{"paper_id":"b47f0eaf-a624-4f39-93fb-5fcf044c5de0","body_text":"Lesani et al. Beni-Suef University Journal of Basic and Applied Sciences          (2026) 15:119 \nhttps://doi.org/10.1186/s43088-026-00848-6\nREVIEW Open Access\nImmunothrombotic endothelial \nreprogramming in endometriosis: GnRH \nagonist–driven vascular destabilization \nand the emergence of a pulmonary \nembolism–prone phenotype\nZahra Lesani1, Ali Amiri3, Masoud Dangeh2, Mahdis Ghorbani1, Pouya Kalantari4, Faegheh Jomehpour5, \nMarziyeh Asadpour1, Fatemeh Asadi1, Faranaz Nayebzadeh1, Somayeh Zamanifard6* and Atoosa Etezadi7\n  * C o r r e s p o n d e n c e :  \nSomayeh Zamanifard\nzamanifard117@gmail.com\nFull list of author information is available at the end of the article\n© The Author(s) 2026. Open Access  This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 \nInternational License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you \ngive appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the \nlicensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the \nmaterial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or \nexceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit  h t    t p : / / c r e  a   t i \nv e  c  o  m  m  o n s . o r g / l i c e n s e s / b y - n c - n d / 4 . 0 /     .    \nAbstract\nBackground Endometriosis affects ~ 10% of reproductive-age women yet its impact extends far beyond pelvic pain: \naccumulating epidemiologic and mechanistic data implicate endometriosis in systemic immunovascular dysfunction \nand elevated risk of arterial and venous thrombotic events.\nMain body Current clinical paradigms treat reproductive disease, endocrine therapy, and thromboembolism as \nseparate domains, overlooking how chronic lesion-level inflammation, iron-driven oxidative stress, and endothelial \nmetabolic reprogramming interact with coagulation and immune effectors to determine embolic risk. Here we \nsynthesize evidence that repetitive hemorrhage and iron overload prime endothelium and immune cells for a pro-\ncoagulant state, that platelet–leukocyte crosstalk and neutrophil extracellular traps stabilize and protect thrombi from \nlysis, and that abrupt estrogen withdrawal (e.g., GnRH agonist therapy) may serve as a biologically meaningful second \nhit within a proposed mechanistic model, potentially promoting vascular destabilization in susceptible individuals. We \npropose the immunothrombotic continuum as a conceptual mechanistic framework, a systems-level framework in \nwhich inflammatory, redox, metabolic, and endocrine axes converge to produce emergent thrombotic vulnerability.\nConclusion This model prioritizes biomarker-guided phenotyping, dynamic surveillance during hormonal therapy, \nand mechanism-targeted prophylaxis, a translational roadmap for precision cardio-reproductive medicine aimed at \npreventing clinically meaningful embolic outcomes.\nClinical trials Not applicable.\nHighlights\n • Immunothrombotic continuum: Conceptualizes thrombotic risk as an emergent property of interacting \ninflammatory, redox, metabolic, and endocrine networks rather than isolated factors.\n\nPage 2 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \n  1 Introduction\nEndometriosis affects approximately 10% of reproduc -\ntive-age women worldwide and has traditionally been \nconceptualized as an estrogen-dependent gynecologic \ndisorder defined by ectopic implantation of endometrial-\nlike tissue and chronic pelvic pain [ 1, 2]. Yet mounting \nepidemiologic and mechanistic evidence indicates that \nits biological footprint extends well beyond the pelvis, \nencompassing systemic inflammation, endothelial dys -\nfunction, and increased long-term cardiovascular risk, \nthereby challenging its confinement to a localized repro -\nductive pathology [ 3]. Large population-based cohort \nstudies and meta-analyses demonstrate that women with \nendometriosis exhibit elevated risks of ischemic heart \ndisease, cerebrovascular events, and other vascular out -\ncomes, even after adjustment for traditional risk factors, \nsuggesting a shared inflammatory-vascular substrate \nrather than coincidental comorbidity [4, 5].\nParallel advances in vascular biology have reframed \nthrombosis as an immunologically orchestrated process, \n“immunothrombosis” , in which innate immune activa -\ntion, neutrophil extracellular trap (NET) formation, \nplatelet–leukocyte aggregates, and endothelial signaling \nconverge to regulate thrombus initiation, propagation, \nand embolic potential [ 6]. NETs, in particular, provide a \nstructural and biochemical scaffold that links inflamma -\ntion to coagulation by activating intrinsic and extrinsic \npathways, amplifying thrombin generation, and impair -\ning endogenous anticoagulant systems [ 7, 8]. Chronic \ninflammatory disorders such as systemic lupus ery -\nthematosus, inflammatory bowel disease, rheumatoid \narthritis, and certain cancers exhibit an increased risk of \nthromboembolism through shared immunothrombotic \nmechanisms, suggesting that immune-vascular coupling \nrepresents a conserved pathogenic feature across diverse \ninflammatory diseases [9– 13].\nWithin this broader framework, endometriosis rep -\nresents a uniquely informative biological model: repeti -\ntive hemorrhage and iron deposition in ectopic lesions \ngenerate persistent oxidative stress and macrophage \nactivation, conditions known to activate redox-sensitive \ntranscriptional programs and promote endothelial dys -\nfunction [ 14– 16]. Iron-driven lipid peroxidation and \nreactive oxygen species production can perturb endo -\nthelial nitric oxide signaling and induce procoagulant \nphenotypic drift, thereby linking lesion-level iron over -\nload to systemic vascular vulnerability [ 17, 18]. Despite \nthis mechanistic plausibility, the integration of chronic \ninflammatory priming, endothelial metabolic reprogram-\nming, and thrombus biology in endometriosis has not \nbeen systematically synthesized within a unified immu -\nnothrombotic framework.\nAn additional, underexplored dimension lies in the \nendocrine modulation of vascular homeostasis. Estrogen \n • Endothelial reprogramming as a therapeutic target: Highlights the endothelium as a dynamic integrator of \nchronic inflammation, iron-driven oxidative stress, and hormonal perturbation, enabling mechanism-guided \ninterventions.\n • Second-hit vulnerability framework: Frames abrupt estrogen withdrawal or endocrine therapy as a biologically \nsignificant “second hit” that unmasks pre-existing vascular priming, refining risk prediction.\n • Personalized surveillance thresholds: Advocates adaptive biomarker trajectories, not single static values, to \ntrigger therapy modification or prophylactic intervention.\n • Cross-disease relevance: Positions lessons from endometriosis to inform thrombotic risk in autoimmune, \nchronic inflammatory, and reproductive-endocrine disorders with systemic vascular impact.\n • Roadmap for precision cardio-reproductive medicine: Integrates mechanistic insights with biomarker-\nguided phenotyping and dynamic intervention strategies, defining a translational pipeline from molecular \nunderstanding to patient-tailored prophylaxis.\nKeywords Endometriosis, Immunothrombosis, Neutrophil extracellular traps, Endothelial dysfunction, Gonadotropin-\nreleasing hormone agonists, Oxidative stress, Cardiovascular toxicity\nGraphical Abstract\n\n\nPage 3 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \nexerts potent vasoprotective effects through genomic \nand non-genomic signaling pathways that enhance endo -\nthelial nitric oxide synthase activity, suppress adhesion \nmolecule expression, and modulate platelet reactivity \nand fibrinolysis [ 19, 20]. Abrupt estrogen withdrawal, \nwhether physiologic (menopause) or therapeutic (e.g., \nGnRH agonist–induced hypoestrogenism), impairs endo -\nthelial function and shifts hemostatic balance toward \nprocoagulant and pro-adhesive states [ 21, 22]. In cardio -\nvascular medicine, hypoestrogenic states are associated \nwith endothelial dysfunction, altered vascular reactivity, \nand increased thrombotic susceptibility, reinforcing the \nconcept that sex steroids are systemic vascular regulators \nrather than isolated reproductive hormones [23, 24].\nDespite these converging lines of evidence, a critical \nconceptual gap persists: endometriosis, endocrine sup -\npression therapy, and venous thromboembolism are typi-\ncally examined in isolation, as separate clinical domains, \nrather than as interconnected nodes within a dynamic \nimmunothrombotic network. Current thromboembolic \nrisk models emphasize static factors such as inherited \nthrombophilias, immobilization, or malignancy, but they \ninsufficiently capture the contribution of chronic inflam -\nmatory endothelial priming and hormone-mediated vas -\ncular modulation to embolic potential [ 25]. Moreover, \nwhile case reports and pharmacovigilance data describe \nthrombotic events in association with GnRH agonist \ntherapy, mechanistic frameworks explaining how endo -\ncrine perturbation interacts with pre-existing inflamma -\ntory vascular conditioning remain sparse [26].