Precision Medical Management of Endometriosis: Neuroimmune Pathophysiology, Pain Phenotyping and Emerging Target Therapies
- 13 de abr.
- 21 min de leitura
WRITTEN BY
Perla Sofía Vera Hernández, Ramiro Cabrera Carranco, Ana Gabriela Sierra Brozón, William Kondo, Jordanna Diniz Osaki, Fernando Heredia Muñoz, Lucia Chaul, Christian Silva Rengifo
Submitted: 09 January 2026 Reviewed: 21 January 2026 Published: 02 March 2026
DOI: 10.5772/intechopen.1014711
Abstract
Endometriosis is a chronic, estrogen-dependent inflammatory disease influenced by complex neuroimmune interactions and pain chronification mechanisms. Modern medical management is increasingly guided by a deeper understanding of neuroinflammation, peripheral and central sensitization, and immune dysregulation, moving beyond traditional hormonal suppression. This chapter will synthesize the latest evidence on precision medicine approaches, integrating pain phenotyping, molecular and inflammatory biomarkers, and mechanisms of treatment resistance. It will explore targeted pharmacologic strategies, including neuromodulators, selective progesterone receptor modulators, immunomodulatory and anti-fibrotic agents, as well as innovative non-hormonal therapies under investigation. Additionally, it will highlight research gaps and opportunities for translational applications. The aim is to provide a rigorous, mechanism-based framework for individualized, effective, and biologically informed medical treatment of endometriosis.
1. Introduction
Endometriosis is a chronic, estrogen-dependent inflammatory disease characterized by the presence of endometrial-like tissue outside the uterine cavity, progressive fibrosis, and a complex pain syndrome that frequently extends beyond lesion burden. Pain and subfertility are the dominant clinical correlates, but over the last decade, endometriosis has been reframed as a systemic neuroimmune disorder with heterogeneous phenotypes rather than a purely pelvic nociceptive condition [1–3].
Traditional medical management of endometriosis has historically relied on ovarian suppression, using combined oral contraceptives, progestins, and gonadotropin-releasing hormone (GnRH) agonists or antagonists, with the aim of reducing lesion activity and controlling cyclical pain [1, 2, 4]. Although this strategy remains effective for a subset of patients, its limitations are increasingly recognized. Treatment resistance, intolerable side effects, fertility considerations, and the frequent persistence of pain despite apparent lesion control have challenged the long-standing view of ovarian suppression as the cornerstone of medical therapy [1, 2]. Moreover, profound ovarian suppression, particularly with GnRH analogues, effectively induces a hypoestrogenic state analogous to iatrogenic menopause, exposing patients to significant short- and long-term adverse effects, including vasomotor symptoms, bone mineral density loss, and potential metabolic and cardiovascular risks, often without achieving durable pain relief [5–7].
Importantly, persistent pain despite “adequate” hormonal therapy underscores that endometriosis-associated pain is not exclusively driven by cyclical bleeding or peripheral nociceptive input. Contemporary pain models conceptualize endometriosis as a neuroimmune disease, in which immune dysregulation, neuroangiogenesis, and maladaptive peripheral and central sensitization play central roles in pain generation and chronification [1, 2, 8]. These mechanisms may persist or even become autonomous after lesion excision or hormonal suppression, contributing to ongoing pain through centrally mediated and nociplastic pathways [8]. As a result, ovarian suppression, once considered the default initial medical treatment, should no longer be viewed as universally sufficient or benign, but rather as one component of a broader, mechanism-based therapeutic framework that acknowledges the complex neuroimmune biology of endometriosis and the need for individualized, precision-oriented pain management [1, 2, 8]. A precision medicine framework integrates molecular, immune, neurobiological, and psychosocial dimensions to tailor treatment to individual patients. This chapter reviews neuroimmune pathophysiology, pain phenotyping, emerging biomarkers, and novel/experimental therapies, with an emphasis on non-hormonal and mechanism-based strategies and their implications for personalized care [9, 10].
2. Conceptual framework: From lesions to systems-level pain
2.1 Endometriosis as a neuroimmune-fibrotic disease
Endometriotic lesions (particularly deep infiltrating endometriosis, DIE) exist within a microenvironment enriched with activated immune cells, cytokines, growth factors, angiogenic mediators, and sensory/autonomic nerve fibers. Lesions are not passive implants; they actively remodel surrounding tissue via inflammation-driven angiogenesis and fibroblast activation, producing a “wound that does not heal” phenotype. The result is a dynamic niche that supports persistent nociceptive drive, neurogenic inflammation, and progressive fibrosis [1, 2].
