{"paper_id":"de3f408f-3967-41b2-bbb0-36d29177cad8","body_text":"REVIEW\nInflammopharmacology\nInflammopharmacology\nhttps://doi.org/10.1007/s10787-026-02356-6\n María Martínez-Esparza\nmaria@um.es\n1 Department of Biochemistry and Molecular Biology (B) and \nImmunology, School of Medicine, University of Murcia, \nRegional Campus of International Excellence “Campus \nMare Nostrum” and Biomedical Research Institute of Murcia \n(IMIB), Edificio LAIB, 4.54. Avda. Buenavista 32,  \n30120 El Palmar, Murcia, Spain\nAbstract\nEndometriosis is a chronic inflammatory and estrogen-dependent disease in which pain remains the leading cause of \nimpaired quality of life. Hormonal therapies constitute the cornerstone of medical management and include progestins, \ncombined estrogen–progestin contraceptives, gonadotropin-releasing hormone (GnRH) agonists and antagonists, selective \nestrogen and progesterone receptor modulators, and aromatase inhibitors. Although these treatments effectively suppress \novarian function and reduce estrogen-dependent lesion activity, their clinical benefits are frequently limited by adverse \neffects, contraceptive implications, and symptom recurrence after treatment discontinuation. Increasing evidence indicates \nthat the persistence of endometriosis-associated pain cannot be explained solely by hormonal dysregulation. A sustained \ninflammatory microenvironment, characterized by innate immune cell activation, pro-inflammatory cytokine production, \nand neuroimmune interactions, contributes to peripheral and central sensitization, thereby limiting the effectiveness of \ntherapies targeting endocrine pathways alone. These disease-driven mechanisms provide a biological explanation for the \nheterogeneous response to hormonal treatment observed in clinical practice. This review summarizes the mechanisms of \naction, clinical efficacy, safety profile and limitations of current hormonal therapies for endometriosis-associated pain. \nIn addition, it discusses the inflammatory and neuroimmune mechanisms underlying persistent pain and highlights the \nrationale for combining endocrine therapies with emerging anti-inflammatory and immunomodulatory strategies. Such \nintegrated approaches may improve long-term pain control, reduce recurrence, and contribute to more personalized man -\nagement of endometriosis.\nKeywords Endometriosis · Pain · Hormonal therapy · Inflammation · Pharmacology\nReceived: 10 July 2026 / Accepted: 27 July 2026\n© The Author(s) 2026\nHormonal therapies for endometriosis-associated pain: inflammatory \nlimitations and pharmacological challenges\nLaura García-Izquierdo1 · Sandra Acedo-Santamaría1 · Cristina García-Belchí1 · María Martínez-Esparza1\ndysmenorrhea and chronic pelvic pain (CPP) are the most \ncommon symptoms associated with endometriosis, pain \nintensity does not consistently correlate with disease stage, \nreflecting the complexity of its underlying mechanisms \n(Masciullo et al. 2021). CPP significantly impacts quality of \nlife (QoL), affecting physical, emotional, and sexual well-\nbeing (ACOG 2020).\nEndometriosis-associated pain is increasingly recognized \nas a multifactorial process involving hormonal, inflamma -\ntory, immune, and neurobiological mechanisms. Besides its \nestrogen dependence, endometriosis is characterized by a \npersistent inflammatory microenvironment, with increased \nconcentrations of cytokines and other immune media -\ntors in the peritoneal fluid, particularly in advanced stages \n(Sikora et al. 2018). Elevated levels of pro-inflammatory \ncytokines, such as interleukin-6 (IL-6) and tumor necro -\nsis factor-α (TNF-α), contribute not only to lesion devel -\nopment but also to peripheral and central sensitization \nIntroduction\nEndometriosis is a chronic inflammatory and estrogen-\ndependent disorder characterized by the abnormal growth \nof endometrium-like tissue outside the uterine cavity. It \naffects approximately 10–15% of women of reproductive \nage, although accurately determining its prevalence remains \na challenge due to delayed diagnosis and clinical heteroge -\nneity (Becker et al. 2021; Giudice et al. 2023). Although \n\n1 3\nL. García-Izquierdo et al.\nprocesses (Machairiotis et al. 2021). This complex interplay \nbetween hormonal, immune, and neural mechanisms may \nhelp explain both the poor correlation between the lesion \nextent and pain intensity and the heterogeneous response to \ncurrent hormonal therapies. Although hormonal therapies \nremain the cornerstone of the pharmacological management \nof endometriosis-associated pain, they primarily suppress \novarian function without directly targeting the inflamma -\ntory and neuroplastic mechanisms that sustain chronic pain, \nwhich may contribute to treatment failure, symptom recur -\nrence after treatment discontinuation, and adverse effects \nthat limit long-term use (Ferrero et al. 2026).\nThe aim of this review is to summarize current hormonal \ntherapies for endometriosis-associated pain, focusing on \ntheir mechanisms of action, clinical efficacy, and adverse \neffects, while discussing their limitations from an inflam -\nmatory and pharmacological perspective. In addition, the \nreview examines the inflammatory and neuroimmune mech-\nanisms that may explain the heterogeneous response to hor-\nmonal treatment and discusses emerging anti-inflammatory \ntherapeutic strategies that could complement current endo -\ncrine approaches.\nMethods\nLiterature search strategy\nA structured literature search was performed in PubMed \nto identify original clinical studies evaluating the efficacy \nand safety of hormonal therapies for the management of \nendometriosis-associated pain. The search included stud -\nies published between January 2000 and June 2026 and was \nconducted using combinations of free-text terms related \nto endometriosis, pain, hormonal treatment and adverse \neffects. The search terms included endometriosis, endome -\ntriosis-associated pain, chronic pelvic pain, dysmenorrhea, \nhormonal therapy, hormonal treatment, side effects, endo -\nmetriosis drugs and endometriosis pills. Reference lists of \neligible articles and relevant reviews were also screened to \nidentify additional studies.