{"paper_id":"993dd631-fff2-412d-8368-269ebe34d00d","body_text":"Copyright © 2026 The Author(s); Published by Society of Diabetic Nephropathy Prevention. This is an open-access article distributed under \nthe terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, \ndistribution, and reproduction in any medium, provided the original work is properly cit ed.\nDual therapeutic role of dienogest and vitamin E in \nendometriosis management and cardiovascular risk \nmodulation; a narrative review study \n J Prev Epidemiol. 2026;11(2):e39346                                                                                                                                                 Review\nJournal of Preventive Epidemiology \nKowsar Foroughi Abari1 ID\n, Amirhossein Derakhshandeh1* ID\n, Fatemeh T ayefi2 ID\n, Seyedeh Mobina Hosseini1 ID\n, \nKian Salehi1 ID\n, Seyedeh Melika Hosseini2 ID\n, Erfan Hossein Zehi Zamani1 ID\n1Zhengzhou University, Zhengzhou, China\n2Zhejiang University, Hangzhou, China\nCorrespondence to:\nAmirhossein Derakhshandeh, \nEmail: \nsajjad.derakhshandeh1831@gmail.com\nReceived: 10 Apr. 2026 \nRevised: 18 May 2026\nAccepted: 19 May 2026\nePublished: 25 May 2026\nKeywords: Endometriosis, \nDienogest, Progestins, Vitamin \nE, Anti-inflammatory agents, \nCardiovascular risk, Oxidative \nstress, Inflammation, Hormone \ntherapy, Women’s health\nEndometriosis is a long-lasting inflammatory condition that depends on estrogen and affects up to 10% \nof women of reproductive age. It is closely linked to pelvic pain, infertility, and higher heart disease risk, \nmainly because of increased oxidative stress and widespread inflammation. Standard treatments often help \nwith symptoms but usually don’t tackle the root causes or long-term health issues. Dienogest, a newer \nprogestin, is well tolerated and effective at reducing pain, shrinking lesions, and preventing recurrence. \nAlongside this, vitamin E, a fat-soluble antioxidant, offers anti-inflammatory, anti-angiogenic, and heart-\nprotective benefits by targeting oxidative stress, NF- κB signaling pathways, and vascular health issues. \nEvidence suggests that using both together might give a stronger effect: dienogest helps regulate hormones \nand immune responses, while vitamin E reduces oxidative damage and supports vascular health. This review \nindicated that combining dienogest and vitamin E could be a useful approach in treating endometriosis \nand lowering the risk of cardiovascular problems, emphasizing the importance of strategies that target both \nreproductive and overall health outcomes.\nAbstract\nCitation: Foroughi Abari \nK, Derakhshandeh A, \nTayefi F, Hosseini SMo, \nSalehi K, Hosseini SMe, \nHossein Zehi Zamani E. \nDual therapeutic role of \ndienogest and vitamin \nE in endometriosis \nmanagement and \ncardiovascular \nrisk modulation; a \nnarrative review study. \nJ Prev Epidemiol. \n2026;11(2):e39346. doi: \n10.34172/jpe.39346.\njprevepi.comhttp\nIntroduction\nEndometriosis is a persistent, estrogen‑driven \ninflammatory disorder defined by the \nectopic growth of endometrial‑like tissue \noutside the uterine cavity (1). It affects \napproximately 5–10% of women of \nreproductive age and is a major cause of \npelvic pain, dysmenorrhea, and infertility. \nThe ectopic growth of endometrial tissue \ntriggers persistent inflammation, fibrosis, \nand lesion formation, leading to significant \nlong‑term health consequences and reduced \nquality of life (2). For a long time, people \nsuffering from endometriosis knew about \nthe common symptoms like severe period \ncramps, ongoing pelvic discomfort, and \npain during sex, and struggles with getting \npregnant. But over time, many also realized \nthat endometriosis might be beyond a local \nissue; it’s possibly a condition that affects \nthe entire body, making it a widespread \ndisease (3). Growing evidence from recent \nstudies and meta‑analyses indicates that \nendometriosis is associated with increased \nrisks of cardiovascular conditions such as \ncoronary artery disease and hypertension, \nlikely driven by chronic inflammation, \noxidative stress, and underlying hormonal \ndysregulation (4,5). A meta‑analysis \nindicates that women with endometriosis \nmay have up to a 60% higher likelihood of \ndeveloping cardiovascular complications \ncompared