\nHere, we propose a unifying systems-level model in \nwhich endometriosis establishes a chronically primed \nimmunovascular state characterized by iron-driven oxi -\ndative stress, endothelial reprogramming, platelet–leu -\nkocyte crosstalk, and low-grade coagulation activation; \nsubsequent endocrine perturbation, particularly abrupt \nestrogen withdrawal induced by GnRH agonists such as \nleuprorelin may function as a biologically significant sec -\nond hit within this proposed mechanistic model, poten -\ntially destabilizing vascular homeostasis and lowering \nthe threshold for immunothrombotic propagation and \nembolization. By synthesizing insights from reproductive \nimmunology, redox biology, endothelial metabolism, and \nthrombus architecture, we delineate an immunothrom -\nbotic continuum that bridges local lesion biology to sys -\ntemic thromboembolic outcomes.\nOur central novelty lies not in identifying individual \nmechanisms, each well supported in isolation, but in \nintegrating them into a coherent, multi-axis paradigm \nthat reconceptualizes thromboembolic risk in endome -\ntriosis as the emergent property of interacting inflamma -\ntory, metabolic, and endocrine networks. This framework \nhas translational implications: it supports biomarker-\nguided vascular phenotyping, anticipatory surveillance \nduring hormonal therapy, and targeted endothelial sta -\nbilization strategies that extend beyond conventional \nanticoagulation. More broadly, it situates endometriosis \nwithin a new class of chronic inflammatory diseases in \nwhich reproductive endocrine dynamics and immu -\nnothrombotic biology intersect, thereby advancing the \nfoundation for precision cardio-reproductive medicine.\n2 Reframing endometriosis as a systemic \nimmunothrombotic disorder\nEndometriosis has increasingly been recognized not \nmerely as a localized gynecological lesion but as a \nchronic systemic inflammatory condition with profound \nimplications for vascular biology and homeostasis [ 27]. \nThis reconceptualization is grounded in robust evidence \nthat ectopic endometrial tissue exists in a milieu char -\nacterized by sustained immune activation, oxidative \nstress, and cytokine dysregulation, a milieu that extends \nbeyond the pelvis and engages systemic endothelial and \nhemostatic networks [ 27]. To synthesize the key mecha -\nnistic themes underlying systemic vascular engagement \nin endometriosis, we summarize the pathways linking \nchronic inflammation, oxidative priming, and immu -\nnothrombosis in Table 1.\nAlthough the epidemiologic literature consistently \ndemonstrates an association between endometriosis and \nadverse cardiovascular outcomes, these findings should \nbe interpreted cautiously because most available studies \nare observational and therefore cannot establish causality \n[28]. Residual confounding may arise from several factors \nassociated with endometriosis, including chronic pain, \nreduced physical activity, obesity, depression, smoking, \nsurgical menopause, and exposure to hormonal thera -\npies, all of which may independently influence cardiovas -\ncular risk. Furthermore, differences in diagnostic criteria, \ndisease severity, treatment history, and adjustment for \ntraditional cardiovascular risk factors contribute to het -\nerogeneity across studies [ 29]. Consequently, while epi -\ndemiologic evidence supports a reproducible association \nbetween endometriosis and cardiovascular disease, it \nshould be interpreted as complementary to, rather than \ndefinitive proof of, the mechanistic pathways discussed \nin this Review. Further prospective longitudinal studies \nincorporating comprehensive adjustment for clinical and \ntherapeutic confounders will be required to clarify the \nextent to which endometriosis itself contributes causally \nto long-term cardiovascular risk.\n2.1 Beyond ectopia: from pelvic inflammation to vascular \nbiology\nTraditionally described by retrograde menstruation and \nectopic implantation, endometriosis pathogenesis is \nnow understood to involve persistent sterile inflamma -\ntion and immune maladaptation, wherein infiltrating \n\nPage 4 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \ndefenses in ectopic stromal cells and macrophages, which \nin turn sustains oxidative stress and reinforces inflam -\nmatory signaling, a state that simultaneously primes the \nendothelium toward dysfunction and promotes systemic \nvascular perturbation [ 33]. Evidence also indicates that \niron-derived reactive oxygen species can activate redox-\nsensitive transcription factors (e.g., NF-κB), further \namplifying cytokine production and endothelial activa -\ntion, thereby linking local iron-driven oxidative priming \nwith global vascular vulnerability [34].\n2.3 Platelet–leukocyte crosstalk and the architecture of \nimmunothrombosis\nThe interplay between inflammation and coagulation \nis a hallmark of chronic inflammatory disorders, and in \nendometriosis, activated platelets accumulate in ecto -\npic lesions, releasing pro-fibrotic and pro-inflammatory \nmediators that not only support lesion progression but \nalso signify systemic activation of hemostatic pathways \n[35, 36]. Activated platelets interact with neutrophils \nand monocytes to induce neutrophil extracellular trap \nformation (NETosis), a process increasingly recognized \nas central to immunothrombosis, whereby neutrophil \nDNA webs decorated with proteases and tissue factor \npromote local thrombus nucleation and amplify coagu -\nlation cascades [ 37– 39]. This platelet–leukocyte cross -\ntalk culminates in the release of extracellular vesicles and \nmicroparticles rich in procoagulant phospholipids and \ntissue factor, which can traffic systemically and interact \nwith vascular endothelium at distant sites, effectively \nlinking the chronic inflammatory state in endometrio -\nsis to a prothrombotic vascular phenotype [ 40]. Indeed, \nmarkers of coagulation activation, including soluble \nmacrophages, lymphocytes, and other immune effec -\ntors generate a pro-inflammatory microenvironment \nthat influences tissues far beyond the lesion site [ 30]. \nChronic inflammation in endometriotic lesions drives \ntissue remodeling and angiogenic signaling, manifested \nby elevated levels of cytokines, chemokines, and growth \nfactors such as TNF-α, IL-6, IL-8, and VEGF that not \nonly sustain local lesion survival but also perturb endo -\nthelial function and vascular integrity systemically [ 31]. \nReflecting this systemic engagement, epidemiological \nand mechanistic studies now link endometriosis with \nincreased markers of endothelial dysfunction, altered \nvascular reactivity, and elevated risk of cardiovascular \nevents, consistent with a broader inflammatory-vascular \ninterface rather than a localized gynecological pathology \n[32].\n2.2 Iron-driven oxidative priming and endothelial \nvulnerability\nRepeated shedding, hemorrhage, and reflux of endome -\ntrial tissue into the peritoneal cavity expose macrophages \nand local tissues to high levels of catalytic iron derived \nfrom erythrocyte breakdown, leading to an iron-over -\nloaded microenvironment [33]. This iron excess catalyzes \nFenton chemistry, generating reactive oxygen species that \ninduce sustained oxidative stress, lipid peroxidation, and \nredox imbalance, processes mechanistically implicated in \nferroptosis and other regulated cell death programs but \nmore importantly capable of compromising endothelial \nbarrier integrity and enhancing procoagulant signal -\ning [33]. The paradox in endometriotic tissue is its abil -\nity to resist ferroptosis despite persistent iron overload, a \nresistance that is mirrored by upregulation of antioxidant \nTable 1 Mechanistic landscape of endometriosis as a systemic immunothrombotic disorder\nPathway Key Mechanisms Molecular/Cellular Mediators Systemic Vascular Consequences\n1. Chronic Sterile \nInflammation\nPersistent immune activation from retrograde \nmenstruation and ectopic implantation; \nimmune maladaptation amplifies local and \nsystemic inflammation\nMacrophages (M2 skewing); lympho-\ncytes; pro-inflammatory cytokines \n(TNF-α, IL-6, IL-8); chemokines; growth \nfactors (VEGF)\nSustained inflammatory milieu \nextends beyond pelvis →  endothelial \nactivation, vascular remodeling, and \nchronic systemic inflammation\n2. Iron-Driven Oxi-\ndative Priming\nPeritoneal hemorrhage and erythrocyte break-\ndown lead to iron accumulation; iron catalyzes \nROS (Fenton chemistry) →  redox imbalance \nand lipid peroxidation\nFree iron, ferrous/ferric iron pools; \nROS (hydroxyl radicals); lipid peroxida-\ntion markers; redox-sensitive TFs (e.g., \nNF-κB)\nOxidative stress damages endothe-\nlium, disrupts barrier integrity, primes \nvascular cells toward pro-inflammato-\nry responses\n3. Immune-Meta-\nbolic Dysregulation\nChronic inflammation fosters metabolic rewir-\ning and antioxidant