\nTo provide biological context for the discussion of the \ninflammatory and neuroimmune mechanisms underlying \npain persistence and the limitations of hormonal therapies, \na complementary narrative review of the literature was \nperformed. Relevant original articles and selected review \npapers addressing inflammation, immune dysregulation, \nneuroimmune interactions, pain sensitization, and emerg -\ning anti-inflammatory therapeutic strategies in endometrio-\nsis were identified through PubMed and by screening the \nreference lists of relevant publications. These studies were \nused to support the mechanistic discussion presented in \nSect. \"Inflammation-driven therapeutic resistance in endo -\nmetriosis-associated pain\".\nStudy selection\nTitles and abstracts retrieved through the structured search \nwere screened for relevance. Potentially eligible articles \nunderwent full-text evaluation according to predefined \ninclusion and exclusion criteria. Only original clinical stud-\nies evaluating currently available hormonal therapies for \nendometriosis-associated pain were included in the qualita-\ntive synthesis. Eligible study designs comprised randomized \ncontrolled trials and prospective or retrospective observa -\ntional studies. Meta-analyses, review articles, case reports, \nconference abstracts, editorials, animal studies, and studies \nlacking sufficient clinical outcome data were excluded from \nthe structured review. The study selection process is sum -\nmarized in Fig. 1.\nTo facilitate interpretation of the available evidence, the \nsupplementary tables summarize the design and sample size \nof the principal clinical studies included for each therapeu -\ntic approach.\nCurrent hormonal therapies\nCurrent management of endometriosis-associated pain com-\nbines surgery and pharmacological treatment, depending on \nsymptom severity, disease characteristics, and reproductive \ngoals (Kalaitzopoulos et al. 2021).\nPharmacological management mainly relies on hor -\nmonal therapies and nonsteroidal anti-inflammatory drugs \n(NSAIDs). Hormonal therapies suppress ovarian function \nor modulate estrogen and progesterone signaling, thereby \nreducing the growth and activity of endometriotic lesions. \nCurrent therapeutic options include progestins, combined \nestrogen–progestin contraceptives, gonadotropin-releasing \nhormone (GnRH) agonists and antagonists, selective estro -\ngen receptor modulators (SERMs), selective progesterone \nreceptor modulators (SPRMs), and aromatase inhibitors \n(AIs) (Fig. 2). Supplementary Tables S1–S5 summarize the \nprincipal clinical studies evaluating hormonal therapies. \nAdditional included studies are discussed in the text when \nthey provide complementary information on compara -\ntive efficacy, combination therapies, long-term follow-up, \nsafety, or specific clinical observations.\nProgestogens (Supplementary Table S1)\nNomegestrol acetate binds specifically to the progester -\none receptor, exerting strong antiestrogenic effects and \npotent antigonadotropic activity. Due to its long half-life \n\n1 3\nHormonal therapies for endometriosis-associated pain: inflammatory limitations and pharmacological…\n(50 h), it can cover the hormone-free interval for 4 days. \nTreatment with nomegestrol acetate is typically combined \nwith 17β-estradiol (E2), resulting in a 24/4 oral contra -\nceptive regimen. Treatment with E2/nomegestrol acetate \n(1.5 mg/2.5 mg) increased amenorrhea over time while \nreducing CPP and improving sexual activity and QoL \n(Caruso et al. 2020).\nDienogest (DNG) is a highly selective progesterone \nreceptor agonist that can be administered continuously \nwithout causing major metabolic disturbances. Since its \napproval in Europe in 2010 for the treatment of endome -\ntriosis, oral DNG (2 mg/day) has become one of the most \nwidely used hormonal therapies (Heinemann et al. 2020). \nTreatment should be maintained for at least 3 months, \nwith 6–12 months generally required to achieve signifi -\ncant reductions in inflammation and endometrioma size. \nThe most common adverse effects include abnormal uter -\nine bleeding, weight gain, headache, and breast tenderness \n(Cho et al. 2020). Clinical studies have consistently demon-\nstrated that DNG reduces dysmenorrhea, dyspareunia, CPP, \nendometrioma size, and deep endometriotic lesions while \nimproving QoL (Grandi et al. 2015; Piacenti et al. 2021; \nSaglik Gokmen et al. 2023). Compared with levonorg -\nestrel/ethinylestradiol, DNG provided greater overall pain \nrelief, whereas both treatments similarly improved dyspa -\nreunia, reduced NSAID use, and enhanced QoL (Piacenti \net al. 2021). Additional benefits have also been reported \nwhen DNG was combined with ethinylestradiol or estradiol \nvalerate, including improvements in dysuria (Del Forno et \nal. 2023).\nIn patients newly diagnosed with endometriosis and ade-\nnomyosis who were not candidates for surgical treatment, \na prolonged flexible oral contraceptive regimen (2 mg of \nDNG/30 µg of ethinylestradiol) was proposed, consisting \nof 120 consecutive 30-day cycles of active tablets followed \nby a 4-day tablet-free interval. A significant decrease in \ninflammation and in the size of ovarian endometriomas and \nin uterosacral ligament involvement in adenomyosis was \nobserved at the 12-month follow-up (Carrillo Torres et al. \n2023).\nEtonogestrel (3-keto-desogestrel), the active metabo -\nlite of desogestrel, is administered as a 68-mg subdermal \nimplant (Nexplanon® or Implanon®) that inhibits ovulation \nfor up to 3 years. Clinical studies have shown significant \nreductions in dysmenorrhea, dyspareunia, and CPP, together \nwith improvements in QoL, including physical pain, general \nhealth, vitality, social functioning, and mental health (San -\nsone et al. 2018). Niu et al. ( 2021) conducted a 24-month \ntrial in which 66 patients experienced complete remission \nof CPP. The most common adverse events were vaginal \nbleeding and menstrual disturbances, together with gener -\nally mild systemic side effects, including weight gain, acne, \nbreast tenderness, mood changes, decreased libido, sleep \ndisturbances, constipation, and skin-related symptoms.