with those without the condition, \nunderscoring the need for broader, more \nintegrative treatment strategies to better \nprotect long‑term health (4). \nFourth‑generation progestin, dienogest, \nhas played a key role in improving the way \nwe treat endometriosis. This medication \nhelps break down abnormal tissue, reduces \npain, and shrinks lesions by promoting a \nprocess called decidualization. Furthermore, \nit lowers inflammation without causing \nunwanted side effects like those associated \nwith androgens or steroids (6,7). Vitamin \nE not only alleviates symptoms but \nalso significantly reduces postoperative \nrecurrence rates, and in many cases \ndemonstrates superior effectiveness and \ntolerability compared with other hormonal \ntherapies (8,9). Moreover, free radicals and \noxidative stress promote the survival of \nendometriotic cells by sustaining vascular \ninjury and dysfunction, highlighting the \n10.34172/jpe.39346doi\n\n\nForoughi Abari et al\n Journal of Preventive Epidemiology   \n2\n           Volume 11, Issue 2, 2026\nsupportive role of vitamin E in counteracting these \npathogenic processes (10). \nVitamin E, a fat‑soluble antioxidant, helps protect \nyour body by removing harmful molecules involved in \ndamaging fats, neutralizing reactive oxygen species, and \ncalming down inflammation pathways. This means it can \nreduce the impact of both endometriosis and heart issues, \nmaking these common health problems less of a concern \n(10). It plays a special role in supporting our heart health \nand helping prevent conditions like atherosclerosis. At the \nsame time, it’s actually at the core of issues related to the \novergrowth of the endometrial lining (11). Taking vitamin \nE and dienogest together makes a lot of sense because \ntheir combination could both help manage symptoms \nand target the underlying cause of the condition. The \nantioxidant properties of vitamin E, combined with the \nhormonal effects of dienogest, might work together to \nprovide more effective relief and address the root issues \nat the same time. \nSearch Strategy\nA comprehensive search strategy was developed using \nPubMed/MEDLINE, Scopus, Web of Science, Embase, and \nGoogle Scholar, covering all publications from database \ninception to March 2026. The search combined MeSH \nterms and free‑text keywords related to endometriosis, \nhormonal therapy, and cardiovascular health, using \nBoolean operators to structure the query. Core terms \nincluded ‘endometriosis’ , ‘dienogest’ , ‘progestins’ , ‘vitamin \nE’ , ‘anti‑inflammatory agents’ , ‘cardiovascular risk’ , \n‘oxidative stress’ , ‘inflammation’ , ‘hormone therapy’ , and \n‘women’s health’ . These were grouped into thematic blocks \nand combined with AND/OR to maximize sensitivity \nand specificity. Additional manual searching included \nbackward and forward citation tracking and screening of \nrelevant gynecology, endocrinology, and cardiovascular \njournals. Only English‑language human studies addressing \nhormonal or antioxidant therapy, inflammation, oxidative \nstress, or cardiovascular outcomes in the context of \nendometriosis were included, while non‑English papers, \ncase reports, and studies without relevant mechanistic or \nclinical data were excluded.\nPathophysiology of endometriosis\nEndometriosis is a chronic gynecological disorder in \nwhich endometrial‑like tissue is implanted outside the \nuterine cavity, particularly on the peritoneal lining, \npelvic structure, and ovaries (12). Approximately 10 \npercent of women of reproductive age are diagnosed with \nendometriosis, presenting symptoms like chronic pelvic \npain, dysmenorrhea, and infertility (13). Its etiology is \nmultifactorial and not completely understood; however, \nevidence underscores the pivotal role of oxidative stress \nand inflammation in lesion establishment, persistence, \nand progression (14). \nOxidative Stress in Endometriosis\nOxidative levels increase when the body’s scavenging \nability decreases, either due to excessive oxidative stress or \nlower levels of antioxidants (15). In retrograde menstrual \nblood, iron released from hemolyzed erythrocytes \ncreates pro‑oxidant factors via Fenton chemistry, leading \nto the formation of hydroxyl radicals and damage to \ncellular macromolecules (16). These oxidative insults \npromote lipid peroxidation, protein oxidation, and DNA \ndamage, generating pro‑inflammatory mediators that \nfacilitate ectopic lesion survival and invasiveness (17). \nFurthermore, numerous studies have demonstrated that \naffected women show a significant decline in antioxidant \nactivity levels, such as superoxide dismutase (SOD), \ncatalase (CAT), glutathione peroxidase (GPx), and non‑\nenzymatic antioxidants like vitamins C and E, which \ncorrelates with disease severity (17). Ferroptosis is a \nregulated, iron‑dependent form of cell death driven by \nuncontrolled lipid peroxidation, particularly fatty acids \nin cell membranes (18). A recent study demonstrates that \nendometriotic stromal cells undergo ferroptosis; these \ncells secrete angiogenic and inflammatory cytokines, \nvascular endothelial growth factor A (VEGFA), and \ninterleukin 8 (IL ‑8), promoting angiogenesis in lesions. \nInterestingly, in the same study, ferrotopic endometrial \nstromal cells treated with an antioxidant N acetylcysteine \n(NAC) reversed ferroptosis‑induced cytokine secretion in \nvitro (19). In another study, it has been demonstrated that \ntreatment with genistein as an antioxidant significantly \nincreases SOD and GPx levels in the peritoneal fluid of \nendometriosis‑induced mice (20).\nAction mechanism of dienogest \nPharmacological profile\nDienogest is an oral progestin with a 9–10‑hour \nhalf‑life and over 90% bioavailability, giving it strong \nprogestogenic activity that effectively reduces endometrial \nlesions. It moderately suppresses gonadotropins and has \nanti‑androgenic and anti‑proliferative effects, while \nremaining well tolerated for long‑term use. The 2 mg daily \ndose is a fourth‑generation progestin originally approved \nfor treating endometriosis (21,22). Lower‑dose dienogest \n(0.5 mg) has been shown to work as effectively as the 1‑mg \nKey point \nFinding highlights that managing endometriosis requires a therapeutic \nperspective that also accounts for long-term systemic health, \nparticularly cardiovascular risk. The combined use of dienogest and \nvitamin E represents a biologically plausible and clinically meaningful \napproach, as their complementary mechanisms address both the \nhormonal–immune dysregulation underlying endometriosis and \nthe oxidative–inflammatory pathways implicated in cardiovascular \ndisease. By simultaneously reducing lesion activity, alleviating pain, \nand improving vascular and metabolic profiles, this dual strategy may \noffer broader protective benefits than symptom-focused treatments \nalone. \n\nEndometriosis management\n Journal of Preventive Epidemiology   \n3\n          Volume 11, Issue 2, 2026\ndose for managing endometriosis. Since it is a progestin \nassociated with a reduced risk of thromboembolic \nevents, it is considered a safer option for patients over \n40 years of age (23,24). Additionally, dienogest is a \n19‑nortestosterone–derived progestin, distinguished from \nsimilar agents by having a cyano‑methyl group instead of \nan ethynyl group at the 17α position. Its pharmacologic \naction is largely localized to endometriotic tissue, with \nvery limited angiogenic, estrogenic, glucocorticoid, or \nmineralocorticoid activity (24,25). \nHormonal modulation\nDienogest moderately suppresses gonadotropin secretion, \nleading to a reduction in the endogenous production of \nestradiol (25). Dienogest inhibits ovulation and, in many \ncases, hypomenorrhea or amenorrhea. The longer the \nperiod between the last gonadotropin‑releasing hormone \n(GnRH) agonist injection and the first dienogest dose, \nthe greater the number of ovulation and menstruation \ncycles becomes. Patients using dienogest within nine \nmonths after the last GnRH agonist had a lower \nreoperation rate than patients using DNG after nine \nmonths (26). Dienogest reduces estrogen levels, thereby \nalleviating symptoms of endometriosis independent of \nits antiestrogenic effect (23). and it has no glucocorticoid \nand no anti‑mineralocorticoid activity. It also has no \nantiestrogenic activity, which suggests that it should not \nantagonize the beneficial effects of estradiol (24,27). \nDienogest also reduces endometriotic lesions by creating \na local progestogenic environment, while only moderately \nsuppressing systemic estrogen levels (27). When taken \nconsistently, dienogest binds to the progesterone receptor \nand inhibits systemic gonadotropin secretion (21). \nMolecular and cellular effects\nDienogest exerts its therapeutic effect by inducing \ndecidualization and subsequent atrophy of ectopic \nendometrial tissue while suppressing cellular proliferation \nthrough downregulation of matrix metalloproteinases \nand aromatase, thereby diminishing the lesion’s \nestrogen‑dependent biological activity (25). Dienogest \ndemonstrates marked local antiproliferative activity \non endometriotic lesions by reducing cell viability and \nsuppressing proliferation in the presence of estrogen and \npro‑inflammatory cytokines, including tumor necrosis \nfactor‑alpha (TNF‑α), interleukin‑1β, and interleukin‑32, \nand by downregulating proliferating cell nuclear antigen \n(PCNA), whose expression is significantly diminished \nin both glandular components and whole lesions of \ndienogest‑treated mice compared with controls (21,28).\n \nAnti-inflammatory and anti-angiogenic actions\nDienogest exhibits well‑documented anti‑inflammatory \nand anti‑angiogenic properties (23,25), as demonstrated \nin both in vivo and in vitro models using eutopic \nand ectopic endometrial cells, where it consistently \nattenuates inflammatory signaling and suppresses \nneovascularization, mechanisms that are directly relevant \nto the regression of endometriotic lesions (25). Dienogest’s \nantiproliferative and antiangiogenic actions distinguish it \nfrom other progestins (21). \nImpact on endometriosis lesions\nDienogest produces a marked reduction in endometrial \nlesion burden (22), with experimental data showing \nthat the volume of implanted endometrial tissue in \nDNG‑treated mice decreases from an average of 53.70 \nmm³ to 21.46 mm³, corresponding to a 61.42% reduction \ncompared with controls, thereby demonstrating its \nrobust inhibitory effect on lesion growth (28). Long‑term \ntherapy with Dienogest has proven effective in controlling \ndisease symptoms and reducing endometrioma size, \nwith greater benefits associated with longer duration \nof intake and the absence of serious adverse events \n(29). Clinical evidence shows that daily administration \nof 2 mg dienogest produces a significant reduction \nin endometriosis‑associated pain within the first 12 \nweeks of therapy, and continued treatment for up to 52 \nweeks yields a sustained and progressive decline in pain \nseverity, underscoring its durable clinical effectiveness \n(30); this long‑term symptom control is attributed to \ndienogest’s strong endometrial activity, which enables its \nuse as a monotherapy by exerting antiproliferative and \nanti‑inflammatory effects that directly target and suppress \nthe biological activity of endometriosis lesions (24). \nClinical use of dienogest \nEffectiveness in symptom relief\nNonsteroidal anti‑inflammatory drugs (NSAIDs), oral \ncontraceptives, and progestins are widely regarded as \nfirst‑line therapies for endometriosis‑associated pain, \nand in this context, our findings indicate that dienogest \nmay serve as an effective treatment option for women in \nreal‑world clinical practice, particularly with respect to \nimproving health‑related quality of life (HRQoL) (22). \nClinical studies conducted in Europe have demonstrated \nthat dienogest, administered at a daily dose of 2 mg, \nprovides significantly greater pain relief in patients \nwith endometriosis than placebo and achieves efficacy \ncomparable to gonadotropin‑releasing hormone agonists, \nwhile producing fewer hypoestrogenic adverse effects; \nmoreover, dienogest 2 mg is characterized by a favorable \nsafety profile, marked by only mild hypoestrogenic effects, \nminimal impact on bone mineral density in adult women, \nand low rates of treatment discontinuation (29). Dienogest \nsignificantly reduced the recurrence rate (RR = 0.37, 95% \nCI [0.15–0.91]; P = 0.03) and the incidence of hot flushes \n(RR = 0.24, 95% CI [0.10–0.59]; P= 0.002), while also \nproviding protection against bone mineral density loss. \nTaken together, these findings indicate that dienogest \nis as effective as gonadotropin‑releasing hormone \nanalogues for the clinical management of endometriosis, \n\nForoughi Abari et al\n Journal of Preventive Epidemiology   \n4\n           Volume 11, Issue 2, 2026\nas no