depletion in local and \nsystemic compartments\nReduced antioxidant enzymes (SOD, \nGPx); increased oxidative damage \n(MDA, 8-HdG); metabolic stress signals\nEndothelial dysfunction, redox imbal-\nance, and altered immune responses \nfacilitate vascular priming\n4. Platelet–Leuko-\ncyte Crosstalk & \nNETosis\nActivated platelets in lesions interact with \nneutrophils and monocytes →  NET formation; \nprocoagulant scaffold generation\nPlatelets (activated); neutrophil extra-\ncellular traps (NETs); proteases; tissue \nfactor; microparticles\nPro-coagulant networks promote \nlocal thrombus nucleation and sys-\ntemic hemostatic activation\n5. Microparticle-\nMediated Systemic \nActivation\nRelease of extracellular vesicles enriched in \ntissue factor/phospholipids from activated \nimmune cells\nProcoagulant microparticles; soluble \nclotting markers (P-selectin, D-dimer, \nprothrombin fragments)\nHemostatic factors circulate and inter-\nact with distant vascular endothelium, \nincreasing thrombotic vulnerability\n6. Epidemiologic \nEvidence for Vascu-\nlar Involvement\nObservational studies link endometriosis with \nincreased cardiovascular risk and endothelial \ndysfunction\nEpidemiologic risk ratios; endothelial \ndysfunction measures (e.g., AGEs, RHI)\nHigher incidence of cardiovascular \ndisease, hypertension, and vascular \nevents in endometriosis cohorts\n\nPage 5 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \nP-selectin, D-dimer, and prothrombin fragments, are \nelevated in patients with endometriosis, aligning with the \nconcept that chronic inflammation, immune activation, \nand hemostatic dysregulation are integrated components \nof the disease’s systemic footprint [35].\nBeyond NET formation, immunothrombosis in endo -\nmetriosis is orchestrated through several interconnected \nhemostatic pathways. Activated platelets provide a cata -\nlytic phospholipid surface that accelerates thrombin \ngeneration while releasing P-selectin, CD40L, and pro-\ninflammatory mediators that amplify leukocyte recruit -\nment and endothelial activation [ 41– 43]. Tissue factor \nexpressed by activated monocytes, endothelial cells, and \ntissue factor-bearing extracellular vesicles initiates the \nextrinsic coagulation cascade, whereas thrombin fur -\nther reinforces platelet activation and fibrin formation \nthrough positive feedback loops [ 44]. Concurrently, \nimpairment of endogenous fibrinolysis, mediated by \nincreased plasminogen activator inhibitor-1 (PAI-1) \nactivity and stabilization of fibrin networks, may favor \nthrombus persistence [45]. Emerging evidence also impli-\ncates complement activation as an important amplifier \nof thromboinflammation through reciprocal interactions \nwith platelets, neutrophils, endothelial cells, and coagula-\ntion pathways, further illustrating that thromboembolic \nrisk arises from a coordinated immunovascular network \nrather than a single effector mechanism [46].\n3 Endothelial reprogramming as the central \nintegrator\nEndothelial cells, long considered passive barriers \nto blood flow, are now recognized as highly plastic, \nimmune-responsive effectors whose phenotype and func-\ntion can be durably reshaped by chronic inflammatory \nconditioning and metabolic stress [ 47]. Under sustained \npathogenic cues, the vascular endothelium undergoes \na dynamic shift from a quiescent, anticoagulant state \ntoward a pro-inflammatory and pro-coagulant pheno -\ntype, fundamentally altering its role in vascular homeo -\nstasis and disease susceptibility [ 48]. This adaptive yet \nmaladaptive reprogramming orchestrates a systemic \nimmunovascular response that integrates inflammatory, \nmetabolic, and redox signals into a unified axis of throm -\nbogenic risk (see Fig. 1).\n3.1 Chronic inflammatory conditioning and procoagulant \ndrift\nChronic exposure of endothelial cells to inflammatory \ncytokines such as TNF-α, IL-1β, and IFN-γ induces \npersistent transcriptional and epigenetic changes that \nencode a “memory-like” inflammatory imprint, predis -\nposing endothelium to exaggerated immune activation \nand leukocyte adhesion even after the initial stimulus \nwanes [ 49]. Such cytokine-driven memory responses in \nendothelial cells have been shown to alter expression \nof adhesion molecules (e.g., ICAM-1, VCAM-1) and \nimmune signaling pathways, linking historical inflamma -\ntory exposures to future vascular dysfunction and disease \nrisk [ 49]. Concomitantly, chronic inflammatory stimuli \ncause a progressive loss of the endothelium’s anticoagu -\nlant phenotype, typified by reduced nitric oxide (NO) \nbioavailability, diminished thrombomodulin expression, \nand disrupted regulation of anti-thrombin pathways, \nthereby facilitating a drift toward procoagulant signal -\ning and enhancing susceptibility to thrombosis [ 50]. This \nshift is mechanistically tied to sustained NF-κB activation \nand inflammasome signaling within endothelial cells, \nwhich not only amplify pro-inflammatory transcriptional \nprograms but also directly promote coagulation cascade \nengagement [51].\n3.2 Metabolic and redox rewiring of the endothelium\nEndothelial metabolic reprogramming is a central feature \nof dysfunctional endothelium under chronic stress, inte -\ngrating altered glycolytic flux, mitochondrial perturba -\ntions, and redox imbalance into pathogenic phenotypes \nthat favor inflammation and thrombosis [ 52]. Chronic \noxidative stress, driven by excess reactive oxygen species \n(ROS) from inflammatory, metabolic, and iron-mediated \npathways, disrupts cellular redox networks, impairing \nmitochondrial function and depleting antioxidant sys -\ntems such as glutathione peroxidase and superoxide dis -\nmutase [ 53]. This redox disturbance not only promotes \nendothelial cell activation but also increases susceptibility \nto regulated cell death pathways like ferroptosis, which is \ncharacterized by iron-dependent lipid peroxidation and \nfurther exacerbates endothelial injury and inflammatory \nsignaling [ 54]. Mechanistically, the integration of oxida -\ntive stress with metabolic shifts skews endothelial behav -\nior toward reduced barrier function, impaired nitric \noxide signaling, and enhanced expression of pro-coagu -\nlant mediators, creating a milieu in which redox imbal -\nance and metabolic rewiring synergistically promote an \nimmunothrombotic endothelial phenotype [55].\n3.3 Microvascular instability and systemic spillover\nAs endothelial reprogramming progresses, microvascu -\nlar networks lose their ability to maintain homeostatic \nvasodilatory, anti-inflammatory, and anticoagulant func -\ntions, transitioning instead to a state of heightened per -\nmeability, leukocyte recruitment, and thrombogenic \npotential [ 56]. This microvascular instability facilitates \nsystemic spillover of inflammatory and pro-coagulant \nsignals, amplifying vascular priming beyond local pel -\nvic or organ-specific environments and predisposing \ndistant vascular beds, including pulmonary and sys -\ntemic circuits, to immune-driven thrombotic events \n[57]. Endotheliitis, basement membrane disruption, and \n\nPage 6 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \nwidespread microthrombus deposition observed in set -\ntings of dysregulated endothelial activation reinforce the \nconcept that local inflammatory and metabolic stress -\nors can reshape the endothelium into a systemic driver \nof thromboinflammation [ 58]. Together, these processes \nunderscore endothelial reprogramming as a central inte -\ngrator of chronic inflammation, metabolic and redox \nimbalance, and thrombogenic signaling, thereby posi -\ntioning the endothelium as the mechanistic fulcrum \nlinking local immune perturbations to systemic vascu -\nlar pathology and thrombotic risk in complex diseases. \nThis primed endothelial state is not static but sensitive \nto systemic hormonal milieus, particularly the neuro -\nendocrine regulation of sex steroids, which profoundly \nmodulate endothelial function and vascular homeostasis. \nIndeed, physiological estrogen signaling engages endo -\nthelial estrogen receptors to enhance nitric oxide produc-\ntion, vasodilation, and anti-inflammatory gene programs, \nwhile hypoestrogenic conditions, such as those induced \nby prolonged GnRH agonist therapy, can attenuate these \nprotective pathways and alter endothelial responses at \nthe genomic and non-genomic level.