2.2 Pain chronification: Peripheral sensitization → central sensitization → nociplasticity
Pain in endometriosis spans menstrual and non-menstrual pelvic pain, dyspareunia, dyschezia, dysuria, and extra-pelvic pain syndromes. A modern model recognizes progression from peripheral sensitization (inflammatory mediator–driven nociceptor hyperexcitability) to central sensitization (amplified spinal and supraspinal processing), with eventual development of nociplastic pain in susceptible individuals. Importantly, lesion activity and central sensitization are not mutually exclusive; mixed phenotypes are common and require combination strategies [8].
2.3 Precision medicine goal
Precision care in endometriosis should answer four questions at each visit:
What is the dominant pain mechanism today? (nociceptive vs. neuropathic-like vs. nociplastic vs. mixed)
What lesion phenotype is present or suspected? (superficial peritoneal, ovarian endometrioma, DIE, adenomyosis overlap)
What systemic modifiers maintain pain? (sleep, mood, trauma, IBS, bladder pain syndrome, migraine, fibromyalgia)
What is the most efficient, lowest-risk intervention aligned with mechanism and reproductive goals?
3. Neuroimmune pathophysiology of endometriosis: Cells, pathways, and circuits
Endometriosis is driven by a complex neuroimmune microenvironment in which immune cells, fibroblasts, and sensory nerve fibers interact to sustain inflammation, neuroangiogenesis, fibrosis, and pain chronification. Figure 1 illustrates this cellular network within a deep infiltrating endometriosis nodule, highlighting key neuroimmune pathways, as described in the following sections.
3.1 Chronic peritoneal inflammation and lesion microenvironment
Endometriotic lesions are embedded in a peritoneal microenvironment characterized by:
Increased peritoneal fluid volume, rich in pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), chemokines, and prostaglandins.
Activated peritoneal macrophages with impaired clearance functions and enhanced production of reactive oxygen species (ROS) and angiogenic factors.
A pro-fibrotic milieu with excess transforming growth factor-β (TGF-β), extracellular matrix (ECM) remodeling, and myofibroblast activation.
This environment supports implantation, survival, and invasiveness of ectopic endometrial cells, as well as sprouting of nociceptive and sympathetic nerve fibers into lesions, particularly in deep infiltrating endometriosis (DIE) [1, 2].
3.2 Cellular players in the endometriosis lesion niche
Macrophages (M1/M2 spectrum). Endometriotic lesions contain abundant macrophages, exhibiting skewed polarization toward a mixed M1/M2 phenotype.
M1 macrophages: produce IL-1β, TNF-α, IL-6 → lesion survival and nociceptor sensitization.
M2 macrophages: secrete IL-10, TGF-β → fibrosis, angiogenesis, immunosuppression.
Dysregulation in macrophage recruitment (via CCL2/MCP-1) contributes to sustained inflammation and neuroangiogenesis [1,2].
T cells and Tregs. Dysregulated adaptive immunity includes altered Th1/Th2/Th17 balance and impaired regulatory T-cell (Treg) function, contributing to persistent inflammation and reduced clearance of ectopic cells. T-cell cytokines can amplify NF-κB–linked inflammatory cascades and perpetuate lesion persistence [1, 2].
Natural killer (NK) cells. Decreased cytotoxicity of NK cells impairs the clearance of ectopic endometrial cells. An altered NK phenotype contributes to immune escape, chronic lesion survival, and reduced apoptosis [1, 2].
Mast cells. Mast cells cluster near nerve fibers and release histamine, tryptase, and cytokines capable of promoting neurogenic inflammation, vasodilation, and nociceptor sensitization – particularly relevant to dyspareunia and localized hyperalgesia [1, 2].
Neutrophils and platelets. Early lesion establishment may involve neutrophil recruitment and platelet activation, which can support angiogenesis and fibrosis via growth factors and TGF-β [1, 2].
3.3 Key inflammatory and pro-nociceptive pathways
NF-κB axis. NF-κB functions as a central transcriptional hub linking inflammatory triggers to cytokine production, COX-2 induction, and cell survival programs. Persistent NF-κB activation in lesion tissue can sustain prostaglandin production and inflammatory sensitization [1, 2].
COX-2/prostaglandin E2 (PGE2). Upregulated COX-2 increases PGE2, which sensitizes nociceptors and contributes to local estrogen biosynthesis through aromatase induction, generating a self-reinforcing inflammatory–estrogen loop [1, 2, 4].
mTOR signaling. mTOR integrates growth, immune activation, and metabolism. Dysregulated mTOR signaling has been implicated in lesion growth, angiogenesis, and potentially immune reprogramming; interest in mTOR modulation persists as a non-hormonal strategy [4, 9].