\nThe levonorgestrel-releasing intrauterine system (LNG-\nIUS) continuously releases levonorgestrel (20 µg/day) into \nFig. 1 Flow diagram of the \nliterature search and study selec-\ntion process. Original clinical \nstudies evaluating currently \navailable hormonal therapies \nfor endometriosis-associated \npain were identified through \na structured PubMed search \nconducted between January 2000 \nand June 2026. Records were \nscreened according to predefined \neligibility criteria, and stud-\nies included in the qualitative \nsynthesis were selected follow-\ning title, abstract, and full-text \nassessment. A complementary \ntargeted narrative search was \nperformed separately to sup-\nport the mechanistic discussion \npresented in Sect. \"Inflammation-\ndriven therapeutic resistance in \nendometriosis-associated pain\" \nand is therefore not represented \nin this flow diagram\n \n\n1 3\nL. García-Izquierdo et al.\nthe uterine cavity for up to 5 years. Treatment significantly \nimproved endometriosis-associated symptoms within the \nfirst 12–18 months, with sustained clinical benefit during \nfollow-up. The most common adverse effects were men -\nstrual irregularities, persistent pelvic pain, and weight gain \n(Lockhat et al. 2005). In a comparative study, the LNG-\nIUS and the etonogestrel subdermal implant showed simi -\nlar efficacy in reducing non-menstrual pelvic pain (NMPP) \nand dysmenorrhea, while improving QoL without inducing \nhypoestrogenism (Carvalho et al. 2018).\nMedroxyprogesterone acetate is administered as a 150-\nmg intramuscular injection every 3 months. In a com -\nparative study with the etonogestrel subdermal implant \n(Implanon®), both treatments achieved a similar reduction \nin endometriosis-associated pain (approximately 50%) dur-\ning the first 3 months, with generally mild and transient \nadverse effects. After one year, amenorrhea was observed \nin a similar proportion of women receiving either treatment \n(14–15%) (Walch et al. 2009). Likewise, postoperative treat-\nment with medroxyprogesterone acetate and combined oral \ncontraceptives showed comparable efficacy in pain control \nand a similar safety profile (Cheewadhanaraks et al. 2012).\nDydrogesterone has high oral bioavailability and, at rela-\ntively low doses, is associated with a favorable safety profile. \nUnlike other progestins, it does not exert androgenic effects \nor inhibit ovulation (Schweppe 2009). In the ORCHIDEA \nstudy, dydrogesterone administered either cyclically (10 mg \ntwo or three times daily from days 5 to 25 of the menstrual \ncycle) or continuously for 6 months significantly reduced \nCPP, dysmenorrhea, and analgesic use, while improving \nsexual well-being and QoL. Uterine bleeding was reported \nin only 1.1% of participants (Sukhikh et al. 2021).\nDanazol has shown limited clinical use because of its \nunfavorable safety profile. Oral administration (600 mg/day \nFig.  2 Current hormonal therapies and emerging pharmacological \nstrategies for endometriosis-associated pain. Hormonal therapies, \nincluding progestins, combined estrogen–progestin contraceptives, \nand GnRH analogs/antagonists, primarily suppress ovarian function \nand reduce estrogen-dependent lesion activity, leading to improve -\nments in CPP, dysmenorrhea, and quality of life. However, these \ntreatments are mainly suppressive rather than curative and are limited \nby adverse effects, symptom recurrence after treatment discontinua -\ntion, and their limited impact on the inflammatory and neuroimmune \nmechanisms underlying pain persistence. Emerging pharmacological \nstrategies, including immunomodulatory therapies, anti-inflammatory \nand antioxidant compounds, and drug repurposing approaches, aim \nto target the inflammatory microenvironment and may complement \nendocrine therapies to improve long-term clinical outcomes. Created \nwith BioRender.com\n \n\n1 3\nHormonal therapies for endometriosis-associated pain: inflammatory limitations and pharmacological…\nfor 6 months) was associated with poor tolerability, with \nthe most frequent adverse effects including weight gain, \nacne, vaginal bleeding, generalized spasms, vaginitis, pain, \nhypertonia, and an unfavorable lipid profile characterized \nby increased LDL and decreased HDL cholesterol, poten -\ntially increasing cardiovascular risk (Cheng et al. 2005). In \ncontrast, intrauterine administration of danazol through a \ndanazol-loaded intrauterine device (400 mg for 6 months) \neffectively reduced dysmenorrhea, pelvic pain, and dyspa -\nreunia in women with moderate-to-severe endometriosis \nwhile minimizing systemic adverse effects (Cobellis et al. \n2004).\nCombined estrogen-progestin contraceptive \ntherapy (Supplementary Table S2)\nCombined estrogen–progestin contraceptives are widely \nused as first-line therapy for women with endometriosis \nwho do not wish to conceive. Their therapeutic effect is \nbased on ovulation suppression and the reduction of estro -\ngen-dependent stimulation of endometriotic lesions.\nTreatment with drospirenone (3 mg)/ethinylestradiol \n(20 µg) stabilized symptom severity and health-related QoL \nin women with posterior deep infiltrating endometriosis \n(DIE), while preventing lesion progression, inflammation, \nand worsening of dysmenorrhea and dyspareunia compared \nwith untreated controls (Mabrouk et al. 2011). No signifi -\ncant differences in symptom relief, lesion progression, or \ntolerability were observed between continuous and cyclic \n(24/4) regimens, although intermenstrual spotting and head-\nache were the most common adverse effects (Mabrouk et \nal. 2012).