\nFig. 1 Systemic Immunothrombotic Remodeling in Endometriosis. Schematic representation of the mechanistic pathways through which endometrio-\nsis transitions from a localized pelvic disorder to a systemic immunothrombotic condition Left panel (Local pelvic pathology): Retrograde menstrua-\ntion delivers endometrial fragments into the peritoneal cavity, where persistent sterile inflammation and immune maladaptation establish a chronic \npro-inflammatory microenvironment with elevated cytokines (e.g., TNF-α, IL-6, IL-8, VEGF) and sustained macrophage and lymphocyte activation that \nextend beyond the lesion site. This local inflammatory niche is compounded by repeated hemorrhage and iron deposition from erythrocyte break -\ndown, creating an iron-overloaded microenvironment that catalyzes Fenton chemistry and the generation of reactive oxygen species, driving oxidative \nstress, lipid peroxidation, and redox imbalance (panel annotations reflect elevated inflammatory and oxidative markers). These processes contribute \nto endothelial perturbation and angiogenic remodeling within and beyond pelvic tissues. Middle panel (Immunothrombotic conversion): Chronic \ninflammation recruits and activates platelets within endometriotic niches. Activated platelets interact with neutrophils and monocytes to induce neu -\ntrophil extracellular trap (NET) formation (NETosis), which is a key effector of immunothrombosis and provides a scaffold of DNA, histones, and proteases \nthat amplifies coagulation signaling and promotes localized thrombus formation. Platelet–leukocyte crosstalk also releases pro-coagulant extracellular \nvesicles and microparticles bearing tissue factor and phospholipids, which enter the circulation and propagate systemic coagulation activation. This \ninterplay between innate immune cells and coagulation pathways evidences the integration of inflammation and thrombosis pathways characteristic \nof immunothrombosis. Right panel (Systemic vascular engagement and priming): Circulating pro-inflammatory and pro-coagulant signals from \nactivated immune cells and platelets interact with vascular endothelium at distant sites. Primed endothelium undergoes functional reprogramming from \nan anticoagulant, vasodilatory phenotype toward a pro-inflammatory, pro-coagulant state, characterized by increased leukocyte adhesion, impaired \nbarrier integrity, and heightened thrombogenic potential. These systemic vascular alterations predispose distant vascular beds, including pulmonary \nand systemic circulations, to immune-driven thrombotic events. The figure highlights this transition from local pelvic inflammation to systemic vascular \npriming, emphasizing the interconnected immunothrombotic architecture underlying endometriosis-associated vascular risk (designed using Power \nPoint and Adobe Illustrator software)\n \n\nPage 7 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \nThe mechanistic observations summarized above pro -\nvide a biologically plausible basis for considering endo -\ncrine therapy as a potential modifier of thrombotic risk. \nHowever, mechanistic plausibility should not be inter -\npreted as proof of clinical causality. Although isolated \ncase reports, observational studies, and pharmacovigi -\nlance analyses have raised concern regarding venous \nthromboembolic events during GnRH agonist therapy, \ndirect clinical evidence remains heterogeneous and sub -\nstantially less robust than the underlying mechanistic \nliterature. Moreover, interpretation of available studies is \ncomplicated by differences in underlying disease states, \nparticularly between oncology populations, in whom \ncancer itself markedly increases thrombotic risk, and \nwomen receiving GnRH agonists for benign conditions \nsuch as endometriosis. Therefore, before presenting the \nproposed mechanistic framework, the current clinical \nevidence linking GnRH therapies with venous thrombo -\nembolism should be considered in its appropriate context \n[59].\n4 The endocrine-vascular axis: a proposed \nmechanistic framework\nChronic inflammatory priming sensitizes vascular net -\nworks to additional perturbations, among which systemic \nhormonal shifts, particularly those induced by gonado -\ntropin-releasing hormone (GnRH) agonist therapy, rep -\nresent a potent modifier of endothelial and hemostatic \nhomeostasis [ 60, 61]. Continuous exposure to GnRH \nagonists such as leuprorelin desensitizes pituitary GnRH \nreceptors, leading to profound suppression of lutein -\nizing hormone (LH) and follicle- stimulating hormone \n(FSH) secretion and consequent hypoestrogenism, a \nstate functionally analogous to medical menopause [ 62]. \nThis induced hypogonadotropic state disrupts the tightly \nregulated endocrine control of vascular function and \nexposes the primed endothelium to vulnerability, altering \nits vasoregulatory, anticoagulant, and barrier integrity \nmechanisms.\n4.1 Estrogen withdrawal and loss of vascular homeostasis\nEndogenous estrogen is a fundamental regulator of vas -\ncular homeostasis, acting through both genomic and \nnon-genomic mechanisms to enhance endothelial nitric \noxide synthase (eNOS) activity and bioavailability of \nnitric oxide (NO), a critical mediator of vasodilation, \nanti-inflammatory signaling, and inhibition of plate -\nlet adhesion [ 20, 63]. Estrogen receptors expressed on \nendothelial cells engage signaling pathways, including \nPI3K/Akt-mediated eNOS phosphorylation, to sus -\ntain NO production and maintain vasodilatory capacity \n[64]. The abrupt withdrawal of estrogen under GnRH \nagonist-induced hypoestrogenic conditions results \nin a marked reduction of NO bioavailability, thereby \nimpairing endothelium-dependent vasodilation and \ndiminishing the vasoprotective “anti-inflammatory” phe-\nnotype of the vascular lining [ 65]. This diminishment is \naccompanied by upregulated expression of vasoconstric -\ntive and pro-adhesive factors such as endothelin-1 and \nadhesion molecules, which further destabilize endothelial \nbarrier integrity and promote leukocyte tethering [ 22]. \nThese alterations converge to produce an endothelial \nmilieu characterized by reduced adaptability to hemody -\nnamic stress, increased oxidative burden, and enhanced \npotential for thrombogenic adhesion events.\n4.2 Leuprorelin-induced hemostatic rebalancing\nBeyond its effects on vasomotor tone, estrogen exerts \nmodulatory influences on hemostatic balance by regu -\nlating both platelet reactivity and the fibrinolytic sys -\ntem [ 66]. Estrogen generally promotes a vasoprotective \nphenotype that suppresses platelet aggregation through \nenhanced NO and prostacyclin signaling, and modulates \nfibrinolytic activity by reducing plasminogen activator \ninhibitor-1 expression while enhancing tissue plasmino -\ngen activator activity, which collectively favor clot resolu-\ntion pathways [22, 67].\nIn contrast, estrogen deprivation induced by sus -\ntained GnRH agonist therapy can shift platelet reactivity \ntoward a more activated state and attenuate fibrinolytic \ncapacity, manifesting as increased expression of adhe -\nsion receptors and pro-coagulant profiles on platelets \nand endothelial surfaces [ 68]. This rebalancing accentu -\nates coagulation amplification and platelet–endothelium \ninteractions, particularly in a vascular system already \nprimed by chronic inflammation and oxidative stress, \nthereby lowering the threshold for thrombus formation. \nAlthough direct human data for leuprorelin’s effects on \ncoagulation profiles remain limited, analogous findings \nfrom estrogen withdrawal models demonstrate impaired \nanticoagulant and fibrinolytic mechanisms with reduced \nestrogenic support [69].\n4.3 Current clinical evidence linking GnRH agonists to \nvenous thromboembolism\nDespite increasing mechanistic evidence suggesting that \nhypoestrogenism may promote endothelial dysfunction \nand immunothrombotic activation, clinical evidence \ndirectly linking GnRH agonist therapy to venous throm -\nboembolism (VTE) remains limited. Unlike the extensive \nliterature describing cardiovascular effects of andro -\ngen-deprivation therapy in prostate cancer, prospective \nstudies specifically evaluating VTE incidence in women \nreceiving GnRH agonists for endometriosis are scarce, \nand thromboembolic events have generally not been \nprimary outcomes in randomized trials [ 70– 72]. Con -\nsequently, current knowledge is derived predominantly \nfrom case reports, retrospective observational studies, \n\nPage 8 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \npharmacovigilance databases, and indirect evidence from \nother disease settings. Notably, randomized controlled \ntrials evaluating GnRH agonists for endometriosis have \nconsistently been designed to assess treatment efficacy \nand general safety, with primary endpoints focused on \npelvic pain, symptom improvement, quality of life, bone \nmineral density, and treatment-related adverse effects \nrather than vascular safety or venous thromboembolism. \nAccordingly, these studies were neither powered nor spe-\ncifically designed to detect uncommon thromboembolic \nevents, precluding reliable estimation of the absolute \nincidence of VTE during therapy [73].\nPharmacovigilance databases provide an additional \nsource of post-marketing safety surveillance and have \nidentified sporadic reports of deep vein thrombosis and \npulmonary embolism following GnRH agonist ther -\napy [ 74]. However, spontaneous reporting systems are \ninherently subject to underreporting, reporting bias, \nincomplete clinical information, and the absence of \ndenominator data, precluding reliable estimation of inci -\ndence or definitive assessment of causality. Consequently, \npharmacovigilance findings should be interpreted pri -\nmarily as hypothesis-generating safety signals that war -\nrant further pharmacoepidemiologic investigation rather \nthan confirmation of a causal association.