statistically significant differences were observed \nbetween treatment groups in the control of pelvic pain, \ndysmenorrhea, or dyspareunia (31). \nImpact on lesion size and disease progression\nThe effects of dienogest on reducing the recurrence of \nendometrioma cysts have been extensively evaluated \nin comparison with treatments such as GnRH agonists \nand combined oral contraceptives, and its selective \nprogestin activity is mediated through anti‑inflammatory, \nanti‑estrogenic, and pro‑apoptotic mechanisms acting \non endometrial tissue (32). Dienogest can also be \nrecommended as a maintenance treatment for patients \nwith endometriosis to decrease the rates of disease \nrecurrence following conservative surgery (33). Dienogest \ninhibits ovulation and frequently induces hypomenorrhea \nor amenorrhea, and because a longer interval between \nthe final GnRH agonist injection and initiation of \ndienogest increases the likelihood of ovulatory and \nmenstrual cycles, patients who began dienogest within \nnine months of their last GnRH agonist exhibited lower \nreoperation rates than those who initiated treatment \nlater, indicating that administering dienogest before \nmenstruation resumes is an important factor in reducing \nendometriosis recurrence requiring surgical intervention \n(26). According to comparative analyses of postoperative \ntherapies for endometriosis, dienogest and GnRH agonists \ndemonstrate broadly equivalent overall efficacy, although \ndienogest appears superior in reducing postoperative \nrecurrence. In summary, postoperative adjuvant treatment \nwith dienogest significantly decreases pain levels and \nrecurrence rates while improving pregnancy outcomes \nin patients with endometriosis, underscoring its clinical \nvalue and potential for broader implementation in practice \n(34). Administration of dienogest for up to five years has \ndemonstrated a favorable safety and tolerability profile, \nand current evidence supports the use of medical therapy, \nincluding dienogest 2 mg, as postoperative management to \nprevent endometriosis recurrence, except in patients with \nan immediate desire for pregnancy. Moreover, dienogest \n2 mg provides an effective and well‑tolerated alternative \nto repeated surgical intervention for the long‑term \nmanagement of endometriosis, offering several advantages \nover combined oral contraceptives in sustaining symptom \ncontrol and reducing disease progression (21).\nTreatment duration and long-term use\nThe study by Kikuno et al is one of the first trial studies \nto compare efficacy and safety between 1 mg/day and \n2 mg/day of long‑term dienogest use in patients with \ndysmenorrhea caused by endometriosis (23). Current \nguidelines and expert consensus identify progestins as the \nfirst‑line medical therapy for endometriosis, reflecting their \nefficacy, tolerability, and suitability for long‑term use. Given \nthat endometriosis is a chronic condition characterized \nby persistent symptoms, including pelvic pain, and a \npropensity for disease progression or recurrence across \nthe reproductive lifespan, increasing emphasis has been \nplaced on sustained medical management. Accordingly, \nlong‑term therapeutic strategies are considered essential \nboth for alleviating endometriosis‑related symptoms and \nfor reducing the risk of recurrence (25). Evidence on the \nlong‑term use of dienogest beyond 15 months demonstrates \nsustained efficacy in the management of endometriosis, \nwith experts emphasizing that its therapeutic value should \nbe assessed primarily through its impact on pain reduction \nand improvements in quality of life. Administration of \ndienogest for up to five years has shown a consistently \nfavorable safety and tolerability profile, and available data \nindicate that observed changes in bone mineral density \nare minimal and should not preclude its long‑term use in \nwomen requiring ongoing management of endometriosis \n(21). Sequential therapy, consisting of an initial course of \nrelugolix followed by dienogest, represents a novel strategy \ndesigned to optimize symptom control and sustain \nlong‑term disease management, with current findings \ndemonstrating that this approach provides effective relief \nof endometriosis‑related symptoms and durable disease \nsuppression. Dienogest maintains these therapeutic gains \nwith minimal adverse effects, supporting its role as a \nwell‑tolerated maintenance therapy within sequential \ntreatment regimens (35).