A narrative review of sex-related differences in inflammatory bowel disease-associated cardiovascular and thrombotic risk: epidemiology, mechanisms, and prevention strategies

Introduction

Cardiovascular disease (CVD) and chronic inflammatory conditions

CVD remains one of the leading causes of death in Western countries, accounting for approximately one in three deaths in the United States. Atherosclerotic cardiovascular disease (ASCVD), particularly ischemic heart disease and ischemic stroke, represents a major component of this burden (1). The global strategy is primarily focused on prevention and identification of high-risk individuals according to the presence of risk factors.

The pathogenesis of atherosclerosis and CVD in general has increasingly been associated with chronic inflammation; in fact, chronic inflammation is considered a fundamental driver of atherosclerosis and CVD. Elevated levels of pro-inflammatory markers such as interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-α) are independently associated with adverse cardiovascular events (2,3). Even statins, drugs which are a mainstay in CVD prevention and treatment, exhibit some of their benefits through anti-inflammatory action (4).

According to the latest data, inflammatory bowel disease (IBD), which encompasses ulcerative colitis (UC) and Crohn’s disease (CD), affects more than 6.8 million people globally, with increasing incidence in newly industrialized and emerging economies, and stable incidence in developed economies. IBD is not a disease confined to the gut and is now widely considered a systemic inflammatory condition with many extraintestinal manifestations. It has long been established that chronic immune-mediated inflammatory diseases, such as IBD, are accompanied by increased CVD risk and associated morbidity and mortality. Accelerated atherosclerosis and increased CVD risk are present in patients with chronic inflammatory diseases such as IBD, rheumatoid arthritis and psoriasis, compared to age- and sex-matched controls (5-9). The excess CVD risk is more pronounced in middle-aged, productive, working-age patients. Several pathophysiological mechanisms have been proposed to explain this increased CVD risk, most prominently chronic inflammation. Because this review primarily discusses biological mechanisms, the term sex-related is used for differences linked to reproductive hormones, physiology and immune responses, whereas gender-related factors should be considered when interpreting health-care access, symptom reporting, treatment behavior and adherence (10).

Recent advancements in IBD therapy have led to a reduction in morbidity and mortality associated directly with the gut-specific effects of the disease. As a consequence, some extraintestinal manifestations and systemic complications have come into the spotlight, including increased cardiovascular risk. Consequently, CVD has become one of the main contributors to morbidity and mortality in patients with IBD (11,12).

Treat-to-target strategies in IBD have evolved beyond symptom control toward objective control of inflammation. Selecting Therapeutic Targets in Inflammatory Bowel Disease II (STRIDE-II) describes clinical remission, endoscopic healing, restoration of quality of life and biomarker normalization as relevant treatment targets, while the newer concept of disease clearance in UC encompasses clinical, biochemical, endoscopic and histological remission (13,14). Whether cardiovascular risk reduction should become part of future composite IBD outcomes remains an important research question rather than an established treatment target.

IBD is associated with a modest but significant increase in arterial thrombotic events, including ischemic heart disease and cerebrovascular events, whereas the relative increase in venous thromboembolism (VTE) risk is larger, approximately twofold in several meta-analyses and consensus statements. Therefore, arterial ASCVD and VTE should be analyzed as related but distinct inflammation-associated complications. Data from a large Danish registry demonstrate that the risk is even higher during disease flares and increased inflammatory burden (11,15-17). Relative risk is most pronounced for certain arterial outcomes such as myocardial infarction (MI) and stroke (18). Higher levels of CRP were associated with increased incidence of IHD in patients with IBD. Multiple coagulation factors are elevated at baseline in patients with IBD, such as fibrinogen and factors V, VIII and IX. While not a coagulation factor, D-dimer, a byproduct of fibrin degradation, is elevated in patients with IBD and has data supporting its role as a risk marker for thromboembolism (6,19). VTE should therefore be discussed as a related thrombotic complication of IBD-associated inflammation, not as a component of ASCVD (20,21).

Relative and absolute risk should be interpreted separately. In younger women, a large relative increase may still correspond to a modest absolute event burden, whereas older men may carry a higher absolute number of events despite smaller relative increases. This distinction is used throughout the review when interpreting sex-stratified cardiovascular risk estimates (20,22,23).

Although the disproportionate relative risk in women is observed in many studies, the mechanisms that may lead to this disproportionate risk are not fully understood (24). In this review, we highlight proposed pathophysiological mechanisms that may predispose traditionally considered low-risk populations to the development of ASCVD, along with prevention strategies that may improve identification of high-risk individuals. The review is narrative in scope and prioritizes meta-analyses, large population-based studies, consensus statements and mechanistic studies with relevance to sex-stratified interpretation.

Operational definitions used in this review are as follows: ASCVD refers to arterial atherosclerotic outcomes, including ischemic heart disease, MI, ischemic stroke and peripheral arterial disease when reported; CVD is used as a broader umbrella term; VTE refers to deep venous thrombosis and pulmonary embolism. Major adverse cardiovascular events (MACE) is used only according to the definition of the cited study and should not be assumed to include the same endpoints across all sources. coronary microvascular dysfunction/ischemia with non-obstructive coronary arteries (CMD/INOCA) is discussed as a non-obstructive ischemic phenotype, not as synonymous with obstructive ASCVD. We present this article in accordance with the Narrative Review reporting checklist (available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0075/rc).

