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Review

Is Adenomyosis Associated with Systemic Vascular Complications?

by
Marwan Habiba
1,*,
Ilary Ruscito
2,
Paola Bianchi
3,
Sun-Wei Guo
4 and
Giuseppe Benagiano
5,6
1
Department of Health Sciences, University of Leicester and University Hospitals of Leicester, Leicester LE1 5WW, UK
2
Gynecologic Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy
3
Department of Medico-Surgical Sciences and Translational Medicine, Sant’Andrea Hospital, Sapienza University of Rome, 00185 Rome, Italy
4
Research Institute, Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200011, China
5
Faculty of Medicine and Surgery, “Sapienza” University of Rome, 00161 Rome, Italy
6
Geneva Foundation for Medical Education and Research, 1202 Geneva, Switzerland
*
Author to whom correspondence should be addressed.
Reprod. Med. 2025, 6(4), 38; https://doi.org/10.3390/reprodmed6040038 (registering DOI)
Submission received: 4 October 2025 / Revised: 18 November 2025 / Accepted: 21 November 2025 / Published: 30 November 2025
Browse Figure
Review Reports Versions Notes

Abstract

We carried out a comprehensive literature search for publications on the range of vascular events that have been linked to adenomyosis. This covered vascular diseases, blood coagulation disorders, thrombosis, hypercoagulation, stroke (embolic, ischemic, thrombotic, hemorrhagic), cerebrovascular episodes, cerebral infarction, cerebral hemorrhage) and renal disease. This review covers 63 articles. Nineteen articles reported clinical manifestations of intravascular thrombosis in women with adenomyosis. Eleven publications were identified that reported on cerebral involvement and adenomyosis, including cases of ischemic stroke or infarction. Dysregulation primarily seems to occur via local factors leading to altered angiogenesis. Five case reports were identified that reported on various vascular complications attributed to the presence of adenomyosis. The search also identified reports of cerebral complications in women with adenomyosis. Through a secondary search, we identified publications dealing with a possible connection between cardiac complications and renal pathology, which the authors attributed to adenomyosis. Vascular involvement in adenomyosis is documented in rare cases by the presence of endometrial tissue in myometrial vessels both in menstrual and non-menstrual uteri. Women with adenomyosis have a higher platelet count, a shorter thrombin and prothrombin time and an activated partial thromboplastin time. These findings has been applied to attempts to identify therapies for adenomyosis based on targeting the vasculature, but the existence of a link between the two conditions is under question for several reasons: only case reports (or very small series) have been published; all published cases come from one region of the world (the Far East); the published literature does not contain objective proof of a causal relationship between the two pathologies, except for the elevation of some markers. In summary, it is not possible to conclude that the presence of adenomyosis has a pathogenetic role in causing vascular events, first and foremost because available evidence consists mostly of case reports.

1. Introduction

For decades, adenomyosis has been seen as an ‘elusive disease’. It is now possible to make a diagnosis using magnetic resonance imaging (MRI), 2D or 3D ultrasound (2D or 3D-US). It is nevertheless important to reiterate that definitive diagnosis remains a challenge, not least because of the lack of agreement on the cut-off point for histological diagnosis.
The pathogenesis of adenomyosis remains uncertain, and several theories have been put forward. The role of platelets in adenomyotic lesions deserves attention: following menstrual bleeding, in which adenomyotic foci also take part, the lesions undergo a process of recurrent tissue injury and repair (ReTIAR) that in turn initiates a number of key molecular events, with platelets acting as first responders eliciting subsequent tissue repair [1,2].
Periodic platelet activation can have consequences beyond the local injury followed by ReTIAR. Local activation could have systemic consequences, as evidenced by reports of hypercoagulability in patients with endometriosis and adenomyosis [3].
Endometriotic stromal cells, and likely adenomyotic stromal cells, produce platelet-activating factors such as thromboxane A2 and thrombin [4], possibly establishing a microenvironment that is conducive to constant platelet activation and increased vascular permeability. Whether platelet activation differs between women with and without adenomyosis remains to be examined. It is uncertain if systemic vascular pathology is associated with adenomyosis. PubMed lists (as of 10 August 2024) 69 articles on “endometriosis and atherosclerosis” and only 2 for “adenomyosis and atherosclerosis”, with only 1 of these 2 articles being relevant. There are numerous case reports suggesting increased intravascular coagulation leading to thrombotic complications and even stroke in women with adenomyosis.
It is for this reason that a comprehensive search for the frequency and seriousness of complications involving increased coagulation occurring in women with adenomyosis can be informative. Hence, we engaged in this review.

2. Search Methodology

This review included all studies without any restriction on publication year.