\nBeyond symptom control, combined oral contraceptives \nmay also modulate the immune microenvironment. Treat -\nment with ethinylestradiol/desogestrel reduced macrophage \ninfiltration while increasing NK and Treg cell populations \nin endometriotic tissue, together with decreased cell prolif -\neration and increased apoptosis in the eutopic endometrium \n(Waiyaput et al. 2021).\nMore recently, continuous treatment with estetrol \n(14 mg)/drospirenone (3 mg) for 6 months significantly \nreduced CPP and dyspareunia, completely resolved dysmen-\norrhea through amenorrhea induction, and reduced endome-\ntrioma size by approximately 30%, although intermenstrual \nspotting was the most frequent adverse event (Dell´Aquila \net al. 2026).\nGonadotropin-releasing hormone (GnRH) analogs \n(Supplementary Table S3)\nGnRH agonists suppress ovarian estrogen production \nthrough pituitary desensitization and are effective in \nreducing endometriosis-associated pain. In a comparative \nstudy, depot goserelin (3.6 mg every 28 days) and intranasal \nnafarelin (200 µg twice daily) produced similar reductions \nin dysmenorrhea, dyspareunia, and CPP, with no significant \ndifferences in efficacy. The most common adverse effects \nwere hot flashes, sweating, vaginal dryness, and headache, \nwhile nasal irritation was reported only with nafarelin \n(Bergqvist 2000).\nA randomized comparative trial showed that 4 months of \ntriptorelin followed by 8 months of combined estrogen–pro-\ngestin therapy (gestodene/ethinylestradiol) provided pain \nrelief comparable to that achieved with continuous com -\nbined hormonal contraception for 12 months (Parazzini et al. \n2000). More recently, a Phase III randomized trial demon -\nstrated that triptorelin acetate administered every 3 months \n(15 mg) achieved comparable efficacy and safety to the con-\nventional monthly regimen (3.75 mg), while reducing the \nfrequency of injections and maintaining pain relief through-\nout the 24-week treatment period (Li et al. 2022).\nGnRH Antagonists (Supplementary Table S3)\nElagolix was the first oral GnRH antagonist approved for \nthe management of endometriosis-associated pain. In the \nELARIS EM trial, both approved doses (150 mg once daily \nand 200 mg twice daily) significantly reduced dysmenor -\nrhea and analgesic use, with greater efficacy observed at \nthe higher dose (Taylor et al. 2017). Long-term treatment \neffectively controlled menstrual pelvic pain while minimiz-\ning hypoestrogenic effects, particularly at the lower dose, \nwhich was associated with only minimal changes in BMD \nand may be used for up to 24 months (Abrao et al. 2021; \nAbbas Suleiman et al. 2020).\nRelugolix also demonstrated efficacy comparable to \nleuprorelin while avoiding the initial hormonal flare asso -\nciated with GnRH agonists and allowing a faster recovery \nof menstruation after treatment discontinuation (Osuga et \nal. 2021). In the SPIRIT 1 and SPIRIT 2 trials, once-daily \nrelugolix combination therapy (relugolix, estradiol, and nor-\nethisterone acetate) significantly improved dysmenorrhea, \nNMPP, and overall endometriosis-related pain, while reduc-\ning opioid use and minimizing bone mineral density loss \n(Giudice et al. 2022).\nThe EDELWEISS clinical development programme \nestablished linzagolix as another effective oral GnRH antag-\nonist. Early studies identified 75 mg/day as the optimal dose \nto relieve pain while maintaining estradiol concentrations \nwithin the therapeutic window and minimizing hypoestro -\ngenic adverse effects (Donnez et al. 2020). Subsequently, \nthe Phase III EDELWEISS 3 trial demonstrated that both \n75 mg monotherapy and 200 mg combined with add-back \ntherapy significantly improved dysmenorrhea and NMPP, \n\n1 3\nL. García-Izquierdo et al.\nwith the higher dose providing greater symptom control \nwhile minimizing vasomotor symptoms and bone loss \n(Donnez et al. 2024). Long-term extension data confirmed \nsustained improvements in pain, QoL, dyschezia, dyspa -\nreunia, and analgesic use, with only minimal reductions in \nBMD after 12 months of treatment (Donnez et al. 2026).\nOpigolix demonstrated dose-dependent efficacy in reduc-\ning overall pelvic pain, dysmenorrhea, and menstrual pelvic \npain in the Phase II TERRA study. The treatment was gen -\nerally well tolerated, with headache, hot flashes, insomnia, \ntinnitus, and gastrointestinal symptoms representing the \nmost common adverse events (D’Hooghe et al. 2019).\nSelective estrogen receptor modulators (SERMs) \n(Supplementary Table S4)\nBazedoxifene is a selective estrogen receptor modulator \nthat antagonizes estrogen-induced endometrial stimula -\ntion while preserving the beneficial estrogenic effects on \nbone and the central nervous system. Treatment with baze -\ndoxifene combined with conjugated estrogens reduced \nmenstrual flow and pelvic pain in a patient with stage III \nendometriosis (Flores et al. 2018). In a single case report, \nprolonged treatment with bazedoxifene/conjugated estro -\ngens in combination with leuprolide effectively controlled \nendometriosis-associated pain while reducing the vasomo -\ntor symptoms and bone mineral density loss typically asso -\nciated with GnRH agonists (Hill et al. 2018).\nSelective progesterone receptor modulators \n(SPRMs) (Supplementary Table S4)\nMifepristone, a progesterone receptor antagonist, has been \nevaluated as an alternative treatment for endometriosis-\nassociated pain. In a 24-week clinical trial, combination \ntherapy with mifepristone (12.5 mg/day) and gestrinone \nachieved greater clinical efficacy than gestrinone alone, sig-\nnificantly reducing dysmenorrhea, dyspareunia, pelvic pain, \npelvic tenderness, and induration. In addition to pain relief, \nthis combination reduced hormone levels and was associ -\nated with improved pregnancy outcomes (Xue et al. 2016).