\nInterpretation of clinical evidence requires careful \ndistinction between oncology and benign gynecologic \npopulations. In prostate cancer, several large observa -\ntional studies have reported modest increases in VTE \namong patients receiving androgen-deprivation therapy \nwith GnRH agonists [75, 76]. However, these findings are \nintrinsically confounded by advanced age, malignancy-\nassociated hypercoagulability, concomitant chemother -\napy or radiotherapy, reduced mobility, and competing \ncardiovascular comorbidities. Accordingly, the throm -\nbotic risk observed in oncology populations cannot be \ndirectly extrapolated to younger women receiving GnRH \nagonists for endometriosis, whose baseline cardiovascu -\nlar risk profile differs substantially.\nAnother unresolved question concerns whether differ -\nent methods of pituitary suppression carry similar vas -\ncular consequences. Emerging pharmacovigilance and \nobservational evidence suggests that GnRH antagonists \nmay exhibit a more favorable cardiovascular safety pro -\nfile than GnRH agonists, particularly in oncology popula-\ntions, although comparative data remain limited and are \nderived primarily from studies evaluating major cardio -\nvascular outcomes rather than VTE specifically. At pres -\nent, comparable evidence in women with endometriosis \nis lacking, precluding definitive conclusions regarding \ndifferential thrombotic risk between these therapeutic \nclasses [77].\nTaken together, the available clinical evidence neither \nconclusively establishes nor excludes a causal association \nbetween GnRH agonist therapy and VTE. Rather, it sup -\nports biological plausibility while highlighting substantial \nevidence gaps. These uncertainties provide the rationale \nfor the proposed mechanistic framework presented in the \nfollowing sections, which seeks to explain how chronic \nendothelial priming in endometriosis might interact with \nendocrine perturbation to increase thrombotic suscepti -\nbility in a subset of vulnerable patients.\n4.4 Hormonal suppression as a second hit in a primed \nsystem\nIntegrating these lines of evidence allows us to propose a \n“two-hit” mechanistic model in which chronic inflamma-\ntory and iron-driven endothelial priming constitutes the \nfirst hit, whereas endocrine withdrawal-mediated vascu -\nlar perturbation induced by leuprorelin may represent a \nbiologically meaningful second hit. Although biologi -\ncally plausible and supported by converging mechanistic \nevidence, this model remains conceptual because direct \nprospective clinical evidence demonstrating this sequen -\ntial causal relationship is currently limited. In this frame -\nwork, the first hit establishes a baseline state of low-grade \nendothelial dysfunction characterized by inflammatory \nmemory responses, redox imbalance, and pro-coagulant \ndrift [ 78]. The second hit, an abrupt systemic hormone \nwithdrawal, exacerbates this vulnerability by suppress -\ning vasoprotective signaling, perturbing hemostatic bal -\nance, and amplifying platelet–endothelium interactions \n[68]. Table 2 captures the combined first- and second-hit \neffects in a clear mechanistic framework.\nImportantly, this framework should be regarded as a \nhypothesis-generating model intended to integrate exist -\ning mechanistic evidence and guide future experimental \nand clinical investigation rather than as confirmation \nof an established causal pathway. The combination of \nthese insults produces a compounded immunothrom -\nbotic predisposition that extends beyond traditional risk \nframeworks, underscoring the critical interplay between \nendocrine and vascular systems in modulating throm -\nbotic risk under therapeutic hormonal perturbation (see \nFig. 2).\n5 Toward a proposed pulmonary embolism-prone \nphenotype\nThe transition from localized venous thrombosis to \nclinically significant pulmonary embolism (PE) reflects \nmore than simple hemodynamic obstruction; it embod -\nies a systemic immunothrombotic evolution in which \npre-existing vascular priming from chronic inflammation \nand endothelial dysfunction synergizes with dynamic \nthrombus propagation processes to generate embolic \npotential [79]. Unlike isolated clot formation, which may \nremain confined within a venous segment, a PE- prone \nphenotype arises when thrombi acquire structural and \n\nPage 9 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \nbiochemical features that favor stability, resistance to \nendogenous fibrinolysis, and dislodgement into the pul -\nmonary circulation, a process underpinned by complex \ninteractions among endothelial cells, neutrophils, plate -\nlets, and circulating biomolecular mediators.\n5.1 From venous stasis to immunothrombotic propagation\nVenous thrombosis traditionally initiates at sites of blood \nflow stagnation, endothelial activation, and hemostatic \nimbalance, where turbulent or low -shear conditions \nfacilitate deposition of fibrin and recruitment of plate -\nlets and leukocytes [ 80]. However, clot initiation (forma -\ntion) and clot propagation (growth and stabilization) are \nmediated by distinct mechanistic pathways, particularly \nin a vascular milieu primed by chronic inflammation and \nendothelial dysfunction [ 81]. Neutrophil extracellular \ntraps (NETs) provide a scaffold that incorporates plate -\nlets, red blood cells, von Willebrand factor (vWF), and \ncoagulation factors, effectively bridging innate immune \nresponses and the coagulation cascade [ 82]. NETs not \nonly enhance the local assembly of intrinsic coagulation \nfactors such as FXII but also bind TF and fibrinogen, aug-\nmenting both intrinsic and extrinsic pathways and fuel -\ning further thrombin generation and fibrin deposition \n[82]. Collectively, this immunothrombotic propagation \nshifts venous clots from unstable, fibrin-rich formations \ntoward more complex, stabilized structures with greater \npotential for embolization.\n5.2 NET-driven thrombus stabilization and embolic \npotential\nNETs play a central structural role in thrombus architec -\nture that directly influences embolic risk. Upon activa -\ntion, neutrophils release decondensed chromatin fibers \ndecorated with histones, myeloperoxidase, and pro -\nteolytic enzymes that form an extracellular meshwork \ncapable of capturing cellular and acellular blood ele -\nments [82]. This NET scaffold, by binding platelets, vWF, \nand fibrin, increases thrombus mechanical integrity and \nresistance to fibrinolysis, rendering clots more stable and \nless susceptible to endogenous degradation. In vitro and \nin vivo models have shown that the presence of NETs \nwithin thrombi is associated with delayed clot resolution \nand increased structural resilience, effects that directly \nenhance the potential for larger portions of clot to detach \nand traverse the venous-to-pulmonary circulation [83].\nMechanistically, NET -associated histones and DNA \ninteract with coagulation factors to amplify thrombin \nproduction and inhibit anticoagulant pathways, while \nproteases such as neutrophil elastase degrade endoge -\nnous anticoagulant proteins like TFPI and thrombomod -\nulin, further fostering prothrombotic conditions and clot \npersistence [ 79]. The resultant thrombus is not merely \na fibrin deposit but a biochemically fortified immu -\nnothrombotic entity with enhanced embolic potential.\nTable 2 Endocrine-vascular perturbations and the emergence of a pulmonary embolism–prone phenotype in endometriosis under \nGnRH agonist therapy\nAxis Mechanistic Feature / \nPerturbation\nDownstream Endothelial & Hemostatic \nConsequences\nPE-Prone Biomolecular / \nCellular Signatures\nTranslational Implications\nEndocrine Hit GnRH agonist therapy \n(e.g., leuprorelin) →  \npituitary desensitization \n→  hypoestrogenism\n↓ Endothelial NO bioavailability, impaired \nvasodilation, ↑ endothelin-1, ↑ adhesion \nmolecule expression; shifts endothelium \ntoward pro-adhesive, pro-thrombotic \nstate\nFunctional hypoestrogenic \nreadouts (e.g., reduced \neNOS activity, impaired \nflow-mediated dilation)\nCandidate for hormone add-\nback or therapy modification; \nendocrine status informs \npersonalized thrombotic risk \nstratification\nInflammatory \nPriming\nChronic lesion-level in-\nflammation →  cytokines \n(TNF-α, IL-6, IL-1β)\nEndothelial “memory” →  persistent \nadhesion molecule expression, NF-κB \nactivation, inflammasome engagement; \nenhanced leukocyte tethering\nElevated CRP , IL-6, NLR; \nheightened leukocyte-\nendothelial interactions\nIdentify high-risk vascular phe-\nnotypes prior to therapy; guide \nintensity of surveillance\nOxidative / \nRedox Stress\nIron overload from \nectopic hemorrhage →  \nlipid peroxidation, ROS \naccumulation\nEndothelial