\nAnti-oxidants in endometriosis treatment \nRole of oxidative stress in endometriosis\nGrowing evidence suggests that oxidative stress plays a key \nrole in both the onset and progression of endometriosis. \nWhen oxidative stress increases, levels of reactive oxygen \nspecies (ROS) rise, and these inflammatory molecules \ncan damage cells. High ROS levels promote the release \nof pro‑inflammatory cytokines and prostaglandins from \nmacrophages and activate C‑fibers through neurogenic \ninflammation. Together, these processes contribute to the \ndevelopment of pain in individuals with endometriosis \n(36).\nRole of antioxidants and vitamins C and E in reducing \nendometriosis-associated pain \nAntioxidants help mitigate reactive oxygen species and \nmay reduce endometriosis‑related discomfort, with \nvitamins A, C, E, zinc, copper, and selenium identified \nfor their antioxidant properties. Among these, vitamins \nC and E are particularly suitable for long‑term daily use \ndue to their minimal adverse effects, and their combined \nadministration enhances antioxidant capacity through \n“vitamin E recycling, ” improving lipid oxidation resistance \nmore effectively than either vitamin alone. Both vitamins \nalso reduce inflammation by inhibiting proinflammatory \ncytokines such as TNF‑α, IL‑1, IL‑6, and monocyte‑\nchemotactic protein‑1 (MCP‑1), and contribute to \nregulating oxidative stress associated with disturbances in \niron metabolism (36). \n\nEndometriosis management\n Journal of Preventive Epidemiology   \n5\n          Volume 11, Issue 2, 2026\nEfficacy of NAC in endometriosis treatment\nThe NAC exerts antiproliferative and antioxidant effects by \npromoting the proliferation‑to‑differentiation switch and \ndownregulating the expression of inflammatory genes and \nproteins. As a precursor of glutathione, NAC provides both \ndirect and indirect antioxidant and anti‑inflammatory \nactivity, and its strong anti‑inflammatory action may also \nreduce Cancer Antigen 125 (Ca125) levels and improve \nfertility. In our study, NAC administration for three \nmonths resulted in a significant reduction in the size of \novarian endometriomas, an effect likely attributable to its \npotent antiproliferative properties. Additionally, serum \nCa125 levels decreased significantly following treatment, \nprobably reflecting NAC’s anti‑inflammatory action at the \nperitoneal level (36). \nMolecular mechanisms of vitamin E\nAntioxidant and anti-peroxidative effects\nA hallmark of endometriosis is a significant imbalance \nin redox homeostasis, with affected women consistently \nexhibiting elevated levels of ROS and lipid peroxidation \nend‑products, such as MDA, in both serum and \nperitoneal fluid. These reactive molecules are not passive \nbyproducts; rather, they actively contribute to DNA \ndamage, mitochondrial dysfunction, enhanced cellular \nadhesion, and ultimately the survival and proliferation \nof ectopic endometrial lesions (37). Vitamin E serves \nas a primary defense against this oxidative assault. It \nstrategically interrupts the propagating chain reactions \nof lipid peroxidation by donating a hydrogen atom to \nperoxyl radicals, thereby converting them into stable \nlipid hydroperoxides. This action significantly reduces \nthe accumulation of toxic aldehydes like MDA and \n4‑hydroxynonenal (4‑HNE) (38,39). By halting this \nprocess, Vitamin E stabilizes plasma and organelle \nmembranes and is particularly crucial for preserving \nmitochondrial integrity, the primary site of ROS \ngeneration (40). \nModulation of inflammatory pathways\nThe link between oxidative stress and inflammation is \ncentral to the pathophysiology of endometriosis, as ROS \nfunction as potent secondary messengers that activate \nthe key inflammatory transcription factor Nuclear factor \nkappa B (NF‑κB). Once activated, NF‑κB translocates \nto the nucleus and induces the expression of multiple \npro‑inflammatory mediators, including TNF‑α, IL‑6, \nand the enzyme cyclooxygenase‑2 (COX‑2). Elevated \nCOX‑2 activity drives the production of prostaglandin E₂ \n(PGE₂), a major contributor to pelvic pain, hyperalgesia, \nand the inflammatory