\nA retrospective clinicopathological study also reported \nthat prolonged mifepristone exposure may induce morpho -\nlogical changes in ovarian endometriosis that can mimic \nborderline endometrioid tumors. These findings highlight \nthe importance of careful histopathological interpretation \nand appropriate clinical correlation, rather than suggesting \nmalignant transformation (Pan et al. 2022).\nUlipristal acetate (15 mg/day) also improved pain \nsymptoms in a patient with treatment-resistant endome -\ntriosis; however, treatment was associated with reversible \nendometrial changes resembling hyperplasia after less than \n3 months of therapy (Bressler 2017).\nEvidence for both SERMs and SPRMs remains limited \ncompared with progestins and GnRH analogs, highlighting \nthe need for further clinical studies to define their role in the \nmanagement of endometriosis-associated pain.\nAromatase inhibitors (AIs) (Supplementary Table S5)\nAromatase inhibitors have been evaluated mainly in combi-\nnation therapies for women with refractory or severe endo -\nmetriosis. Anastrozole has demonstrated efficacy both as \nmonotherapy and in combination with oral contraceptives. \nCombined treatment with anastrozole (1 mg/day) and ethi-\nnylestradiol/levonorgestrel provided greater symptom relief \nthan oral contraceptives alone, although pelvic pain exacer-\nbation associated with intermenstrual bleeding was reported \nin some patients. Adverse effects, including headache, hot \nflashes, mood changes, and myalgia, were generally mild \nand resolved during follow-up (Amsterdam et al. 2005). \nMore recently, preoperative treatment with anastrozole \n(1 mg/day for 6 months) significantly improved dysmenor-\nrhea and CPP while delaying symptom recurrence after sur-\ngery (Acién et al. 2021).\nClinical studies with letrozole have focused primarily \non combination therapy for rectovaginal endometriosis. \nLetrozole plus norethisterone acetate was associated with \nfewer adverse effects, lower treatment discontinuation rates, \ngreater patient satisfaction, and no significant loss of BMD \ncompared with letrozole plus triptorelin. Both regimens sig-\nnificantly reduced pain symptoms, although the reduction \nin the volume of endometriotic nodules was greater with \ntriptorelin (Ferrero et al. 2011). Likewise, the combination \nof letrozole with oral contraceptives achieved greater reduc-\ntions in CPP and dyspareunia than oral contraceptives alone, \nwith a lower incidence of adverse effects (Zhao et al. 2021).\nInflammation-driven therapeutic resistance \nin endometriosis-associated pain\nAlthough hormonal therapies effectively suppress ovarian \nestrogen production and reduce lesion activity, a substantial \nproportion of women continue to experience CPP despite \nadequate endocrine suppression (Becker et al. 2022; Giu-\ndice et al. 2023). This clinical observation suggests that pain \npersistence reflects disease-driven inflammatory and neuro-\nimmune mechanisms that progressively become uncoupled \nfrom ovarian steroid production rather than true pharma -\ncological resistance (Machairiotis et al. 2021; Sikora et al. \n2018). Collectively, these mechanisms provide a biological \nframework for understanding the heterogeneous clinical \n\n1 3\nHormonal therapies for endometriosis-associated pain: inflammatory limitations and pharmacological…\nresponse to endocrine therapies and support the develop -\nment of complementary therapeutic strategies targeting \ninflammation and neuroimmune dysfunction (Ramírez-\nPavez et al. 2021; Wang et al. 2025).\nThe inflammatory microenvironment characteristic of \nendometriosis is sustained by the continuous recruitment and \nactivation of innate immune cells within the peritoneal cav-\nity (Ramírez-Pavez et al. 2021; Wang et al. 2025). Among \nthese, macrophages constitute the predominant leukocyte \npopulation and play a central role in lesion establishment, \nangiogenesis, fibrosis, immune dysregulation, and pain \ngeneration (Ruiz-Alcaraz et al. 2020; Ramírez-Pavez et al. \n2021, 2023; Wang et al. 2025). Endometriotic lesions recruit \ncirculating monocytes that differentiate into activated mac -\nrophages under the influence of local cytokines and growth \nfactors. During disease progression, macrophages undergo \ndynamic changes in their activation profile. Although they \nexhibit remarkable phenotypic plasticity and encompass \na broad spectrum of activation states, endometriosis pro -\ngression is accompanied by a progressive shift towards \nM2-like macrophages, resulting in an increased M2/M1 \nratio that promotes immune tolerance, angiogenesis, extra -\ncellular matrix remodelling and fibrosis while impairing the \nclearance of ectopic endometrial tissue (Ramírez-Pavez et \nal. 2021; Kobayashi and Imanaka 2022; Wang et al. 2025).\nThese activated immune cells release increased levels of \nIL-1β, IL-6, TNF-α, transforming growth factor (TGF)-β, \nprostaglandins, and other inflammatory mediators, thereby \ncontributing to a self-perpetuating inflammatory loop that \nfavours lesion survival while continuously stimulating \nperipheral nociceptors. In parallel, mast cells accumulate \naround endometriotic lesions and sensory nerve fibres, \nwhere they release histamine, tryptase, prostaglandins, and \nnerve growth factor (NGF), further amplifying neurogenic \ninflammation and pain transmission. Neutrophils also con -\ntribute during the early stages of lesion development through \nthe release of inflammatory cytokines, reactive oxygen spe-\ncies, and angiogenic factors, facilitating lesion vasculariza -\ntion and maintaining local inflammation (Ramírez-Pavez et \nal. 2021; Wang et al. 2025). Together, these processes may \nhelp explain why inflammatory pathways may remain active \ndespite adequate ovarian suppression, allowing chronic pain \nto persist in a subset of patients. The mechanisms linking \npersistent inflammation and neuroimmune activation with \nthe limited efficacy of current hormonal therapies are sum -\nmarized in Fig. 3.