TGF-β and fibrosis. TGF-β promotes fibroblast activation, extracellular matrix remodeling, and neuroangiogenesis. Fibrosis itself becomes a mechanical and biochemical driver of pain, particularly in DIE [9, 10].
Neurotrophins (NGF/BDNF) and neurogenic inflammation. Neurotrophins facilitate nerve sprouting and nociceptor sensitization. Sensory nerve activation triggers the release of neuropeptides (e.g., substance P, CGRP), which further amplify immune activation, creating a feed-forward loop of neurogenic inflammation [1, 2].
3.4 Neuroangiogenesis in DIE: Why nerves and vessels grow together
DIE nodules frequently exhibit dense innervation and vascular remodeling. Angiogenic mediators (VEGF, angiopoietins) and neurotrophins (NGF) act synergistically, supporting both vessel formation and nerve sprouting. This “neuroangiogenic unit” creates a highly pain-generating tissue interface, especially where lesions infiltrate richly innervated planes, such as the uterosacral ligaments, rectovaginal septum, bowel serosa, and pelvic sidewall [1, 2].
3.5 Neuroangiogenesis and peripheral sensitization
Nociceptive and sympathetic nerve fibers infiltrate DIE nodules and peritoneal implants alongside neovessels (neuroangiogenesis). Nerve fibers express TRPV1, Nav1.7, ASICs, and purinergic receptors, rendering them hyper-responsive to inflammatory mediators. Clinically, this peripheral sensitization manifests as lowered pain thresholds, spontaneous pain, and mechanical allodynia in the pelvis and adjacent structures [1, 2].
3.6 Central sensitization, brain plasticity, and glial activation
Chronic nociceptive input from pelvic organs in endometriosis can induce central sensitization (CS), as illustrated in Figure 2, a state characterized by increased neuronal excitability and enhanced synaptic efficacy within the spinal dorsal horn and supraspinal pain-processing networks. Neuroimaging studies in individuals with endometriosis-associated pelvic pain have demonstrated altered functional connectivity within somatosensory and limbic circuits, as well as changes in cortical oscillatory activity related to stress reactivity and cholinergic tone, supporting the presence of maladaptive brain plasticity in this population [2, 8].
Beyond functional alterations, experimental and translational evidence indicates that endometriosis can induce central neuroinflammation, with widespread activation of glial cells, including microglia and astrocytes, throughout the central nervous system. Animal models have shown CNS-wide glial activation in response to endometriosis, providing a biological substrate for persistent pain amplification, impaired pain modulation, and the emergence of comorbid mood and cognitive symptoms [3]. These central neuroimmune changes are consistent with clinical phenotypes characterized by pain persistence despite lesion-directed therapy, particularly in patients presenting with widespread pain, fatigue, sleep disturbance, affective symptoms, and high levels of pain catastrophizing [2, 8].
3.7 Microbiome, systemic inflammation, and neuroimmune crosstalk
Emerging data implicate gut, endometrial, and vaginal microbiota in endometriosis pathogenesis and symptom modulation. Systematic reviews and large cohorts describe:
Altered alpha and beta diversity of gut microbiota in women with endometriosis versus controls [11, 12].
Dysbiosis patterns associated with increased pro-inflammatory taxa and reduced short-chain fatty acid (SCFA)–producing bacteria [11, 12].
Preliminary evidence suggests that probiotic supplementation may modulate dysbiosis and improve symptoms, though trials remain small and heterogeneous.
Microbial metabolites can influence estrogen metabolism (estrobolome), intestinal permeability, and systemic immune activation, thereby feeding into neuroimmune circuits and central sensitization [11,12].
4. Pain phenotyping in endometriosis
4.1 Why phenotyping matters clinically
Pain phenotype predicts therapeutic response and guides mechanism-based management in endometriosis. Neuropathic-like and nociplastic pain components often require neuromodulatory strategies and multidisciplinary rehabilitation, rather than lesion- or hormone-centered approaches [2, 8]. Recent cohort data demonstrate a substantial neuropathic-like component in endometriosis-associated pain, as identified by painDETECT, a validated patient-reported questionnaire designed to screen for neuropathic pain features based on characteristic sensory descriptors and pain patterns. Using this instrument, neuropathic-like pain was classified in approximately 40% of patients, with mixed phenotypes in an additional 35% in a large questionnaire-based cohort [13]. Furthermore, population-based studies employing latent class analysis have identified distinct pain phenotypes that correlate with quality-of-life impairment and comorbidity burden, reinforcing the clinical value of phenotype-driven care pathways in endometriosis [14].