Methods

This narrative review was developed from targeted searches of PubMed/MEDLINE and major society statements, prioritizing meta-analyses, population-based cohorts, sex-stratified analyses, and consensus or guideline documents. Searches were conducted from database inception through April 2026, with final update searches performed on 23 June 2026. English-language peer-reviewed literature was prioritized, including meta-analyses, population-based cohorts, sex- or age-stratified analyses, prospective and retrospective clinical studies, pharmacovigilance analyses, mechanistic and translational studies, and major guideline or consensus documents. Because this was a narrative and mechanistically oriented review rather than a systematic review or meta-analysis, no formal risk-of-bias assessment, duplicate screening process, or pooled quantitative synthesis was performed.

The review was conceived as a narrative, mechanistic and clinically oriented synthesis rather than as a systematic review or meta-analysis. Therefore, no pooled effect estimates were generated, and the goal was to integrate epidemiological, translational and practical prevention evidence relevant to sex-related cardiovascular and thrombotic risk in IBD.

Searches were organized around four prespecified domains: (I) epidemiology of ASCVD, MACE, stroke, MI and VTE in IBD; (II) sex-stratified and age-stratified cardiovascular outcomes in IBD; (III) biological mechanisms linking IBD activity, estrogen signaling, endothelial function, coagulation, microbiome function and the estrobolome; and (IV) preventive strategies, including lipid-lowering therapy, thromboprophylaxis, corticosteroid avoidance, JAK inhibitor safety and selected imaging for subclinical atherosclerosis.

Key search terms included “inflammatory bowel disease, ulcerative colitis, Crohn’s disease, cardiovascular disease, atherosclerotic cardiovascular disease, major adverse cardiovascular events, myocardial infarction, stroke, venous thromboembolism, women, female sex, sex differences, gender, estrogen, estradiol, estrogen receptor beta, menopause, oral contraceptives, hormone replacement therapy, estrobolome, gut microbiome, beta-glucuronidase, JAK inhibitors, tofacitinib, upadacitinib, thrombosis and pharmacovigilance”.

Mechanistic and microbiome studies were included when they provided biologically plausible explanations for the epidemiological findings, but such evidence was interpreted as hypothesis-generating unless linked directly to adjudicated cardiovascular outcomes. The literature search strategy, including databases, search terms, timeframe, selection criteria, and synthesis approach, is summarized in Table 1.

Because endpoint definitions vary substantially across the literature, ASCVD, VTE, MACE and CMD were interpreted according to the definitions used in each source study. Risk estimates were also interpreted by separating relative risk measures, such as hazard ratios and relative risks, from absolute event rates or cumulative incidence; this distinction is central to clinical prevention because most therapeutic thresholds are based on absolute risk over a defined time horizon rather than relative risk alone (22).

The review uses the term sex-related differences when discussing biological factors such as hormones, chromosomes, reproductive status, endothelial function and coagulation. The term gender is reserved for social, behavioral or health-system factors when these are relevant. This distinction is important because many available IBD datasets record binary sex but do not adequately capture gender identity, access to care, diagnostic delay, risk perception or treatment patterns.

Epidemiology

Risk profiles in IBD patients differ from the general population

Traditional risk factors for the development of CVD are distributed differently in patient populations with IBD (25). Identifying higher risk in the IBD population is not straightforward because data from studies in IBD populations have shown a lower prevalence of several traditional CVD risk factors. These findings support the hypothesis that chronic inflammation is a major driver of atherosclerosis in IBD patients. Major societies have recognized this residual inflammatory risk as an important risk factor in an often overlooked and undertreated patient population (25-28).

Additionally, presentations of cardiovascular ischemia can be different in IBD populations than in the general population. There is evidence that intestinal inflammation in IBD patients is closely related to the degree of CMD, a form of functional and structural myocardial ischemia without overt obstructive coronary artery disease. Blunted vasodilation and microvascular spasm in CMD seem to be mediated by inflammatory mechanisms (29). CMD should not be used interchangeably with obstructive ASCVD, but it may represent an important inflammatory and sex-relevant pathway of ischemic symptoms in women.

Both European and American expert cardiology societies consider chronic inflammatory states, such as IBD, a factor that decreases the threshold for preventive intervention, such as lipid-lowering therapy (28,30,31). Commonly used CVD risk predictive scores take into account more traditional risk factors. For example, the ASCVD Risk Estimator considers sex, age, ethnicity, smoking, diabetes, systolic blood pressure, antihypertensive medication, and total and high-density lipoprotein (HDL) cholesterol. The Systematic Coronary Risk Evaluation 2 (SCORE2) algorithm proposed by European guidelines takes into account similar factors. Established and commonly used risk stratification tools should be used carefully, especially in certain populations, particularly younger women, because they may underestimate their CVD risk, as will be discussed below (28,32-34).

A recent Danish population-based study in 1,203 IBD patients reported a different prevalence of traditional CVD risk factors compared with controls across both sex and IBD diagnoses (26). IBD patients had a higher prevalence of hypertension, abdominal obesity and hypertriglyceridemia, while a lower prevalence of hypercholesterolemia and increased body weight was observed. Smoking and diabetes mellitus were equally represented overall, while smoking among male patients with CD was more prevalent, with the highest prevalence in middle-aged men (26,35). Data for an IBD subgroup can therefore be skewed by the prevalence of these more traditional risk factors.