\nFig.  3 Inflammatory and neuroimmune mechanisms contributing to \nthe limited efficacy of hormonal therapies in endometriosis-associated \npain. Endometriotic lesions promote a persistent inflammatory micro-\nenvironment characterized by the activation of innate immune cells \nand the release of pro-inflammatory mediators, leading to peripheral \nand central sensitization and the maintenance of CPP. Current hor -\nmonal therapies primarily suppress ovarian function and reduce estro-\ngen-dependent lesion activity but have limited effects on inflammatory \nand neuroimmune pathways. Emerging pharmacological strategies \ntargeting these mechanisms may complement endocrine therapies and \nimprove long-term pain control. Created with BioRender.com\n \n\n1 3\nL. García-Izquierdo et al.\nInflammatory and neuroimmune mechanisms \nsustaining persistent pain\nPersistent activation of innate immune cells establishes a \ncomplex inflammatory network that extends beyond local \ntissue injury and plays a central role in pain chronification. \nActivated macrophages, mast cells, neutrophils, and ectopic \nendometrial cells release a broad repertoire of cytokines, \nchemokines, and lipid mediators that interact through mul -\ntiple positive feedback loops, perpetuating inflammation \neven in the presence of effective endocrine suppression \n(Ramírez-Pavez et al. 2021; Wang et al. 2025; Shifon et al. \n2025).\nAmong these mediators, IL-1β, IL-6, TNF-α, and IL-8 \npromote leukocyte recruitment, amplify cytokine produc -\ntion, and stimulate cyclooxygenase-2 (COX-2)-dependent \nprostaglandin E2 (PGE2) synthesis, thereby reinforcing \ninflammatory signalling and nociceptor activation (Burns et \nal. 2018; Pizzo et al. 2002; Machairiotis et al. 2021). In par-\nallel, TGF-β contributes to tissue remodelling and fibrosis, \ncreating a microenvironment that favours lesion persistence \nand may further impair normal tissue homeostasis (Hull et \nal. 2012; Young et al. 2017; Matsuzaki et al. 2022, 2023). \nOxidative stress, generated by activated immune cells and \niron overload derived from repeated cyclic bleeding, is also \nthought to amplify these inflammatory pathways by enhanc-\ning cytokine production, promoting inflammasome activa -\ntion, and sustaining chronic tissue damage (Donnez et al. \n2016; Machairiotis et al. 2021). Together, these mediators \nare thought to establish a self-perpetuating inflammatory \nnetwork that contributes not only to lesion progression but \nalso to the maintenance of persistent pain.\nThe interaction between immune and nervous system \ncomponents further amplifies pain signalling through a \nbidirectional neuroimmune communication network. NGF \npromotes the sprouting of sensory nerve fibres and increases \nnociceptor excitability, whereas brain-derived neurotrophic \nfactor (BDNF) contributes to neuronal plasticity and pain \nsensitization. A recent systematic review and meta-analysis \ndemonstrated increased expression of both neurotrophins in \nwomen with endometriosis, supporting their involvement \nin disease pathophysiology, although evidence for NGF \nremains limited (Liu et al. 2023). Experimental studies fur-\nther indicate that endometriotic cells represent an important \nsource of neurotrophins and that reducing NGF and BDNF \nexpression is accompanied by attenuation of macrophage \nactivation and inflammatory signalling, highlighting the \nclose interplay between neurotrophic and immune path -\nways (Browne et al. 2012; Woo et al. 2019). In addition, \nthe CX3CL1/CX3CR1 signalling axis has emerged as an \nimportant mediator of communication between immune \ncells and sensory neurons, promoting neuroinflammation \nand sustaining peripheral sensitization (Wang et al. 2025). \nMacrophages further contribute to neuroimmune crosstalk \nthrough the release of inflammatory mediators and insulin-\nlike growth factor-1 (IGF-1), which promotes nerve fibre \ngrowth and neuronal sensitization (Greaves et al. 2015; \nForster et al. 2019; Wang et al. 2025). These reciprocal \ninteractions are thought to establish a neuroinflammatory \nmicroenvironment that reinforces nociceptive signalling \nand favours pain persistence despite suppression of ovarian \nhormone production.\nSustained peripheral nociceptor activation eventually \ninduces functional and structural changes within the central \nnervous system, leading to central sensitization, a process \ncharacterized by exaggerated pain responses, allodynia, and \nhyperalgesia that may persist independently of the initial \nperipheral stimulus (Machairiotis et al. 2021; Wang et al. \n2025). Consequently, although hormonal therapies effec -\ntively reduce estrogen-dependent lesion activity, they may \nbe insufficient to reverse the neuroimmune mechanisms \nresponsible for pain chronification once central sensiti -\nzation has been established. Althought further studies are \nneeded to stablish the clinical contribution of these mecha -\nnisms, this concept provides a plausible mechanistic expla -\nnation for the heterogeneous clinical response observed \namong women receiving endocrine therapies and supports \nthe development of complementary therapeutic strategies \ntargeting inflammatory and neuroimmune pathways (Mach-\nairiotis et al. 2021; Wang et al. 2025).\nEmerging anti-inflammatory pharmacological \nstrategies\nThe growing recognition that persistent inflammation and \nimmune dysregulation may contribute to disease progres -\nsion and pain chronification has prompted the development \nof novel pharmacological strategies that extend beyond \nendocrine suppression. Rather than targeting ovarian func -\ntion, these approaches aim to modulate the inflammatory \nmicroenvironment, restore immune homeostasis and inter -\nfere with the molecular pathways that sustain lesion per -\nsistence, fibrosis and chronic pain (Symons et al. 2018; \nSaunders and Horne 2021; Chen et al. 2023; Perrone et al. \n2025).