metabolic rewiring →  \nmitochondrial dysfunction, ferroptosis \nsusceptibility; barrier disruption; impaired \nNO signaling\nLipid peroxides, catalytic \niron, glutathione depletion\nTargetable with antioxidants, \nNAC, or redox-modulating \nco-therapies\nHemostatic \nRebalancing\nEstrogen deprivation →  \nplatelet hyperreactivity; \nimpaired fibrinolysis\n↑ Platelet adhesion, ↑ PAI-1, ↓ tPA; proco-\nagulant endothelial shift\nPlatelet–leukocyte aggre-\ngates, elevated P-selectin, \nvWF, TF exposure\nMechanism-guided antiplatelet \nprophylaxis (low-dose aspirin) \nin biomarker-selected patients\nImmu-\nnothrombotic \nPropagation\nNET formation & stabili-\nzation of thrombi\nNET scaffolds recruit platelets, RBCs, and \ncoagulation factors →  amplify thrombin \ngeneration; resist fibrinolysis\nMPO-DNA complexes, \ncitrullinated histone \nH3, stabilized thrombus \narchitecture\nPredictive biomarker for early \nthromboembolic risk; candi-\ndate for NET-targeted therapies\nClinical \nPhenotype \nEmergence\nCumulative two-hit \ninsult: chronic endo-\nthelial priming + abrupt \nhypoestrogenism\nFormation of systemic PE-prone pheno-\ntype with enhanced embolic potential\nConvergent biomarker pro-\nfile: PNAs, EMPs, NET mark-\ners, inflammatory indices, \niron/lipid peroxidation\nSupports dynamic risk-adapted \nmonitoring, therapy modifica-\ntion, and personalized prophy-\nlactic interventions\n\nPage 10 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \n5.3 Defining the PE-prone phenotype: biomolecular \nsignature\nEmergence of a PE- prone phenotype can be concep -\ntualized as the convergence of multiple measurable \nbiomarkers reflecting immune, endothelial, and hema -\ntologic contributions to thrombus evolution and sys -\ntemic vulnerability [ 84]. Prominent among these are: \nPlatelet–leukocyte aggregates (PNAs): Complexes of \nactivated platelets and neutrophils or monocytes that \nsignal heightened immunothrombotic engagement and \npredict propagation of thrombotic processes [ 85, 86]. \nPNAs facilitate NETosis and represent a mechanistic \nbridge between innate immunity and coagulation ampli -\nfication. Endothelial microparticles (EMPs): Vesicles shed \nfrom activated or apoptotic endothelial cells that carry \npro-coagulant phospholipids, tissue factor, and adhesion \nmolecules [ 87]. EMP levels correlate with endothelial \ndysfunction and have been linked to elevated risk of \nthrombotic events including deep vein thrombosis and \nPE. Inflammatory indices (NLR, CRP , IL-6): Systemic \ninflammatory markers such as neutrophil- to-lymphocyte \nratio (NLR), C -reactive protein (CRP), and interleukin-6 \n(IL-6) reflect the systemic immune activation that pre -\ndisposes to immunothrombotic propagation and have \nbeen associated with PE severity and prognosis [ 88, 89]. \nIron/lipid peroxidation indices: Biomarkers of oxidative \nstress such as lipid peroxides and catalytic iron reflect \nredox imbalance that can drive endothelial injury, neu -\ntrophil activation, and NET formation, all of which con -\ntribute to thrombus stability and resistance to fibrinolysis \n[90]. Together, these biomolecular signatures delineate a \npathophysiologically distinct PE- prone phenotype, char -\nacterized by enhanced immunothrombotic activity, clot \nstabilization mechanisms, and systemic inflammatory \nFig. 2 Endothelial reprogramming as the central integrator of immunothrombotic risk. Chronic inflammatory conditioning and iron-driven oxidative \nstress induce durable endothelial reprogramming that integrates immune, metabolic, and redox signals into a unified axis of thrombogenic suscep -\ntibility. Persistent exposure to cytokines (e.g., TNF-α, IL-1β, IFN-γ) establishes transcriptional and epigenetic “memory-like” imprints within endothelial \ncells, sustaining adhesion molecule expression (ICAM-1, VCAM-1) and sensitizing the vasculature to exaggerated inflammatory responses. Concomitant \nsuppression of anticoagulant pathways—including reduced endothelial nitric oxide synthase activity, diminished nitric oxide bioavailability, and de -\ncreased thrombomodulin expression—promotes procoagulant drift through sustained NF-κB and inflammasome signaling. Metabolic rewiring toward \nenhanced glycolytic flux and mitochondrial dysfunction, coupled with iron-mediated reactive oxygen species generation and lipid peroxidation, destabi-\nlizes endothelial redox homeostasis and increases susceptibility to ferroptotic injury. These integrated alterations compromise barrier integrity, enhance \nplatelet–leukocyte adhesion, and facilitate microparticle and neutrophil extracellular trap (NET)–associated thrombus stabilization. The reprogrammed \nmicrovasculature thus transitions from a quiescent anticoagulant interface to a pro-inflammatory, pro-thrombotic effector, enabling systemic spillover of \nthromboinflammatory signals to distant vascular beds. Inset: Estrogen signaling maintains endothelial vasoprotective tone via PI3K/Akt-mediated eNOS \nactivation and anti-inflammatory gene programs; hypoestrogenic states (e.g., GnRH agonist–induced suppression) attenuate these protective pathways, \nlowering the threshold for immunothrombotic propagation in a primed endothelium (designed using Power Point and Adobe Illustrator software)\n \n\nPage 11 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \nengagement that collectively extend traditional views of \nvenous thromboembolism into a broader systemic dis -\nease framework. Recognizing this phenotype’s complex \nmolecular and cellular underpinnings not only refines \nrisk stratification for thromboembolic events in women \nwith endometriosis, a group already demonstrably at \nhigher risk of broader cardiovascular pathology, but \nalso highlights the pressing need for translation of these \ninsights into personalized clinical strategies. Indeed, \nwomen with endometriosis exhibit elevated risks of \nadverse cardiovascular outcomes such as ischemic heart \ndisease and cerebrovascular events, reflecting the inter -\nplay between chronic inflammation, endothelial dysfunc -\ntion, and systemic vascular perturbation, which standard \ndiagnostic paradigms alone fail to capture.\nThis evolving understanding sets the stage for preci -\nsion cardio-reproductive medicine, an integrative clinical \ndiscipline that seeks to tailor risk assessment, prediction, \nprevention, and therapeutic approaches to the unique \npathobiological profiles of individuals, bridging repro -\nductive endocrinology with cardiovascular systems sci -\nence to improve outcomes across health trajectories. \nThe concept of precision medicine, which has already \nreshaped fields such as oncology and cardiology by lever -\naging detailed molecular, imaging, and computational \nphenotyping to optimize individualized risk prediction \nand therapy, provides a compelling framework for this \nintegration.\nJust as precision cardiology is moving from generalized \ntreatment paradigms toward risk stratification based on \ngenomic and multi-omic signatures and advanced analyt-\nics, the integration of reproductive hormonal dynamics, \nimmune–vascular phenotypes, and molecular biomark -\ners offers an analogous opportunity in women’s cardio -\nvascular health. Together, these advances underscore the \nneed to translate mechanistic insights from endometrio -\nsis-associated immunothrombosis into clinically action -\nable strategies, forming the basis for the next section on \ntranslational implications and precision cardio-reproduc-\ntive medicine.\n6 Future research directions toward precision \ncardio-reproductive medicine\nTranslating the mechanistic insights above requires a \ndeliberate shift from population-level pharmacovigilance \nto individualized, mechanism-driven clinical care that \nintegrates reproductive endocrinology with cardiovas -\ncular systems science, a precision cardio-reproductive \nmedicine paradigm that combines biomarkers, multi-\nomic phenotyping, and dynamic surveillance to predict, \nprevent, and mitigate vascular complications of therapies \nsuch as GnRH agonists [91].\n6.1 Risk stratification before GnRH agonist initiation\nAlthough not part of current routine clinical practice, \nfuture precision cardio-reproductive medicine may \nincorporate pre-treatment vascular phenotyping to iden -\ntify women at increased thrombotic susceptibility. Such \napproaches require prospective validation before clini -\ncal implementation [ 92]. First-line stratification should \ninclude careful clinical cardiovascular risk appraisal \n(personal and family history of VTE/PE, prior arterial \nevents, and traditional risk factors) combined with tar -\ngeted laboratory screening for high-yield thrombophil -\nias or hypercoagulable states when indicated by history; \nthis combined strategy improves detection of patients at \nmaterially elevated thrombotic risk [ 93]. Baseline mea -\nsurement of mechanistically relevant circulating bio -\nmarkers, for example, D-dimer and soluble P-selectin \n(coagulation/hemostatic activity), endothelial micropar -\nticles (endothelial activation), and platelet–leukocyte \naggregates (cellular immunothrombosis), provides a \nbiologically anchored risk snapshot that augments clini -\ncal assessment [ 94]. Where available, integration of \nmolecular phenotyping (e.g., targeted proteomics, tran -\nscriptomic endothelial signatures, or single-cell immune \nprofiling) can further resolve subphenotypes of vascular \nvulnerability and identify patients for intensified surveil -\nlance or alternative therapies [95].