Obesity is becoming an ever-increasing problem in IBD patients, as studies have shown that approximately 15–40% of IBD patients are obese while an additional 25–40% can be classified as overweight (36). The prevalence of above-normal weight and obesity differs between sexes. Being overweight was more likely in men, but obesity, especially severe obesity class II and class III, was more common in women (37). Obesity itself is now considered a state of low-level inflammation and can contribute to the overall inflammatory burden seen in IBD patients (38). Mesenteric fat in IBD is considered a pool of excess pro-inflammatory cytokines such as TNF-α and IL-6. Biologic therapy is prone to pharmacokinetic and pharmacodynamic changes in obesity. Obese patients have lower drug trough levels because of a higher volume of distribution and faster drug clearance (39). Chronic low-level inflammation from obesity increases the inflammatory cytokine burden that biologics, especially anti-TNF agents, must antagonize (40).

Some current IBD therapeutic options may modify cardiovascular or thrombotic risk through different mechanisms, particularly systemic corticosteroids, JAK inhibitors and, to a lesser extent, S1P receptor modulators. These drug-related risks are heterogeneous: corticosteroids mainly worsen metabolic and thrombotic profiles, JAK inhibitor risk is most relevant in patients with baseline thrombotic or cardiovascular risk, while S1P receptor modulators require cardiovascular screening mainly because of bradyarrhythmia, conduction and blood-pressure concerns (20,41-44).

Sex-related differences in CVD risk

Multiple population-wide studies have shown sex-related differences in disease incidence, disease extension, disease phenotype, response to therapies and prevalence of extraintestinal manifestations (10,21,32).

The topic of elevated CVD risk in IBD patients has been studied extensively, with observed sex-related differences, but without much focus on a unifying pathophysiological mechanism that can explain these differences (10,24,30,32).

When considering the general population, men have a higher CVD risk compared to women, especially at younger ages. This is usually ascribed to differences in behavior, lifestyle and hormonal factors. Among populations with IBD, an opposite pattern has been observed for relative risk estimates in several studies (45,46).

CVD risk in IBD patients is dynamic and dependent on the course of the disease. During remission, risk profiles may be more aligned between sexes; however, disease flares and active inflammation are associated with increased cardiovascular risk overall, and available data do not consistently demonstrate a female-specific excess during flares (11,30). Data from large registries that stratified sex-specific data have often reported elevated relative risk in women, especially for cerebrovascular events, MI and IHD. This difference was noted regardless of the presence or absence of traditional CVD risk factors. Compared to remission, histologic inflammation was associated with a higher relative risk of MACE in women (47). The relative risk for MACE was higher in women and peaked shortly after IBD diagnosis (47). These findings should be interpreted using the relative-versus-absolute risk distinction outlined above. In several studies, women with IBD show a higher relative increase compared with women without IBD, rather than a higher absolute event rate than men with IBD. For prevention, absolute risk remains most relevant for pharmacotherapy intensity, while relative risk helps identify groups in whom IBD may act as a disproportionate risk enhancer (24,30,45,46).

Sex-stratified cardiovascular risk should also be interpreted alongside gender-related health-care processes. Although older men with IBD may carry a higher absolute cardiovascular event burden, women may be less likely to be recognized as cardiovascular-risk patients when standard calculators weight female sex as protective and do not incorporate IBD activity or cumulative inflammatory burden. Gender-related factors may therefore influence symptom attribution, cardiovascular screening intensity, referral patterns, lipid-lowering initiation, evaluation of ischemic symptoms, preventive counseling, and treatment adherence. In IBD specifically, female patients may also experience diagnostic delay, symptom misattribution, reproductive-health concerns, and greater psychosocial burden, which may further modify cardiovascular prevention pathways. Future studies should therefore report sex- and gender-stratified data on cardiovascular screening, specialist referral, preventive pharmacotherapy, thromboprophylaxis, and access to specialist and gender-affirming care (10,48-50).

One of the first published meta-analyses from 2014 by Singh et al. on arterial thromboembolic events, including cerebrovascular accidents (CVAs) and IHD, showed that women with IBD have an excess risk for CVA and IHD compared with men, which is the opposite of the general population (24). Quantitatively, Singh et al. reported a larger relative arterial risk increase in women than in men. For CVAs, the pooled estimate was odds ratio (OR) 1.28 [95% confidence interval (CI): 1.17–1.41] in women compared with OR 1.11 (95% CI: 0.98–1.25) in men; for ischemic heart disease, the corresponding estimates were OR 1.26 (95% CI: 1.18–1.35) in women and OR 1.05 (95% CI: 0.92–1.21) in men. These data support a disproportionate relative increase in women but should not be interpreted as a higher absolute event burden than in men. As absolute event-count context, Kristensen et al. reported 365 MIs, 454 strokes, and 778 cardiovascular deaths among 20,795 patients with IBD during follow-up, with risk concentrated during flares and persistent disease activity. However, directly comparable sex-stratified absolute event rates remain inconsistently reported across studies (11,24). Interestingly, when looking at hospitalized patients with IBD and rates of VTE, a nationwide American analysis showed a higher rate in male sex (51). Hospitalized patients with acute severe UC, regardless of sex, have a very high risk of VTE; thromboprophylaxis in acute severe UC is therefore considered standard of care (52,53). More broadly, hospitalized patients with IBD should be assessed for pharmacological thromboprophylaxis unless contraindicated, particularly during active disease, surgery, immobility, pregnancy/postpartum or corticosteroid exposure (20,54).