4.2 Definitions: Nociceptive, neuropathic-like, and nociplastic pain
Endometriosis-associated pain is best understood as a spectrum:
Nociceptive pain: ongoing tissue inflammation/ischemia/mechanical distortion; typically proportional to peripheral input; often cyclic and lesion-linked (e.g., cyclic dysmenorrhea, deep dyspareunia directly linked to lesion sites) [1, 2].
Neuropathic-like pain: associated with nerve infiltration, compression, or surgical injury, presenting with burning, electric shocks, tingling, allodynia, and shooting pain; may reflect nerve entrapment/injury or persistent somatosensory dysfunction [13, 15].
Nociplastic pain: pain arising from altered nociception without clear tissue damage or nerve injury. It is characterized by central sensitization, pain disproportionate to peripheral nociceptive drivers, widespread and fluctuating pain, hypersensitivity, and a high burden of associated symptoms, including fatigue, sleep disturbances, and cognitive difficulties. Clinically, nociplastic pain frequently co-occurs with central sensitivity syndromes (CSS), such as fibromyalgia, irritable bowel syndrome, and bladder pain syndrome, reflecting shared mechanisms of maladaptive central pain modulation [8].
Large cohort studies indicate that neuropathic-like features are present in up to 40% of patients, with mixed phenotypes in an additional substantial proportion [13].
4.3 Clinical tools for pain phenotyping
A structured and clinically feasible approach to pain phenotyping in endometriosis can be implemented without specialized equipment, integrating targeted history-taking, validated questionnaires, and patient-reported outcome measures. The primary objective is to identify dominant pain mechanisms nociceptive, neuropathic-like, nociplastic, or mixed, in order to guide mechanism-based medical management [2, 8].
Targeted clinical assessment should begin with detailed pain mapping, documenting pain location, cyclicity, temporal relationship with menstruation, triggering factors, and pain qualities. Particular attention should be paid to the dyspareunia subtype (superficial versus deep), bowel and bladder associations, and postural or activity-related exacerbation, as these features may suggest distinct peripheral or centrally mediated drivers [2, 5].
Validated questionnaires support systematic phenotyping and improve the detection of non-nociceptive pain components. Neuropathic-like pain may be screened using instruments such as painDETECT, DN4, and the Neuropathic Pain Symptom Inventory (NPSI) [13, 15].
Screening for nociplastic pain and central sensitization requires instruments that assess systemic symptom patterns rather than focal nerve injury. The Central Sensitization Inventory (CSI) is the most widely used and validated tool for this purpose and provides clinically actionable information when interpreted in the context of the overall pain phenotype.
Additional instruments, such as the Fibromyalgia Survey Questionnaire, may help identify overlapping central sensitivity syndromes. The Pain Sensitivity Questionnaire (PSQ/PSQ-M) has also been explored in endometriosis populations; however, recent data suggest that it is only weakly associated with central sensitivity and does not reliably predict postsurgical quality of life, underscoring the need for more robust and disease-specific tools.
Quantitative sensory testing (QST), including the assessment of pressure pain thresholds and temporal summation, offers objective characterization of pain processing and central excitability. At present, these techniques are primarily confined to research settings due to limited availability and standardization, but they provide important mechanistic insights into central sensitization [8].
Finally, patient-reported outcome measures (PROMs) remain essential for capturing the functional and quality-of-life impact of pain. Disease-specific instruments, such as the Endometriosis Health Profile (EHP-30 and EHP-5) and pelvic pain impact questionnaires, are widely used, systematically reviewed, and valuable for longitudinal monitoring of treatment response [16].
Together, this multimodal approach enables a nuanced and clinically meaningful characterization of pain phenotypes in endometriosis, facilitating precision-oriented medical management beyond lesion- or hormone-centered strategies [2,8].
5. Biomarkers and precision stratification
5.1 Why biomarkers are needed
Current clinical decision-making still relies heavily on symptoms, imaging, and response to empiric therapy. Biomarkers could improve: (i) noninvasive diagnosis, (ii) prediction of treatment response/resistance, (iii) endotyping (inflammatory vs. fibrotic vs. neurogenic dominance), and (iv) monitoring. However, most candidates remain investigational, with variability due to cycle timing, phenotype heterogeneity, and methodological differences [10–12, 17–20].
5.2 Classical inflammatory and hormonal markers
Non-specific laboratory findings (e.g., mild elevations in CA-125, CA-19-9, high-sensitivity CRP) have limited sensitivity and specificity for diagnosis but may reflect global inflammatory burden and comorbid conditions [4, 9, 10].
A simple inflammatory ratio often explored is the neutrophil-to-lymphocyte ratio (NLR): NLR = Neutrophil count.