\nCytokine-targeted therapies have also emerged as prom -\nising strategies to complement endocrine treatment by \ndirectly modulating the inflammatory microenvironment \n(García-Izquierdo et al. 2024; Shifon et al. 2025; Perrone \net al. 2025). Among these approaches, inhibition of TNF-\nα, IL-6, IL-1 family signalling, IL-8, CCL2/CCR2 and \nTGF-β has shown encouraging preclinical results by reduc-\ning inflammatory signalling, angiogenesis, immune cell \nrecruitment and lesion growth, although clinical translation \n\n1 3\nHormonal therapies for endometriosis-associated pain: inflammatory limitations and pharmacological…\nremains limited (Shifon et al. 2025). IL-6 has received par-\nticular attention owing to its central role in endometriosis \npathophysiology and the availability of clinically approved \ninhibitors for other inflammatory diseases. In experimental \nmodels, IL-6 blockade with tocilizumab reduced lesion vol-\nume and promoted ectopic endometrial atrophy, although \nevidence in women with endometriosis is still lacking \n(Shifon et al. 2025). Likewise, targeting the IL-1 signal -\nling pathway has demonstrated therapeutic potential, with \nsoluble IL-1 receptor type II reducing lesion development in \nanimal models, probably through inhibition of IL-1-induced \nangiogenesis and IL-6 production (Shifon et al. 2025). \nAdditional experimental evidence indicates that inhibition \nof the IL-33/MyD88 signalling axis also suppresses lesion \ngrowth and cellular proliferation, further supporting IL-1 \nfamily members as promising therapeutic targets (Kato et \nal. 2019). IL-17 has likewise emerged as a potential target, \nas increased Th17 cells and IL-17 expression contribute to \nchronic inflammation, lesion progression and immune dys -\nregulation in endometriosis (Kang et al. 2023). Despite this \nstrong biological rationale, most cytokine-targeted therapies \nremain at the preclinical or early clinical stage, highlighting \nthe need for biomarker-guided patient stratification and pre-\ncision medicine approaches rather than reliance on single-\ncytokine blockade (Shifon et al. 2025).\nBeyond cytokine-targeted therapies, several additional \nnon-hormonal immunomodulatory strategies are currently \nbeing investigated to overcome the inflammatory and \nimmune dysfunction that persists despite endocrine treat -\nment. These include inhibitors of prostaglandin synthe -\nsis, antioxidants, inflammasome modulators and therapies \naimed at restoring macrophage function (García-Izquierdo \net al. 2024; Shifon et al. 2025; Perrone et al. 2025). Among \nthese, macrophage-directed therapies appear particularly \nattractive because macrophages occupy a central position \nin the inflammatory, fibrotic and angiogenic networks that \ndrive endometriosis. Restoring macrophage homeostasis \nmay therefore represent a promising strategy to simulta -\nneously reduce inflammation, fibrosis, angiogenesis and \nlesion progression (Ramírez-Pavez et al. 2021; Wang et al. \n2025). Recent studies using macrophage-derived extracel -\nlular vesicles and macrophage-targeted nanoparticle deliv -\nery systems have further demonstrated that macrophage \nreprogramming can attenuate disease progression in experi-\nmental models, reinforcing its potential as a non-hormonal \ntherapeutic approach (Zhang et al. 2024; Wu et al. 2025).\nIncreasing attention has also been devoted to drug \nrepurposing as a strategy to accelerate the identification \nof effective non-hormonal treatments. Several approved \ndrugs with anti-inflammatory, antioxidant or immuno -\nmodulatory properties have shown the ability to attenuate \ninflammatory signalling and reduce lesion progression in \nexperimental studies, highlighting the potential of reposi -\ntioned compounds as complementary therapies. Neverthe -\nless, their clinical utility in endometriosis-associated pain \nremains to be established through adequately powered ran -\ndomized clinical trials.\nOverall, current evidence supports the concept that hor -\nmonal suppression alone is unlikely to provide optimal long-\nterm symptom control in all patients. Future therapeutic \nstrategies will likely require a more personalized approach \ncombining endocrine therapies with pharmacological inter-\nventions targeting inflammation and immune dysregula -\ntion. A comprehensive review of emerging pharmacological \napproaches for endometriosis-associated pain has recently \nbeen published; therefore, these strategies are not discussed \nhere in detail (García-Izquierdo et al. 2024).\nDiscussion and conclusions\nThe present review highlights that, despite the availability \nof several hormonal therapies with different mechanisms of \naction, their overall efficacy in controlling endometriosis-\nassociated pain is broadly comparable, while long-term \ndisease management remains limited by adverse effects, \nsymptom recurrence after treatment discontinuation, and the \ninability of endocrine therapies to fully address the inflam -\nmatory mechanisms underlying pain persistence (Ferrero et \nal. 2026).\nImportantly, despite differences in their mechanisms of \naction, the currently available hormonal therapies show \nbroadly comparable efficacy in pain control, and treatment \nselection is therefore mainly guided by patient characteris -\ntics, adverse-effect profiles, treatment duration, contracep -\ntive needs, and reproductive goals.\nLong-term management remains challenging because \nsymptom recurrence after treatment discontinuation is com-\nmon, while adverse effects—including abnormal uterine \nbleeding, weight gain, headache, vasomotor symptoms, and \ndecreased BMD—may compromise adherence and limit \nprolonged use. Consequently, no single hormonal therapy is \nuniversally suitable for all women, highlighting the need for \nindividualized therapeutic strategies.\nThe present review also emphasizes that the limited long-\nterm efficacy of hormonal therapies cannot be explained \nsolely by endocrine mechanisms. Increasing evidence indi -\ncates that persistent inflammation and neuroimmune dysreg-\nulation contribute to pain chronification through biological \nprocesses that may remain active despite adequate suppres-\nsion of ovarian steroid production. Rather than representing \ntrue pharmacological resistance, this phenomenon reflects \ndisease-driven mechanisms that are insufficiently targeted \nby current endocrine therapies.