microenvironment that supports \nthe persistence and growth of endometriotic lesions (41). \nVitamin E exerts potent anti‑inflammatory effects by \ndirectly disrupting this signaling pathway, suppressing \nthe phosphorylation and nuclear translocation of NF‑κB \nand thereby reducing the downstream expression of \nits target cytokines and COX‑2 (37). This upstream \ninhibition is a key mechanism underlying the documented \nanti‑inflammatory and analgesic benefits of vitamin E in \nboth experimental models of endometriosis and clinical \nobservations (38). By suppressing NF‑κB activation, \nvitamin E effectively disrupts the critical crosstalk \nbetween oxidative stress and chronic inflammation that \ndrives lesion persistence and symptom severity.\nRegulation of apoptosis\nVitamin E has been shown to modulate the intrinsic \napoptotic pathway by downregulating the anti‑apoptotic \nprotein Bcl‑2 and upregulating the pro‑apoptotic \nprotein Bax, thereby increasing the Bax/Bcl‑2 ratio. \nThis shift promotes mitochondrial outer membrane \npermeabilization, enabling cytochrome c release and \nactivation of the caspase cascade, ultimately driving \nprogrammed cell death in endometriotic cells (42). This \npro‑apoptotic action supports tissue homeostasis by \nfacilitating the selective clearance of ectopic cells while \nminimizing collateral damage to surrounding healthy \ntissue due to its targeted mechanism (43). \nInhibition of angiogenesis\nThe survival and growth of established ectopic lesions \nrely heavily on the development of a new blood supply, \na process driven by angiogenesis. Consistent with this, \npro‑angiogenic factors, most notably VEGF , are found \nat elevated levels in the peritoneal fluid of women with \nendometriosis, underscoring the central role of aberrant \nangiogenic signaling in sustaining lesion viability and \nexpansion (44). \nCardiovascular implications in endometriosis \nWomen with laparoscopically confirmed endometriosis \nhave been shown in a growing body of epidemiological \nresearch to face a markedly elevated long‑term risk of \ncardiovascular diseases, including ischemic heart disease, \nmyocardial infarction, and angiographically verified \ncoronary atherosclerosis, underscoring endometriosis as \na systemic condition with significant implications beyond \nreproductive health (4). \nOxidative stress and lipid peroxidation in atherogenesis \nThe excessive OS burden characteristic of endometriosis \nhas far‑reaching systemic effects, including the oxidation \nof circulating low‑density lipoprotein (LDL) particles. \nOnce oxidized, LDL becomes a highly pro‑atherogenic \nform (ox‑LDL) that is rapidly taken up by macrophages, \ndriving their transformation into lipid‑laden foam cells, \nthe defining early feature of atherosclerotic plaque \nformation (45). Vitamin E, which is incorporated into \nLDL particles, serves as a crucial first‑line antioxidant \ndefense by interrupting lipid peroxidation chains within \nthe LDL core. Through this chain‑breaking activity, it \n\nForoughi Abari et al\n Journal of Preventive Epidemiology   \n6\n           Volume 11, Issue 2, 2026\nprevents the conversion of native LDL into its highly \natherogenic oxidized form, thereby reducing macrophage \nuptake, limiting foam‑cell formation, and ultimately \nslowing the early initiation and subsequent progression of \natherosclerotic lesions (9,45,46). \nRestoration of endothelial function and nitric oxide \n(NO) bioavailability\nThe vascular endothelium, a single‑cell layer lining all \nblood vessels, is especially vulnerable to oxidative stress, \nand in women with endometriosis, it shows clear signs \nof dysfunction (47,48). Excess ROS diminishes both the \nproduction and the bioavailability of NO, the endothelium’s \nprincipal vasodilator. Superoxide anion, in particular, \nreacts rapidly with NO, effectively neutralizing it and \nreducing its capacity to maintain vascular relaxation. The \nresulting deficit in NO promotes heightened vascular tone, \nincreased vasoconstriction, and a greater susceptibility \nto developing hypertension (49). Vitamin E preserves \nvascular function by scavenging superoxide to protect \nNO from degradation while simultaneously enhancing \nendothelial NO synthase activity, a dual action that \nimproves vascular reactivity and helps guard