Achieving sustained inflammatory control is likely one of the principal modifiable strategies for reducing cardiovascular and thrombotic risk, as clinical and histologic disease activity independently increase MACE (47). However, direct interventional evidence showing that treat-to-target IBD therapy reduces hard cardiovascular endpoints remains limited, so cardiovascular prevention should not rely on intestinal remission alone. The key studies and consensus documents supporting cardiovascular and thrombotic risk stratification in IBD are summarized in Table 2.

Possible mechanisms of sex-related differences in CVD risk

The role of inflammation in the pathogenesis of CVD appears to differ between sexes and is an independent driver of excess risk. Women are believed to have a greater inflammatory burden in the development of CVD (55). One of the known drivers of elevated CVD risk is endothelial and microvascular dysfunction. Even in the general population, a paradox is observed in which younger women generally have fewer coronary artery plaques but still have higher rates of myocardial ischemia-related mortality compared with age-matched men (45). This is attributed to a higher burden of CMD that is driven partly by chronic inflammation.

Women have elevated baseline levels of pro-inflammatory markers such as CRP and D-dimer, regardless of other comorbidities, and CRP levels correlate well with increased CVD risk. Chronic inflammation damages the endothelium, leading to an increased build-up of pro-inflammatory cells and blunted normal vasodilation, especially nitric-oxide-mediated vasodilation (3,55).

When looking at IBD patients, proposed pathophysiological mechanisms for excessive relative risk in women include hormonal differences and their connection to endothelial and microvascular dysfunction. The effect of environmental factors, such as hormone replacement therapy (HRT) and oral contraceptives, is still debated (29,46,56-58).

The overall conceptual relationship between dynamic IBD-related inflammatory burden, sex-related risk interpretation, biological pathways, and cardiovascular and thrombotic outcomes is summarized in Figure 1.

Figure 1 Sex-related cardiovascular and thrombotic risk in inflammatory bowel disease: from dynamic inflammatory burden to clinical outcomes. This conceptual figure summarizes how IBD may contribute to both arterial and venous cardiovascular complications, while also highlighting the importance of sex-specific interpretation of risk. The left panel emphasizes that cardiovascular risk should be interpreted by distinguishing relative risk from absolute risk. Younger women with IBD may exhibit a greater relative increase in cardiovascular risk compared with age-matched women without IBD, whereas older men may still carry a greater absolute burden of events. Accordingly, standard cardiovascular risk assessment tools may underestimate inflammation-related risk in selected IBD subgroups. The second panel illustrates the dynamic inflammatory burden of IBD. Active disease, including flares and ongoing mucosal or histologic inflammation, promotes a systemic inflammatory response characterized by increased circulating inflammatory mediators, including CRP, IL-6, and TNF-α, together with D-dimer elevation and increased thrombin generation. This risk may be further amplified by flare-related clinical factors such as hospitalization and immobility. Although remission is expected to reduce inflammatory burden and associated cardiovascular risk, it should not be regarded as a substitute for formal cardiovascular prevention. The third panel outlines the principal biological pathways linking IBD-associated inflammation with cardiovascular and thrombotic complications. These include endothelial dysfunction and vascular inflammation, CMD/INOCA associated with reduced nitric oxide bioavailability, and platelet activation with hypercoagulability and enhanced thrombin generation. Together, these mechanisms provide a biologically plausible link between intestinal inflammation and systemic vascular injury. The right panel summarizes the major clinical outcomes. Arterial complications include ASCVD, represented here by IHD, MI, and ischemic stroke. Venous complications include VTE, particularly DVT and PE. The lower summary boxes highlight the key interpretive and clinical messages of the figure: relative risk should not be conflated with absolute risk; inflammation remains the central driver of excess cardiovascular risk, while sex modifies its expression; and prevention should integrate conventional cardiovascular risk reduction with IBD-specific risk enhancers. Created in BioRender. ASCVD, atherosclerotic cardiovascular disease; CMD, coronary microvascular dysfunction; CRP, C-reactive protein; DVT, deep vein thrombosis; IBD, inflammatory bowel disease; IHD, ischemic heart disease; IL-6, interleukin-6; INOCA, ischemia with non-obstructive coronary arteries; MI, myocardial infarction; NO, nitric oxide; PE, pulmonary embolism; TNF-α, tumor necrosis factor-α; VTE, venous thromboembolism.

Female sex hormones, more specifically estrogen, have been explored in detail in the context of sex-related differences in IBD populations due to proposed broad anti-inflammatory effects, vasoprotective characteristics and modulation of the intestinal barrier and gut microbiota (46,56,59). Research on sex hormones and cardiovascular outcomes in the general population postulates that female sex hormones such as estrogen and progesterone can have protective effects on endothelial function and vascular tone. At the same time, estrogen also modulates immune responses, coagulation and intestinal barrier biology, so its net effect in active IBD may differ from its effect in healthy women.

The chronic inflammatory state in IBD seems to alter the effect of estrogen and may be responsible for loss of some cardioprotective benefits. Some studies have shown that women with IBD have reduced ovarian reserve (60). However, reduced ovarian reserve should not be presented as direct proof of earlier menopause or higher cardiovascular event rates unless longitudinal data demonstrate that association.

Menstrual-cycle physiology provides a real-time example of fluctuating estrogen and progesterone exposure. Estradiol is relatively low in the early follicular phase, rises through the late follicular phase, and peaks before ovulation, whereas progesterone predominates during the luteal phase before both hormones fall premenstrually. These fluctuations may influence gastrointestinal motility, visceral sensitivity, prostaglandin-mediated cramping and diarrhea, mucosal permeability, cytokine signaling, and symptom perception. Women with IBD may therefore report worsening gastrointestinal symptoms during the premenstrual and menstrual phases, although symptom fluctuation should be distinguished from objective inflammatory activity. Hormonal contraceptives may reduce cyclic hormonal variability and improve menstrual-related symptoms in some patients, but they should not be interpreted as established anti-inflammatory therapy for IBD or as cardiovascular-risk-modifying therapy (61-63).