Lymphocyte count
Although elevated NLR has been associated with more severe disease in some cohorts, it remains non-specific and is not used alone for decision-making.
5.3 Proteomics and inflammatory mediator panels
Proteomic studies of serum, peritoneal fluid, and ectopic tissue have identified panels of cytokines, chemokines, complement components, adhesion molecules, and metabolic enzymes associated with disease presence and severity. However:
5.4 Circulating microRNAs and extracellular vesicle (EV) biomarkers
Multiple studies have evaluated circulating miRNAs (cell-free and EV-encapsulated) as minimally invasive biomarkers:
Systematic review and bioinformatics analysis of exosomal miRNAs identified reproducibly dysregulated miRNAs linked to pathways such as EMT, angiogenesis, and immune regulation [20].
A detailed review on small extracellular vesicle-miRNAs summarizes diagnostic/ mechanistic relevance and translational priorities [17].
Recent work connects EV signatures with reproductive outcomes: serum-derived sEVs carrying specific small non-coding RNAs can predict pregnancy and delivery in women with endometriosis undergoing ART [18].
Additional EV biomarker work links pelvic inflammation, oocyte quality, and IVF outcomes through EV molecular signatures [19].
Collectively, EV-miRNA signatures are one of the most promising biomarker avenues for precision stratification (e.g., predicting disease phenotype, pain severity, fertility prognosis, and therapeutic response), but they require large, standardized prospective cohorts before entering routine practice [17–19].
5.5 Microbiome and the gut–immune–estrogen axis
The microbiome is increasingly recognized as a modifier of immune tone, systemic inflammation, and estrogen metabolism in endometriosis, particularly through the estrobolome, which regulates estrogen deconjugation and enterohepatic recirculation. Alterations in gut and reproductive tract microbiota may influence inflammatory signaling, immune tolerance, and local estrogen availability, thereby contributing to lesion persistence and pain chronification [16–18].
Systematic reviews and cohort studies have identified distinct microbial profiles in stool, endometrial, and vaginal samples from individuals with endometriosis compared with controls, with putative associations to disease presence, stage, and symptom severity [16–18]. Although early data suggest that uterine or endometrial microbiome analysis could contribute to risk stratification, findings remain preliminary and heterogeneous [16, 17]. Recent comprehensive reviews emphasize substantial methodological variability, modest effect sizes, and inconsistent directionality across studies, highlighting the need for standardized sampling, rigorous control of confounders, and mechanistic validation [16–18].
Overall, microbiome profiles may eventually complement molecular and clinical biomarkers within multimodal phenotyping models. At present, however, evidence supports cautious, hypothesis-driven investigation within research settings rather than routine clinical implementation [11, 12, 21].
5.6 Clinical translation challenges
Barriers to biomarker implementation include:
Small, heterogeneous cohorts and a lack of external validation [11, 12, 17–20].
Variability in sampling methods, timing within the menstrual cycle, and confounders (e.g., hormonal therapy, antibiotics, diet) [11, 12, 21].
Limited cost-effectiveness data and uncertain impact on clinical decision-making [11, 12, 17–20].
6. Treatment resistance and pain chronification
6.1 Hormone resistance and lesion heterogeneity
Many patients exhibit partial or complete resistance to progestins and combined hormonal contraceptives. Proposed mechanisms include:
These mechanisms support the rationale for non-hormonal and adjunctive therapies targeting inflammation, fibrosis, angiogenesis, and neuroimmune pathways [4, 9, 10].
6.2 Fibrosis and mechanical distortion as “non-hormonal” pain drivers
Fibrotic remodeling in DIE can cause traction, organ tethering, and nerve involvement. Anti-fibrotic strategies remain investigational, but fibrosis is increasingly recognized as a key therapeutic target [4, 9, 10].
6.3 Maladaptive neuroplasticity and comorbidities
High pain phenotype clusters are associated with comorbidities such as IBS, bladder pain, migraine, fibromyalgia, and anxiety/depression [14]. These comorbidities can amplify central sensitization and worsen outcomes, contributing to pain persistence despite optimal surgical excision and hormonal therapy [2, 8]. Failure to recognize nociplastic pain phenotypes may lead to repeated surgeries with diminishing returns, opioid escalation, and patient frustration, unless treated directly [2, 8, 14].