against early \nvascular aging (50). \nAttenuation of vascular inflammation via NF -κB \nsuppression\nChronic, NF‑κB–driven systemic inflammation in \nendometriosis directly impacts the vasculature by \nactivating NF‑κB signaling within endothelial cells, which \nsubsequently increases the expression of intercellular \nadhesion molecule‑1 (ICAM‑1) and vascular cell adhesion \nmolecule‑1 (VCAM‑1) (51). These adhesion molecules \nfunction as molecular “glue, ” promoting the recruitment \nand firm attachment of monocytes and other leukocytes \nto the vessel wall, a pivotal early event in atherogenesis, \nand because vitamin E potently suppresses NF‑κB nuclear \ntranslocation, it lowers the expression of these endothelial \nadhesion molecules, thereby reducing leukocyte, \nendothelial interactions and the vascular inflammation \nthat follows (37,52). \nModulation of platelet function and hemostatic balance\nEndometriosis is accompanied by a subtle but clinically \nmeaningful shift toward hypercoagulability and heightened \nplatelet activation, a combination that further amplifies \nthe risk of thrombotic events, including myocardial \ninfarction and stroke, within an already vulnerable \nvascular system (53). Vitamin E exerts mild antiplatelet \neffects by inhibiting protein kinase C, a key driver of \nplatelet activation and aggregation, and by reducing the \nsynthesis of thromboxane A₂, a potent pro‑thrombotic \nand vasoconstrictive mediator (54).\nConclusion\nEndometriosis and cardiovascular health are closely \ninterconnected, requiring treatment approaches that \ngo beyond symptomatic relief. The combined use of \ndienogest and vitamin E offers a promising strategy that \nnot only reduces pain and lesion progression but may \nalso lower long‑term cardiovascular risk. This synergistic \neffect arises from their complementary actions: dienogest \nregulates hormonal imbalance and immune responses, \nwhile vitamin E counteracts oxidative stress, inhibits NF ‑\nκB signaling, and supports vascular function. In addition \nto pharmacological therapy, lifestyle interventions such \nas a Mediterranean diet and regular physical activity may \nfurther enhance cardiovascular protection. Ultimately, \nthe synergistic combination of dienogest and vitamin E \nrepresents a mechanism‑based, long‑term management \nstrategy for endometriosis, addressing both reproductive \nsymptoms and systemic cardiovascular complications. \nDespite these encouraging findings, current evidence \nremains limited regarding optimal dosing, treatment \nduration, and reproductive outcomes, highlighting the \nneed for well‑designed clinical trials.\nAuthors’ contribution \nConceptualization: Kowsar Foroughi Abari and Amirhossein \nDerakhshandeh\nData curation: Kowsar Foroughi Abari and Seyedeh Melika Hosseini.\nInvestigation: Amirhossein Derakhshandeh and Kian Salehi.\nSupervision: All authors.\nValidation: Fatemeh Tayefi and Seyedeh Mobina Hosseini.\nVisualization: Erfan Hossein Zehi Zamani.\nWriting–original draft: All authors.\nWriting–review and editing: All authors.\nConflicts of interest\nThe authors declare that they have no competing interests. \nDeclaration of generative AI and AI-assisted technologies in the \nwriting process\nDuring the preparation of this work, the authors utilized Copilot to \nrefine grammar points and language style in writing. Subsequently, \nthe authors thoroughly reviewed and edited the content as necessary, \nassuming full responsibility for the publication’s content.\nEthical issues\nEthical issues (including plagiarism, data fabrication, and double \npublication) have been completely observed by the authors.\nFunding/Support\nNone.\nReferences\n1. Osuchowska-Grochowska I, Blicharska E, Gogacz M, Nogalska \nA, Winkler I, Szopa A, et al. Brief Review of Endometriosis and \nthe Role of Trace Elements. Int J Mol Sci. 2021;22:11098. doi: \n10.3390/ijms222011098. \n2. Zondervan KT, Becker CM, Koga K, Missmer SA, Taylor RN, \nViganò P. Endometriosis. Nat Rev Dis Primers. 2018;4:9. doi: \n10.1038/s41572-018-0008-5. \n3. Giudice LC, Kao LC. Endometriosis. Lancet. 2004;364:1789–\n99. doi: 10.1016/s0140-6736(04)17403-5. \n4. Mu F, Rich-Edwards J, Rimm EB, Spiegelman D, Missmer \nSA. Endometriosis and Risk of Coronary Heart Disease. 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