Estrogen mediates its function through two main receptors, estrogen receptor alpha (ERα) and beta (ERβ), the latter being expressed in the vascular endothelium, circulating T lymphocytes and the intestinal mucosa, and has been independently researched in the context of general CVD risk and IBD pathogenesis. The protective effect of estrogen may be diminished in women with IBD partly due to alterations in ERβ, whose expression is downregulated in active disease (57). Direct evidence linking ERβ changes in IBD to cardiovascular events remains limited, so this mechanism should be framed as biologically plausible rather than proven.

ERβ is believed to have vasodilatory effects through nitric oxide production and anti-atherogenic effects (64). In general populations of women, reduced intimal ERβ expression has been associated with coronary calcification and atherosclerosis (58). Research in female patients with IBD shows that the expression of ERβ is downregulated in peripheral T lymphocytes and in the intestinal mucosa during active disease (57). In contrast, patients with a response to anti-TNFs show a higher expression of Erβ (57). Higher circulating levels of IL-6 in IBD, one of the main drivers of many chronic inflammatory diseases, inversely correlate with ERβ expression in both circulating T lymphocytes and intestinal mucosa. IL-6 is central to research linking chronic inflammatory states and CVD, reaching as far as being a potential treatment target in CVD risk reduction (57,65).

Regarding the direct estrogen action on the endothelium, it can enhance the release of nitric oxide, leading to vasodilation and lower blood pressure (58). Endogenous estradiol, the most potent form of estrogen, is the primary factor for this because it has a direct effect on platelet activity. In healthy women, estradiol has an antiplatelet effect mediated by nitric oxide pathways; however, when estradiol action on platelets is combined with elevated levels of thrombin, the effect is the opposite, leading to platelet activation (66,67). Thrombin is markedly elevated in patients with IBD and correlates with inflammatory burden and CRP (68).

The estrobolome as a microbiome-estrogen missing link

An additional mechanism that may connect intestinal inflammation with sex-specific vascular biology is the estrobolome. The estrobolome refers to the aggregate of intestinal microbial genes and enzymes capable of metabolizing estrogens, particularly beta-glucuronidases, beta-glucosidases and sulfatases that deconjugate biliary estrogen metabolites and influence enterohepatic recirculation and systemic estrogen exposure (69-72). In IBD, dysbiosis, mucosal inflammation, barrier dysfunction and altered bile acid metabolism could plausibly disturb this estrogen recycling system, making the estrobolome a potential missing link between gut inflammation, systemic estrogen availability and vascular phenotype in women.

This hypothesis is attractive because it bridges several otherwise separate observations: sex-related microbiome differences, estrogen receptor signaling, menstrual and menopausal influences, endothelial function, platelet activation and inflammation-driven thrombosis. Menopause-related changes in the gut microbiome and estrobolome have also been linked with adverse cardiometabolic risk features, supporting biological plausibility for a gut-hormone-cardiometabolic axis (73). However, direct evidence linking estrobolome signatures to ASCVD, VTE, MACE or CMD in women with IBD is currently lacking. At present, the estrobolome should be treated as a hypothesis-generating gut-hormone-vascular pathway. Future studies should combine longitudinal microbiome and metabolomic profiling with estrogen metabolite measurement, inflammatory biomarkers, disease activity indices and adjudicated cardiovascular outcomes stratified by menstrual status, menopause, exogenous hormone exposure and IBD activity.

Exogenous hormone exposure, pregnancy and menopausal status

Oral contraceptives and HRT, especially formulations containing estrogen, can increase or have a neutral effect on VTE risk in the general population of women depending on age, formulation and route of administration (74,75). In IBD, the thrombotic implications of exogenous estrogen should be interpreted in the context of disease activity, inflammatory burden, hospitalization, smoking, age, prior VTE, pregnancy/postpartum status and concomitant therapies such as corticosteroids or JAK inhibitors (20,54,76).

The topic of exogenous exposure to hormones in women with IBD is still debated. Exogenous hormone exposure should also be interpreted differently according to the endpoint considered. Several observational studies and meta-analyses have reported associations between combined oral contraceptive exposure and incident IBD, particularly CD, and between menopausal hormone therapy and UC in some datasets. This apparent paradox is important: associations with incident IBD do not prove that hormonal contraception or HRT worsens established IBD activity in all patients. Rather, estrogen-containing exposures may influence intestinal permeability, immune signaling, microbiome function, symptom stability, and thrombotic risk differently according to formulation, route, dose, duration, age, smoking, disease activity, and baseline VTE risk (77-79). On one hand, a large retrospective study by Freeman et al. showed that HRT in postmenopausal women with IBD is linked to reduction of clinical disease activity and protection against osteoporosis. The quality of evidence regarding this beneficial effect is not strong, and most research did not show a statistically significant difference (20,35,80-82). The weak point of this particular study is that it used combined physician global assessment (PGA) score to determine disease activity, not specific biochemical, endoscopic and histological endpoints. On the other hand, the international consensus on the prevention of venous and arterial thrombotic events in patients with IBD states that exposure to exogenous estrogens should be minimized (20). Contraceptive counseling should distinguish combined estrogen-containing methods from progestin-only and intrauterine methods; the Centers for Disease Control and Prevention (CDC) U.S. Medical Eligibility Criteria provide condition-specific eligibility categories and support individualized method selection rather than a blanket prohibition (76). When HRT is required, oral and transdermal estrogen should not be treated as interchangeable: oral estrogen has a stronger prothrombotic signal in general menopausal populations, whereas transdermal formulations may be less prothrombotic (75). Transgender and nonbinary patients with IBD provide an important, although still understudied, context for interpreting exogenous hormone exposure. In a population-based database study, transgender and nonbinary patients with IBD had greater comorbidity and health-care utilization, while subgroup analyses comparing patients with and without hormone therapy did not detect significant differences in thrombotic or cardiovascular events. These findings are reassuring but not definitive, because hormone formulation, route, dose, achieved hormone levels, duration of exposure, disease activity, and adjudicated VTE or ASCVD outcomes remain incompletely characterized (83). In conclusion, systemic oral estrogen-containing therapy should generally be avoided or reconsidered in women with IBD who have active disease, severe disease requiring hospitalization, current smoking, previous VTE, pregnancy/postpartum status or treatment with JAK inhibitors.