\n6.2 Biomarker-guided surveillance during therapy\nRather than applying binary contraindications, we advo -\ncate dynamic, biomarker-guided monitoring during \nGnRH agonist exposure to detect early signals of vascu -\nlar destabilization and enable timely intervention [ 96]. \nFuture biomarker-guided surveillance strategies could \nincorporate serial assessment of coagulation, endothe -\nlial, platelet, and NET-related biomarkers to detect early \nvascular perturbation. However, none of these biomark -\ners has yet been prospectively validated for routine moni-\ntoring of women receiving GnRH agonists, and their \nclinical utility remains investigational [ 92]. Point-of-care \ntechnologies that quantify platelet–leukocyte aggregates \nor cell-aggregate signatures may permit near-real-time \nrisk detection in outpatient settings and facilitate rapid \ndecisions about therapy continuation, intensification \nof prophylaxis, or alternative strategies [ 97]. Crucially, \nsurveillance must be adaptive: biomarker trends (trajec -\ntory, not single value) should trigger predefined clinical \nactions (e.g., intensified monitoring, short-term throm -\nboprophylaxis, endocrine therapy modification), thereby \nconverting mechanistic signals into actionable clinical \nworkflows.\n\nPage 12 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \n6.3 Preventive co-therapies and vascular stabilization \nstrategies\nMechanism-driven prevention focuses on stabilizing \nendothelium, reducing platelet hyperreactivity, and buff -\nering redox stress, interventions selected to counter the \nspecific axes identified during phenotyping [98].\n6.3.1 Endothelial protectants\nStatins, antiplatelet agents, antioxidant therapies, and \nindividualized hormone-management strategies repre -\nsent biologically plausible approaches deserving future \nprospective evaluation rather than established preven -\ntive strategies for GnRH-associated thrombotic risk. \nRandomized clinical studies will be required before such \ninterventions can be recommended in routine practice \n[98]\n6.3.2 Antiplatelet modulation\nLow-dose aspirin and other antiplatelet agents reduce \nVTE risk in select high-risk settings and may be con -\nsidered where platelet-driven immunothrombosis pre -\ndominates, recognizing that the absolute benefit must be \nbalanced against bleeding risk and that randomized data \nin the GnRH-treated endometriosis population are lack -\ning [99]\n6.3.3 Redox buffering and mitochondrial support\nInterventions such as N-acetylcysteine (NAC) and other \nantioxidant strategies can attenuate oxidative stress and \nhave preliminary evidence for improving endothelial \nfunction in metabolic and inflammatory settings, sug -\ngesting potential adjunctive roles to reduce NETosis and \nferroptotic vulnerability in iron-primed phenotypes [100]\n6.3.4 Therapeutic hormone management:\nWhere vasculoprotective estrogenic signaling is essen -\ntial (and reproductive goals allow), add-back estrogen \nor dose/schedule modifications may mitigate abrupt \nendothelial deconditioning during GnRH therapy and \nhave been shown to restore endothelium-dependent \nrelaxation in controlled studies [ 101] Finally, the choice \nbetween GnRH agonists versus antagonists may itself \nbe an actionable decision point in patients with elevated \ncardiovascular vulnerability, since emerging compara -\ntive data suggest differential cardiovascular risk profiles \nacross these drug classes and thus inform personalized \ntherapeutic selection (Fig. 3). \n6.4 Redefining safety: from adverse event to mechanistic \npredictability\nLooking ahead, future integration of longitudinal bio -\nmarkers, multi-omic profiling, and machine-learning \nmodels may enable individualized prediction of ther -\napy-associated vascular complications. However, these \napproaches remain investigational and require analyti -\ncal validation, external validation, prospective clinical \nevaluation, and demonstration of clinical utility before \nimplementation into routine care [ 102]. Achieving this \nrequires harmonizing longitudinal biomarker data with \ndeeper molecular and imaging phenotypes, and apply -\ning machine-learning and multi-omic integration to \ngenerate predictive risk models and decision tools that \nare interpretable and clinically actionable [ 103]. Pilot \nimplementation should follow an iterative translational \npathway: [1] cohort discovery and multi-omic phenotyp -\ning [2], prospective biomarker validation with predefined \nintervention thresholds [ 3], randomized evaluation of \nbiomarker-guided risk-reduction strategies (e.g., statin/\nantiplatelet/add-back approaches), and [ 4] deployment \nof validated clinical decision support into routine care, \na pathway that parallels successful precision approaches \nin other cardiovascular domains [95]. Ultimately, embed-\nding mechanistic assays and predictive models into the \nstandard workflow will convert ad hoc safety signals into \npredictable, preventable events and will allow clinicians \nto tailor reproductive therapies to minimize vascular \nharm while preserving reproductive and symptomatic \nbenefits.\n7 Conceptual synthesis: the immunothrombotic \ncontinuum\nThe mechanistic threads developed above, chronic pel -\nvic inflammation, iron-driven oxidative priming, plate -\nlet–leukocyte crosstalk, endothelial reprogramming, \nand hormonal perturbation, are not discrete phenom -\nena but elements of a continuous immunothrombotic \nspectrum in which immune activation and coagulation \nare reciprocally reinforcing and progressively remodel \nvascular biology toward thrombotic vulnerability. This \nimmunothrombotic continuum reframes endometriosis \nfrom a localized gynecologic disorder into a systemic, \nmulti-axis disease in which local lesion biology can prop -\nagate to distant vascular beds through defined cellular \nand molecular pathways.\n7.1 Endometriosis as a model of reproductive \nimmunovascular crosstalk\nEndometriosis offers a uniquely informative human \nmodel to study reproductive-immune-vascular interac -\ntions because it couples repetitive, hormone-driven tis -\nsue injury and repair with sustained local iron overload \nand chronic sterile inflammation, providing a natural \nexperiment in how cyclical reproductive physiology can \nentrain persistent vascular perturbations [ 104]. At the \ncellular level, the lesion microenvironment, rich in acti -\nvated macrophages, cytokines, and oxidative products, \nconditions neighboring endothelium and releases cir -\nculating mediators (microparticles, NET remnants) that \n\nPage 13 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \nconvey inflammatory and procoagulant signals systemi -\ncally, thereby mechanistically linking pelvic biology to \nremote vascular dysfunction [ 105]. Because endometrio -\nsis commonly affects women in their reproductive years \nand is managed with hormonal therapies that themselves \nmodulate vascular biology, it serves as a tractable context \nfor testing how reproductive endocrine shifts interact \nwith immunothrombotic mechanisms to modulate short- \nand long-term vascular risk.\n7.2 Hormonal therapies as systemic vascular modulators\nSex steroids exert powerful, pleiotropic effects on vas -\ncular cells: estrogen promotes endothelial nitric oxide \nsynthase activity, accelerates endothelial repair, and sup -\npresses pro-inflammatory gene programs, while estro -\ngen withdrawal impairs these protective pathways and \nunmasks endothelial vulnerability [ 106]. Therapeutic \nmanipulations of the hypothalamic–pituitary–gonadal \naxis, for example, continuous GnRH agonists, therefore \nact as systemic biological perturbations that can tip a \nprimed endothelium into overt dysfunction by abruptly \nremoving vasoprotective signaling, altering platelet and \nfibrinolytic balance, and modifying metabolic state. Com-\nparative clinical and mechanistic data indicate that differ-\nent classes of gonadotropin-suppressing agents (agonists \nvs. antagonists) and add-back strategies produce distinct \ncardiovascular and metabolic footprints, supporting the \nconcept that endocrine therapies should be considered \nvascular modulators rather than organ-restricted treat -\nments [107].