \nFunding \nThis study has not received any external funding. \n \nConflict of interest \nThe authors declare that there is no conflict of interest. \n \nData and materials availability \nAll data associated with this study will be available based on the reasonable request to corresponding author.   \n \nREFERENCES \n1. 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