Differences not attributable to sex hormones

Building on the previously mentioned disproportionally increased CVD risk in premenopausal, younger women, another possible cause could be linked to the compounding effect of inflammation and a more procoagulable state present in women generally. Women have higher baseline levels of coagulation factors, primarily fibrinogen (factor I) and factor VII (84). This effect may contribute to the hypercoagulable state present in IBD, but it should not be interpreted as sufficient to explain arterial and venous outcomes without considering inflammation, disease activity and treatment exposure.

Testosterone and androgen-related mechanisms

Compared with estrogen, testosterone has been less extensively studied in IBD-associated cardiovascular risk. Low testosterone in men with IBD may reflect systemic inflammation, chronic disease burden, undernutrition, obesity, and cardiometabolic vulnerability. In small IBD-specific observational data, physiologic testosterone replacement in hypogonadal men with CD was associated with improved clinical activity and lower inflammatory biomarkers, and non-IBD data suggest that testosterone replacement may shift selected cytokine and lipid profiles toward a less inflammatory pattern. However, testosterone should not be assumed to be uniformly vascular-protective. In men with hypogonadism and preexisting or high cardiovascular risk, a large cardiovascular-safety trial found testosterone replacement noninferior to placebo for major adverse cardiovascular events, but pulmonary embolism, atrial fibrillation, acute kidney injury, blood-pressure elevation, and erythrocytosis remain relevant safety considerations. In men with IBD, testosterone exposure should therefore be considered a potential modifier of inflammatory, metabolic, and thrombotic risk, particularly in the presence of active disease, obesity, prior VTE, atrial fibrillation, uncontrolled hypertension, corticosteroid exposure, estrogen exposure, or JAK inhibitor therapy (85-88).

Emerging and lower-evidence mechanisms: selenium and oral health

An often-overlooked mineral deficiency is selenium, an important structural component of antioxidative enzymes. Female patients with IBD seem to have markedly lower levels of selenium compared to males (89), but the reason is not fully understood. Selenium deficiency has been linked to increased risk of thromboembolism and cardiac arrhythmias. Increased levels of previously mentioned inflammatory mediators such as IL-6 and TNF-α inversely correlate with serum selenium levels (90). Selenium should currently be interpreted as a possible marker of nutritional status and inflammatory burden rather than as a proven independent causal driver of sex-specific cardiovascular risk in IBD.

Oral health is a major contributor to overall health and a proposed novel independent risk factor for CVD. Apical periodontitis, also a form of chronic low-level systemic inflammation, is more common in female patients with IBD and can contribute to dysbiosis of the oral microbiome and overall inflammatory burden (91,92). Dysbiosis is believed to be one of the main drivers in the development of IBD in general. However, evidence directly linking oral disease to sex-specific cardiovascular events in IBD remains preliminary.

IBD therapy and CVD risk: possible sex-related differences?

Available evidence suggests that some IBD medications have different effectiveness, persistence or safety profiles between sexes, but this literature is inconsistent and often limited by retrospective design, pharmacovigilance bias and incomplete adjustment for disease severity.

A recently published article using pharmacovigilance data regarding JAK inhibitor use in IBD and rheumatoid arthritis indicated that women have a higher reporting signal for thrombosis when treated with JAK inhibitors compared to men, especially postmenopausal women (93). Available sex-stratified JAK inhibitor safety data are mainly derived from trials and pharmacovigilance analyses not primarily powered for cardiovascular outcomes. The topic around JAK inhibitors is controversial. For example, guidelines from various IBD societies propose a prolonged induction phase (10 mg twice daily for 16 weeks) of tofacitinib in the induction of remission of UC because it captures a significant amount of first-line non-responders, without increased incidence of MACE in IBD trials; however, data from rheumatoid arthritis patients receiving this higher dose report an increased risk for thromboembolic events (42,43). Other advanced therapies, including anti-IL-12/23 agents, vedolizumab and S1P receptor modulators, do not show clear inter-sex variability so far, but prospective randomized controlled trials are lacking on this topic. Pharmacovigilance data should be interpreted as hypothesis-generating safety signals rather than proof of incidence or causality (20,93-95).