6.4 Iatrogenic contributors and repeated intervention cycles
Repeated surgical interventions may increase the risk of neuropathic-like pain and further sensitization of peripheral and central pain pathways, with neuropathic features associated with greater pain intensity and psychological distress [13]. Precision-oriented care, therefore, emphasizes avoiding cycles of repeated lesion-directed interventions when pain phenotyping suggests central or neuropathic dominance. This highlights the importance of accurate initial diagnosis with comprehensive preoperative endometriosis mapping to achieve a complete, single-stage (“one-shot”) excisional surgery, as technique matters: excision rather than ablation reduces residual disease and ongoing nociceptive input. These principles should be integrated within a multidisciplinary management approach to address peripheral, central, and psychosocial contributors to endometriosis-associated pain and improve long-term outcomes [2, 8, 13].
7. Targeted therapies: Hormonal, neuromodulatory, immunologic, anti-fibrotic, and emerging non-hormonal strategies
7.1 Principles of therapy selection
Therapies should be selected by:
Reproductive goals (trying to conceive vs. contraception acceptable)
Dominant pain mechanism (Table 1)
Lesion phenotype (e.g., DIE with fibrosis/nerve proximity)
Risk profile (thromboembolism, bone density, mood disorders, hepatic function)
Treatment history (prior response, tolerability, adherence)
Selecting targeted pharmacologic and non-pharmacologic strategies, combining
Hormonal suppression (when acceptable)
Neuromodulators
Immunomodulatory/anti-fibrotic therapies
Microbiome-directed and lifestyle interventions
Psychological and physical rehabilitation approaches [11–14, 21].
7.2 Hormonal therapies (backbone, but not the whole plan)
Although the chapter focuses beyond hormones, it is important to contextualize:
Combined hormonal contraceptives (CHCs) and progestins remain first-line options for many patients with nociceptive/cyclic pain and acceptable contraception needs [1, 2].
Progestins: oral dienogest, norethindrone acetate; LNG-IUS [1, 2, 4].
Common adverse effects: irregular bleeding, mood changes, acne, breast tenderness [1, 2, 4].
Precision note: in suspected progesterone resistance, consider alternative progestins, route changes (e.g., LNG-IUS), or non-hormonal adjuncts.
Oral GnRH antagonists provide reversible ovarian suppression with add-back therapy; however, despite reducing cyclic nociceptive input, their risk–benefit profile increasingly limits routine use. Even with add-back, hypoestrogenic effects, bone loss, mood changes, and metabolic concerns persist, while pain often continues due to unaddressed neuroimmune and central sensitization mechanisms; therefore, these agents should be reserved, if used at all, for highly selected, time-limited scenarios within a broader mechanism-based approach [5–7].
7.3 Neuromodulators for neuropathic-like and nociplastic components (off-label but mechanism-aligned)
Evidence for neuromodulators in endometriosis is often extrapolated from neuropathic pain and chronic pelvic pain literature, but their use is increasingly recommended when the phenotype is neuropathic-like or nociplastic [2, 8, 13]. Figure 3 summarizes a phenotype-guided framework for escalation to neuromodulatory therapy in endometriosis-associated pain.
a) Serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., duloxetine, venlafaxine)
Typical dosing (pain): duloxetine 30 mg daily → 60 mg daily; venlafaxine XR 37.5 mg → 75–150 mg daily.
Adverse effects: nausea, insomnia/somnolence, sweating, BP increase (venlafaxine), and sexual dysfunction.
Best fit: comorbid anxiety/depression, widespread pain, central sensitization.
b) Gabapentinoids (gabapentin, pregabalin)
Typical dosing: gabapentin 100–300 mg nightly → titrate to 900–1800 mg/day, divided; pregabalin 25–75 mg nightly → 150–300 mg/day, divided.
Mechanism: α2δ-subunit calcium channel modulation, reducing neuronal excitability.
Adverse effects: dizziness, somnolence, edema, weight gain; caution with sedation.
Best fit: neuropathic-like symptoms, sleep disturbance.
c) Tricyclic antidepressants (amitriptyline, nortriptyline)
Typical dosing: 10–25 mg nightly → 25–75 mg nightly.
Adverse effects: anticholinergic effects, QT prolongation risk (dose-related), sedation.
Best fit: sleep + pain, bladder pain syndrome overlap.
d) Low-dose naltrexone (LDN) (investigational/off-label)
Proposed neuroimmune modulation and glial effects; clinical evidence remains limited and heterogeneous. Consider only with careful counseling and monitoring, ideally in research-informed settings.
7.4 Non-pharmacological neuromodulation (first-class therapy for nociplastic pain)
For nociplastic pain and central sensitization phenotypes, optimal outcomes generally require interdisciplinary, non-pharmacologic approaches rather than the escalation of lesion- or drug-centered strategies. Core components include:
Pain neuroscience education focuses on central sensitization and neuroimmune mechanisms underlying pain amplification.