\n\n1 3\nL. García-Izquierdo et al.\nThese observations provide a mechanistic framework \nfor understanding the marked heterogeneity in treatment \nresponse observed in clinical practice. They also support the \nconcept that inflammation, immune cell activation, periph -\neral and central sensitization, and neuroimmune interac -\ntions represent complementary therapeutic targets that may \nimprove long-term symptom control when combined with \nendocrine approaches.\nFrom a translational perspective, future management of \nendometriosis-associated pain will likely evolve toward \nmore personalized therapeutic strategies integrating hor -\nmonal treatments with pharmacological interventions tar -\ngeting inflammatory and neuroimmune pathways. The \nidentification of biomarkers capable of identifying the pre -\ndominant pathogenic mechanisms driving pain in individ -\nual patients may further facilitate individualized treatment \nselection and optimize clinical outcomes.\nThe interpretation of the available evidence should also \nconsider that clinical studies evaluating hormonal therapies \ndiffer substantially in study design, patient populations, \ntreatment duration, outcome measures, and sample size. \nAlthough randomized controlled trials are available for sev-\neral therapeutic options, a considerable proportion of the \nevidence derives from observational studies or relatively \nsmall cohorts, which should be considered when interpret -\ning the reported efficacy and generalizability of the findings.\nEndometriosis-associated pain is therefore a complex \nmultifactorial condition in which hormonal, inflamma -\ntory, immune and neurobiological mechanisms interact to \nsustain chronic pain and impair quality of life. While hor -\nmonal therapies remain the cornerstone of treatment, their \nintegration with immunomodulatory therapies, particularly \nthose targeting macrophage dysfunction, together with anti-\noxidant and anti-inflammatory compounds, and drug repur-\nposing strategies represents a promising avenue for future \nresearch rather than an established clinical practice (García-\nIzquierdo et al. 2024; Ferrero et al. 2026). Although encour-\naging preclinical evidence is accumulating, robust clinical \ntrials are still required to validate their efficacy and safety \nbefore their incorporation into routine clinical management.\nThe interpretation of the available evidence should also \nconsider that many clinical studies evaluating hormonal \ntherapies differ substantially in study design, patient popu -\nlations, treatment duration, outcome measures, and sample \nsize. Although randomized controlled trials are available for \nseveral therapeutic options, a considerable proportion of the \nevidence derives from observational studies or relatively \nsmall cohorts, which should be taken into account when \ninterpreting the reported efficacy.\nFinally, although the evidence supporting current hor -\nmonal therapies was identified through a structured litera -\nture search, the mechanistic discussion of inflammatory and \nneuroimmune pathways is based on a complementary nar -\nrative review of the literature. This approach was intended \nto provide biological context for the clinical findings and \nto facilitate their interpretation rather than to systematically \nevaluate emerging non-hormonal therapies.\nSupplementary Information  The online version contains \nsupplementary material available at  h t t  p s : /  / d o  i . o  r g / 1 0 . 1 0 0 7 / s 1 0 7 8 7 - 0 \n2 6 - 0 2 3 5 6 - 6     .  \nAcknowledgements The authors gratefully acknowledge Dr. María \ndel Pilar Marín for her valuable clinical advice and for her critical \nreview of an early version of this manuscript.\nAuthor contributions All authors contributed to the study conception \nand design. Literature search and data analysis were performed by \nL.G.I. and M.M.E. The first draft of the manuscript was written by \nL.G.I. and M.M.E. and all authors commented on previous versions \nof the manuscript. The manuscript was critically reviewed and edited \nby S.A.S. and C.G.B. M.M.E. supervised the study and validated the \nfinal manuscript. All authors read and approved the final manuscript.\nFunding Open Access funding provided thanks to the CRUE-CSIC \nagreement with Springer Nature. The authors declare that no funds, \ngrants, or other support were received during the preparation of this \nmanuscript.\nData availability No datasets were generated or analysed during the \ncurrent study.\nDeclarations\nConflict of interest The authors declare that they have no conflict of \ninterest.\nEthical approval  Not applicable. This article does not contain any \nstudies with human participants or animals performed by any of the \nauthors.\nConsent to participate  Not applicable. This review article does not \ninvolve human participants.\nConsent to publication Not applicable. This manuscript does not con-\ntain any individual person's data in any form.\nOpen Access   This article is licensed under a Creative Commons \nAttribution 4.0 International License, which permits use, sharing, \nadaptation, distribution and reproduction in any medium or format, \nas long as you give appropriate credit to the original author(s) and the \nsource, provide a link to the Creative Commons licence, and indicate \nif changes were made. The images or other third party material in this \narticle are included in the article’s Creative Commons licence, unless \nindicated otherwise in a credit line to the material. If material is not \nincluded in the article’s Creative Commons licence and your intended \nuse is not permitted by statutory regulation or exceeds the permitted \nuse, you will need to obtain permission directly from the copyright \nholder. 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