However, the cardiovascular and thrombotic safety signal for JAK inhibitors should not be interpreted as uniform across the entire class or across all IBD patients. Results are heterogeneous by disease indication, molecule, selectivity, dose, treatment duration, comparator, baseline cardiovascular risk and study design. ORAL Surveillance enrolled older rheumatoid arthritis patients with cardiovascular risk factors, whereas many IBD trials included younger and more selected populations with few adjudicated MACE or VTE events (42). Recent IBD-focused and broader immune-mediated inflammatory disease analyses have produced mixed findings, with some suggesting no consistent increase in MACE and others suggesting a modest VTE signal compared with TNF antagonists (94,96). Therefore, treatment decisions should individualize risk according to age, smoking, prior VTE, established ASCVD, menopause, obesity, active inflammation, concomitant corticosteroids, estrogen-containing therapy and the availability of alternative effective IBD therapies.

Systemic corticosteroids may increase cardiovascular and thrombotic risk through both indirect metabolic toxicity and direct vascular effects. Glucocorticoid-receptor activation promotes hepatic gluconeogenesis and insulin resistance, visceral adiposity, dyslipidemia, and blood-pressure elevation through sodium-water retention and increased vascular reactivity. Chronic exposure may also impair endothelial function, promote oxidative stress, and contribute to procoagulant changes, thereby amplifying the inflammatory and thrombotic milieu already present during active IBD. Corticosteroids should therefore be considered a modifiable risk amplifier and a major reason to prioritize steroid-sparing inflammatory control (41,97). Historically, patients with IBD were exposed to a large cumulative dose of corticosteroids. Data from large registries show that overall cumulative exposure to these medications was higher in men; however, adolescent girls and older women more often develop steroid dependence (98). It is important to note that advances in IBD therapy have led to significantly lower exposure to corticosteroids overall in both sexes.

A study exploring chronic use of corticosteroids and adverse cardiovascular events showed that early switch to anti-TNF agents reduces cardiovascular events in CD (99). Observational data in inflammatory diseases suggest that anti-TNF therapy may reduce arterial events by suppressing systemic inflammation; however, causality is difficult to prove because treatment choice is confounded by disease severity, steroid exposure and baseline risk. One study by Kirchgesner et al. demonstrated that men with CD benefit significantly more from anti-TNF medication in lowering ASCVD risk compared with women (100,101). Data from large retrospective studies show that drug persistence of anti-TNFs is lower in women due to increased side effects, particularly drug hypersensitivity reactions and paradoxically induced psoriasiform eruptions (102,103).

In conclusion, focus should still be on decreasing inflammation because it is the primary driver of increased CVD risk, while endogenous and exogenous sex hormones should be treated as important modifiers rather than the sole explanation (30).

Prevention, treatment and risk evaluation strategies

Risk stratification in patients with chronic inflammatory conditions is different compared with the general population. Due to the described elevated CVD risk, it is important to develop prevention strategies tailored to IBD and associated risk. A practical baseline assessment should include blood pressure, lipid profile, glucose or glycated hemoglobin (HbA1c), body mass index (BMI) and waist circumference, smoking status, family history of premature ASCVD, prior VTE or arterial events, IBD activity, CRP or fecal calprotectin when available, cumulative steroid exposure, hospitalization history, and exposure to therapies with thrombotic or cardiovascular warnings. Among women, assessment should additionally document menopausal status, pregnancy/postpartum state, estrogen-containing contraception or HRT, history of hypertensive disorders of pregnancy or gestational diabetes, and prior pregnancy-associated VTE (20,28,30,54,104).

Major cardiology expert societies recognize chronic inflammatory conditions as a risk factor, and American societies recommend less restrictive thresholds for starting lipid-lowering, particularly statin, therapy. Statin benefit is expected in both sexes, and no study has shown a clinically meaningful difference in statin effectiveness between sexes. Statin-associated muscle symptoms are more commonly reported in women in some settings, but randomized trial data suggest that most muscle symptoms occurring during statin therapy are not caused by the statin itself (28,30,105). Reduced adherence may occur if gastrointestinal side effects, such as diarrhea, are misinterpreted as an IBD flare.

Clinical practice must identify IBD patients as a population with different CVD risk profiles, with suppression of inflammatory burden being one of the main treatment goals. Inflammatory control should complement, not replace, conventional prevention: smoking cessation, blood-pressure control, lipid lowering, diabetes prevention and treatment, weight management and physical activity remain essential. Among adjunctive lifestyle strategies, improving adherence to a Mediterranean dietary pattern may be particularly relevant in IBD because it aligns anti-inflammatory dietary management with cardiovascular prevention goals; extra-virgin olive oil and selected wine-derived polyphenols have been proposed as potentially relevant bioactive components, although the latter should not be interpreted as an endorsement of alcohol consumption (106-108).

As mentioned before, CVD risk may be underrecognized in younger women due to the absence of traditional risk factors. Most commonly used prediction scores, such as the ASCVD score and SCORE2 algorithm, do not take chronic inflammatory disease activity into account and consider female sex protective against CVD in both scores (33,34). A recently published paper by Sinh et al. proposed IBD-related risk-enhancing factors, including disease activity and younger age <45 years, that can be combined with traditional risk factors (109). The newer AHA PREVENT equations estimate 10- and 30-year risk for total CVD, ASCVD and heart failure, but they also do not incorporate IBD disease activity, flare frequency or cumulative inflammatory burden (104).