Psychological therapies, including cognitive-behavioral therapy (CBT), acceptance and commitment therapy (ACT), and mindfulness-based interventions, are aimed at reducing catastrophizing, fear-avoidance, and maladaptive coping.
Graded activity and exercise programs addressing lumbopelvic biomechanics, physical deconditioning, and autonomic dysregulation.
Pelvic floor physical therapy, with emphasis on down-training, desensitization, biofeedback, and myofascial release, rather than isolated strengthening.
These interventions directly target central amplification, altered pain modulation, fear-avoidance behaviors, and autonomic imbalance, and are consistently supported in chronic pain and endometriosis-related nociplastic pain literature [2, 8].
7.5 Immunomodulatory and anti-fibrotic approaches
Several non-hormonal pharmacologic strategies target inflammatory and fibrotic drivers of pain and lesion persistence:
NSAIDs and COX-2 inhibitors
Remain appropriate for episodic nociceptive flares, particularly dysmenorrhea.
COX-2–selective agents may reduce gastrointestinal toxicity but carry cardiovascular risks, requiring individualized risk assessment [4, 10].
Pentoxifylline
A phosphodiesterase inhibitor with immunomodulatory and anti-fibrotic properties.
Small human studies report mixed effects on pain and fertility outcomes, and routine use is not recommended [4].
Cytokine-targeted therapies (TNF-α, IL-6, IL-1 inhibitors)
Preclinical models demonstrate reduced lesion growth and inflammatory signaling.
Robust clinical trials in endometriosis are lacking, and the high cost and immunosuppressive risk restrict their use to research settings [4, 9, 10].
mTOR inhibitors (e.g., sirolimus, everolimus)
Conceptually attractive due to evidence of mTOR overactivation in endometriotic lesions.
Current evidence is limited to animal models and early translational studies [4, 9].
7.6 Non-hormonal targeted therapies
Multiple non-hormonal compounds aim to modulate angiogenesis, oxidative stress, and inflammation:
7.6.1 Antioxidants and anti-inflammatory nutraceuticals
N-acetylcysteine (NAC): Reduces reactive oxygen species and has been associated with decreased lesion size and CA-125 levels in small clinical studies [8].
Resveratrol: A polyphenol with anti-inflammatory and anti-angiogenic properties. Preclinical and early clinical data suggest symptom improvement and potential lesion modulation, though optimal dosing and long-term safety remain undefined [10].
Other candidates: Curcumin, omega-3 fatty acids, and vitamin D have mechanistic and low-level clinical support and may be considered as adjunctive strategies [9, 10].
7.6.2 Metabolic and endocrine modulators
Metformin: Exhibits indirect anti-proliferative and anti-inflammatory effects via AMPK activation; human data on endometriosis remain preliminary [9].
Statins (e.g., simvastatin): Modulate the mevalonate pathway and demonstrate anti-angiogenic effects in experimental models, though without definitive clinical validation [9].
7.7 Microbiome-directed interventions (experimental)
Based on consistent evidence of dysbiosis in endometriosis, potential microbiome-directed strategies include:
Targeted probiotics and synbiotics, aiming to restore short-chain fatty acid–producing bacteria and reduce mucosal and systemic inflammation; early studies suggest improvements in pain and quality of life in selected cohorts [11, 12, 21].
Dietary interventions, such as Mediterranean-style or anti-inflammatory diets, and low-FODMAP approaches in patients with IBS comorbidity, aim to modulate microbiota composition and immune activation [11, 12, 21].
Future approaches, including postbiotics, fecal microbiota transplantation (FMT), or microbe-derived metabolites, which remain experimental and should be confined to research protocols [11, 12, 21].
7.8 Emerging molecular and cellular therapies
Several innovative strategies aim to directly target the molecular drivers of endometriosis:
miRNA-based therapies, designed to modulate dysregulated miRNAs (e.g.,miR-20a, miR-200c) involved in angiogenesis, fibrosis, and immune regulation [17, 20].
Extracellular vesicle (EV)-based therapeutics, leveraging EVs as delivery systems for anti-inflammatory or anti-fibrotic molecular cargo [17–19].
Epigenetic modulators, including HDAC or DNMT inhibitors, are proposed to reverse progesterone resistance and aberrant gene expression patterns [4, 9].
These approaches remain preclinical or early translational and are not yet suitable for routine clinical use.
These complementary and emerging strategies underscore the need for an integrated, mechanism-based approach to endometriosis management. Figure 4 summarizes a practical, stepwise algorithm for precision clinical implementation in endometriosis.