\n7.3 A new paradigm for thromboembolic risk in chronic \ninflammatory disease\nBeyond endometriosis, a broader body of evidence \nshows that chronic inflammatory and autoimmune \ndiseases reconfigure thrombotic risk through shared \nimmunothrombotic mechanisms, NETosis, endothelial \nactivation, procoagulant microparticles, and dysregulated \nanticoagulant pathways, arguing for a paradigm shift \nfrom risk estimation based on classical hemodynamic or \nFig. 3 Translational pipeline for precision cardio-reproductive medicine in endometriosis. Legend: This figure illustrates a systems-level, translational \nframework for preventing immunothrombotic complications during GnRH agonist therapy in women with endometriosis. Panel A — Pre-treatment \nPhenotyping & Risk Stratification: Clinical history, conventional cardiovascular risk factors, and mechanistic biomarkers (e.g., D-dimer, platelet–neutro-\nphil aggregates [PNAs], endothelial microparticles [EMPs], iron/lipid-peroxidation indices, endothelial transcriptomic signatures) stratify patients into low-, \nintermediate-, and high-risk vascular phenotypes. Panel B — Adaptive Biomarker-Guided Surveillance : Serial, trajectory-based monitoring of coagu-\nlation, platelet activation, endothelial injury, NETosis, and redox markers informs real-time decision nodes. Upward trends trigger graded clinical actions, \nfrom intensified monitoring to prophylactic intervention, enabling dynamic management of immunothrombotic risk. Panel C — Mechanism-Targeted \nInterventions: Phenotype-driven preventive strategies include endothelial stabilizers (e.g., statins), antiplatelet agents (low-dose aspirin), redox/mito -\nchondrial support (N-acetylcysteine, antioxidants), anti-NET therapies, and tailored hormonal regimens (GnRH agonist vs antagonist, add-back estrogen). \nIterative monitoring ensures therapy is adapted to evolving vascular states. Panel D — Predictive Modeling & Clinical Decision Support : Multi-omic \nand biomarker data integrate into predictive algorithms, validated through prospective trials and embedded in clinical decision support systems, en -\nabling mechanistic forecasting of thromboembolic events and personalized intervention (designed using Power Point and Adobe Illustrator software)\n \n\nPage 14 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \nthrombophilia models toward integrated immunovascu -\nlar phenotyping [ 108]. This new paradigm emphasizes \n(i) dynamic network-level drivers of thrombosis rather \nthan single biomarkers, (ii) the importance of host-state \n(immune, metabolic, endocrine) in determining whether \na clot will form, propagate, or embolize, and (iii) the ther-\napeutic consequences, namely, that targeting immuno -\nlogic and endothelial nodes (for example, NET inhibitors, \nendothelial stabilizers, redox modulators) may comple -\nment anticoagulation to prevent clinically meaningful \nembolic events [109].\n7.4 Limitations of the proposed mechanistic model\nThe framework presented in this Review is intended as a \nhypothesis-generating mechanistic model rather than an \nestablished causal sequence. While substantial experi -\nmental and epidemiologic evidence supports individual \ncomponents of the model, including endothelial dysfunc-\ntion in endometriosis, the vascular effects of hypoestro -\ngenism, and immunothrombotic mechanisms, direct \nprospective clinical evidence demonstrating that endo -\nmetriosis-induced endothelial priming is sequentially \nfollowed by GnRH agonist-mediated vascular destabiliza-\ntion culminating in thromboembolism remains limited. \nConsequently, the proposed “two-hit” paradigm should \nbe interpreted as a conceptual framework that integrates \ncurrent knowledge, identifies testable biological hypoth -\neses, and provides a foundation for future mechanistic \nstudies and prospective clinical validation. Similarly, the \nprecision cardio-reproductive medicine framework pro -\nposed in this Review, including biomarker-guided sur -\nveillance, NET and endothelial microparticle monitoring, \nand machine-learning-assisted risk prediction, should be \nregarded as future research priorities rather than com -\nponents of current standard clinical care. These concepts \nare intended to stimulate prospective translational inves -\ntigation aimed at determining their analytical validity, \nclinical utility, cost-effectiveness, and impact on patient \noutcomes before routine implementation can be consid -\nered [92].\n8 Conclusion\nWe propose reframing endometriosis not as an isolated \ngynecologic lesion but as a systemic immunothrombotic \ndisorder whose local biology (iron-rich hemorrhage, ster-\nile inflammation, platelet–leukocyte crosstalk) durably \nprimes the endothelium and hemostatic systems. This \nreframing dissolves the artificial barrier between repro -\nductive pathology and vascular medicine: the lesion is \nthe signal, and the vasculature is the transducer that con-\nverts cyclical reproductive injury into persistent throm -\nboinflammatory risk.\nMechanistically, the evidence converges on an inte -\ngrated cascade, iron-driven oxidative priming →  immune \namplification →  endothelial reprogramming →  immu -\nnothrombotic propagation, in which therapeutic endo -\ncrine perturbations (for example, GnRH-agonist-induced \nhypoestrogenism) can act as a biologically meaningful \nsecond hit that unmasks embolic vulnerability. Thinking \nin these terms shifts emphasis away from isolated risk \nfactors toward network states and dynamic transitions: \nit is less whether a patient “has” a risk factor and more \nwhich vascular state the patient occupies and how close \nthat state is to a tipping point for thrombus propagation \nand embolization.\nThe clinical implication is equally transformative. Pre -\nventing thromboembolic harm in reproductive-aged \nwomen requires prediction, prevention, and personal -\nization rather than retrospective pharmacovigilance. We \nmust [1] phenotype patients before therapy using clinical, \ncellular, and molecular assays that capture endothelial, \nimmune, and redox axes; [ 2] monitor trajectories during \ntherapy with mechanistically informative biomarkers and \npoint-of-care tools; and [ 3] deploy targeted co-therapies \n(endothelial stabilizers, selective antiplatelet strategies, \nredox modulators, tailored endocrine regimens) tested \nin biomarker-selected cohorts. In short, safety becomes \na function of mechanistic anticipation rather than event \ncounting.\nResearch priorities to realize this agenda are clear \nand urgent: validate compact, clinically deployable \nbiomarker panels that predict an immunothrombotic \nphenotype; perform mechanistic human and transla -\ntional studies that link lesion biology to systemic vas -\ncular readouts; compare endocrine regimens for their \nvascular footprints; and ethically design randomized, \nbiomarker-guided prevention trials of vascular stabiliz -\ners in high-risk patients. Parallel efforts should develop \ninterpretable predictive models that integrate multi-\nomic, imaging, and clinical time-series data and that can \nbe prospectively validated in diverse populations.\nIf realized, this program will accomplish more than \nprevent rare adverse events: it will generate a replicable \ntemplate for how reproductive biology informs sys -\ntemic vascular health, create a new subspecialty ethos, \nprecision cardio-reproductive medicine, and provide \nmechanistically grounded interventions that preserve \nreproductive choices while minimizing vascular harm. \nThe path forward is translational and collective: rigorous \nmechanistic inquiry, prospective phenotyping, and prag -\nmatic trials conducted in concert between reproductive \nendocrinology and vascular medicine will convert the \nimmunothrombotic insight from concept to clinical care.\nAcknowledgements\nNone.\nAuthor contributions\nAll authors reviewed the manuscript.\n\nPage 15 of 17\nLesani et al. Beni-Suef University Journal of Basic and Applied Sciences           (2026) 15:119 \nFunding\nNone.\nData availability\nNo datasets were generated or analysed during the current study.\nDeclarations\nEthics approval and consent to participate\nNot applicable.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare no competing interests.\nAuthor details\n1Department of Obstetrics and Gynecology, Tehran University of Medical \nSciences, Tehran, Islamic Republic of Iran\n2Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic \nof Iran\n3Pulmonary Subspecialty, Lorestan University of Medical Sciences, \nKhorramabad, Islamic Republic of Iran\n4Rajaie Cardiovascular Medical and Research Center, Iran University of \nMedical Science, Tehran, Islamic Republic of Iran\n5Department of Obstetrics and Gynecology, School of Medicine, \nHormozgan University of Medical Sciences, Bandar Abbas, Islamic \nRepublic of Iran\n6Department of Cardiology, School of Medicine, Hajar Hospital, \nShahrekord University of Medical Sciences, Shahr-e Kord, Islamic Republic \nof Iran\n7Reproductive Health Research Center, Department of Obstetrics & \nGynecology, Alzahra Hospital, Guilan University of Medical Sciences, \nRasht, Islamic Republic of Iran\nReceived: 20 June 2026 / Accepted: 29 September 2026\nReferences\n1. 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