Atherosclerosis is driven partly by chronic inflammation, and screening tools that assess subclinical atherosclerosis burden may be useful in selected patients. Due to these observations, specific scores were developed for certain chronic inflammatory conditions, such as QRISK3, which incorporates rheumatoid arthritis as a direct risk-enhancing variable, and SLECRISK for systemic lupus erythematosus (110,111). To date, no specific predictive score has been developed and validated for IBD, and QRISK3 should not be described as an IBD-specific tool. In patients with IBD, QRISK3 has shown comparable performance to SCORE for subclinical atherosclerosis assessment, with a non-significant trend toward higher discrimination in one study. Therefore, QRISK3 should be interpreted as a potentially useful but not validated IBD-specific tool. More specifically, QRISK3 correlated better with carotid intima-media thickness in IBD patients, while no difference was found in the correlation with the presence of carotid plaques (110,112). Until an IBD-specific calculator is validated, conventional risk scores should be interpreted together with IBD-specific risk enhancers such as active disease, persistent biomarkers of inflammation, corticosteroid exposure, hospitalization, smoking, obesity and high-risk therapies.

Calculators that take general inflammatory markers into account may show better predictive value in IBD patients, one of which is the Reynolds Risk Score, which includes high-sensitivity CRP (hsCRP). Literature is still lacking regarding its use in IBD patients (109,113).

Besides using predictive calculators and formulas, focus should be placed on selected detection of subclinical ASCVD (18,114,115). Imaging methods such as Doppler ultrasound can measure arterial stiffness using carotid-femoral pulse-wave velocity. Increased carotid intima-media thickness, which has long been described as increased in patients with IBD, can also be measured non-invasively with ultrasound. Subclinical atherosclerosis can also be assessed by coronary artery calcium scoring with non-contrast computed tomography (116,117). However, current evidence is insufficient to recommend routine vascular imaging for all patients with IBD; imaging is best reserved for cases in which calculated risk appears low despite substantial inflammatory or treatment-related risk enhancers (28). In borderline cases, non-imaging risk markers such as hsCRP, apolipoprotein B (apoB) and lipoprotein(a) may help refine preventive discussions, although IBD-specific thresholds are not validated (27). A practical framework for cardiovascular and thrombotic risk assessment and prevention in patients with IBD is presented in Table 3.

Research gaps and limitations

Current evidence is limited by heterogeneous endpoint definitions, incomplete sex-stratified reporting, insufficient reporting of absolute risk, residual confounding by disease activity and steroid exposure, and limited data on menopausal status, pregnancy/postpartum periods, HRT route, transgender and gender-diverse patients, and gender-related access to care. Evidence in transgender and gender-diverse patients with IBD remains limited and should be interpreted separately from binary sex-stratified analyses. Current retrospective data suggest that gender-affirming hormone therapy has not been associated with an overall increase in IBD flares in all patients, although baseline active disease and testosterone exposure may identify subgroups requiring closer monitoring. Population-based data in transgender and nonbinary patients with IBD suggest greater comorbidity and health-care utilization, with no detected increase in thrombotic or cardiovascular events in the hormone-therapy subgroup, but the evidence is not yet sufficient to define VTE or ASCVD risk by hormone type, route, dose, duration, or achieved hormone levels. Future prospective studies should prespecify ASCVD, VTE, CMD/INOCA and MACE endpoints, report relative and absolute event rates stratified by sex and age, and capture sex assigned at birth, gender identity, hormone type, route, dose, duration, achieved hormone levels, IBD activity, VTE prophylaxis, cardiovascular screening, specialist referral, preventive medication initiation, access to affirming care, and adjudicated cardiovascular outcomes (10,48,49,83,120,121). Future prospective studies should prespecify ASCVD, VTE, CMD/INOCA and MACE endpoints, report relative and absolute event rates stratified by sex and age, and test whether treat-to-target control of intestinal inflammation reduces hard cardiovascular outcomes.

Conclusions

Increased CVD and thrombotic risk in IBD patients suggest that CVD should be considered an important systemic complication and comorbidity of IBD. Patients with IBD often have associated morbidity and mortality that is not directly linked to gastrointestinal manifestations of the disease. Elevated relative risk is especially pronounced in groups that are not traditionally labeled as high risk, particularly younger women, which can lead to worse outcomes in this population if risk is underrecognized. VTE is more clearly recognized within the extraintestinal and systemic complication framework, while ASCVD should be described more cautiously as an inflammation-associated cardiovascular comorbidity rather than a classical extraintestinal manifestation (21).

Clinical awareness is warranted in recognizing high-risk patients without more traditional risk factors. This supports the development of preventive IBD-specific CVD risk calculators, improved sex-stratified reporting and selective use of diagnostic modalities that detect subclinical atherosclerosis when conventional calculators appear discordant with inflammatory burden.

Research is needed in the field of sex-related differences in IBD-associated CVD risk because there currently are no all-encompassing pathophysiological mechanisms that can explain the more pronounced relative risk in women. Current findings may point to estrogen signaling as one important contributor in the complex interaction between the intestinal barrier and vascular endothelium, but available evidence supports a multifactorial model rather than a single central mechanism. Future studies should test whether cardiovascular morbidity can be incorporated into broader IBD outcome frameworks; this should be presented as a research priority rather than an established extension of deep remission. Additionally, it may be appropriate to consider sex-specific IBD therapy tailoring, or at least sex-specific risk stratification, in future research and subsequent guidelines. Prospective studies should report both relative and absolute cardiovascular event rates stratified by sex, age, menopausal status, disease activity and treatment exposure.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-2026-0075/rc

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Funding: This research was funded by NPOO (grant No. IP-UNIST-32 to J.B.).

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