8. Clinical cases: Nociceptive vs. nociplastic phenotypes
8.1 Case A: Predominantly nociceptive phenotype
Patient A is a 28-year-old with severe dysmenorrhea and deep dyspareunia, cyclic low back pain, and bowel symptoms during menses. MRI suggests DIE affecting the uterosacral ligaments and rectovaginal septum. She has no widespread pain, normal sleep, no history of migraine or IBS, and CSI and fibromyalgia questionnaire scores are low. Neuropathic screening (painDETECT, DN4) is negative.
Phenotype: Nociceptive-dominant (lesion-linked).
Management strategy:
Hormonal backbone: continuous oral progestin or combined oral contraceptive.
NSAIDs/COX-2 inhibitors for breakthrough pain.
Pelvic floor physical therapy focuses on deep dyspareunia and lumbopelvic alignment.
Short-term neuromodulator (e.g., amitriptyline 10–25 mg nocte) should be used only if sleep disturbances or residual burning pain components appear.
Lifestyle and microbiome support (Mediterranean-style diet).
In this phenotype, peripheral lesions and inflammatory drivers are dominant; effective hormonal suppression and post-surgical rehabilitation can lead to substantial improvement without heavy reliance on centrally acting drugs.
8.2 Case B: Nociplastic-dominant phenotype
Patient B is a 34-year-old G1P0 with a 12-year history of pelvic pain. She has undergone two prior laparoscopic excisions of endometriosis, most recently 18 months ago, and has tried multiple hormonal regimens with partial benefit. The current MRI shows only small residual peritoneal implants and a stable ovarian endometrioma. However, she reports:
Widespread pain (pelvis, lower back, shoulders, jaw) accompanied by fatigue, unrefreshing sleep, and cognitive fog.
Comorbid IBS and migraine.
High CSI and positive fibromyalgia survey, suggesting nociplastic pain and CS.
Neuropathic descriptors (burning, tingling), but non-dermatomal distribution and negative nerve conduction studies.
Phenotype: Dominant nociplastic + neuropathic-like components.
Management strategy: (nociplastic-focused):
De-emphasize further surgery, given poor correlation between lesion load and pain.
Continue lowest effective hormonal regimen mainly to prevent cyclical flares, but acknowledge that it will not fully resolve the pain.
Introduce SNRI (duloxetine 30→60 mg/day), targeting both pain and mood; consider a gabapentinoid if prominent sleep disruption and neuropathic features persist.
Structured program of pain neuroscience education and graded exercise with a physiotherapist experienced in CS and chronic pelvic pain.
Pelvic floor PT with emphasis on down-training, desensitization, and breathing rather than solely strengthening.
Consider sleep interventions (Cognitive Behavioral Therapy, or low-dose Tricyclic Antidepressants) and the management of migraine and IBS as part of the same CS spectrum.
In this case, the dominant driver is nociplastic pain, and therapeutic success depends more on central neuromodulation and interdisciplinary rehabilitation than on additional lesion-directed interventions.
9. Research gaps and future directions
Key gaps include: (i) standardized pain phenotyping integrating clinical tools, questionnaires, QST, imaging, and biomarkers to distinguish nociceptive, neuropathic-like, and nociplastic pain [8, 14, 15]; (ii) validation of multi-omic biomarker panels (EV-miRNAs, proteomics, microbiome) in large, prospectively phenotyped cohorts [11, 12, 17–20]; (iii) high-quality randomized trials of non-hormonal and immunomodulatory therapies with mechanistic endpoints [6–10]; and (iv) translation of preclinical neuroimmune targets (e.g., glial activation, mTOR, cytokine pathways) into safe, effective clinical interventions [3, 4, 9].
10. Conclusion
Understanding endometriosis as a neuroimmune, multisystem disease with heterogeneous pain phenotypes and molecular signatures provides a powerful framework for precision medical management. Moving beyond the “one-size-fits-all” hormonal suppression, this approach integrates pain phenotyping, biomarkers, and mechanism-based therapies, including neuromodulators, immunomodulatory and anti-fibrotic agents, microbiome-directed strategies, and, in the future, EV- and miRNA-based interventions.
For the clinician, the practical message is to match the treatment to the dominant mechanism, peripheral inflammatory/nociceptive, neuropathic or nociplastic, while acknowledging that most patients present with mixed phenotypes. For researchers, the challenge is to refine molecular and neuroimmune phenotyping and generate high-quality evidence that links these profiles to therapeutic response, ultimately enabling truly individualized, biologically informed care for people living with endometriosis.
Acknowledgments
This work did not receive any specific funding from public, commercial, or non-profit funding agencies.
Conflict of Interest
The authors declare no conflict of interest.
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