Data Identification and Selection

During July 2024, a literature search was carried out using the electronic databases PubMed, MEDLINE and Scopus. The following terms were used in the search: [Adenomyosis AND (cerebrovascular disorders OR vascular pathology, OR vascular disease, OR blood coagulation disorders, OR thrombosis, OR hypercoagulation, OR stroke, OR embolic stroke, OR ischemic stroke, OR thrombotic stroke, OR hemorrhagic stroke, OR cerebral infarction, OR cerebrovascular disorders, OR cerebral hemorrhage)].
All original reports, reviews, case series and case reports were considered for inclusion, and their reference lists were analyzed to identify other potential studies. Review articles, editorials and letters were excluded. Two independent reviewers (PB and IR) identified and selected the studies. Differences were resolved by a third author (GB).

3. Results

The search identified 277 studies; 5 (1.8%%) were removed as duplicates and 249 (89.9%) were excluded after title and abstract evaluation (Figure 1). Twelve studies were added after reading the reference lists of the identified studies. Forty-one articles were tabulated for comparison at the end of the selection process.
This review included all studies without any restriction on publication year. We identified additional publications based on our review of the published literature; thus, in total, this review includes 41 relevant articles (see the tables).

3.1. Coagulation Disorders in Adenomyosis

Nineteen articles reported clinical manifestations of peripheral vascular thrombosis or deep-vein thrombosis (DVT) in women with adenomyosis (Table 1).
The first evidence of localized platelet aggregation in adenomyotic lesions was presented some 10 years ago [24,25] but not confirmed in a recent study [26]. An explanation for this discrepancy has been provided in a recent review [2]. Another piece of evidence that suggests the role of platelets in adenomyosis is the overexpression of the tissue factor (TF) [27,28]. Whether the local effects have wider clinical implications is a distinct, yet unanswered, question.
There are numerous case reports documenting thromboembolism in women with adenomyosis [14]. The case report by Okuda et al. [14] was of a pulmonary embolus in a woman receiving combined contraception, which is itself a risk factor for venous thromboembolism, but the article was concerned with anesthetic management during the removal of the uterus in the acute phase as it was considered to be the source of the thrombi. Table 1 includes articles that report cases of intravascular coagulation that may have relevance to platelet or coagulation function in women who have concomitant adenomyosis.
It has been proposed that soluble serum carbohydrate antigen 125 (CA-125) plays a vital role in coagulation [29]. Consistent with this notion, women with adenomyosis have a higher platelet count, a shorter thrombin time (TT) and an activated partial thromboplastin time (APTT) compared to women without adenomyosis [30]. Another study reported shorter prothrombin time (PT) and the negative correlation between uterine size and APTT/TT [22]. Women with adenomyosis had significantly higher platelet counts than controls, and had shorter PT [18]. In addition, in women with adenomyosis, APTT and TT were significantly shorter in those who had anemia due to heavy menstrual bleeding (HMB) than those who did not [22]. However, increased coagulability is a feature in women with anemia, which can accompany adenomyosis and/or fibroids. This was not considered a confounding factor in the case reports.
In a retrospective study, Yang et al. [30] compared a group with adenomyosis with two control groups: women with fibroids and women with carcinoma in situ (CIN). Women with adenomyosis were far more likely to have menorrhagia and anemia and to have elevated CA128 and CA19.9. The TT values were 17.7 (17.1–18.4), 17.9 (17.3–18.5), and 18.2 (17.65–18.55) s in the adenomyosis, fibroid and CIN groups, respectively. There was a statistically significant difference between the adenomyosis and the fibroid and carcinoma groups. The corresponding values for the APTT were 26.7 (25.3–28.0), 26.75 (25.4–28.5) and 27.6 (26.25–28.95) s, respectively. There was a statistically significant difference between the adenomyosis and the carcinoma group, but not the fibroid group. Whilst the clinical significance of the identified differences is unclear, it is unknown if the difference can be accounted for by anemia. The study did not comment on the use of tranexamic acid by the various groups. It is also unclear how to account for the increased incidence of menorrhagia in the presence of apparent increased coagulability.
Women with adenomyosis who experienced HMB are in a hypercoagulable state manifesting as a higher platelet count and shorter PT and APTT, as compared to women without adenomyosis [3]. In addition, within the adenomyosis patients who complained of HMB, women who reported excessive menstrual blood loss had significantly higher plasma D-dimer (DD) and fibrin degradation product (FDP) levels but shorter APTT and lower fibrinogen levels than those who complained of moderate or heavy menstrual blood loss [3].
There are several case reports documenting the systemic thrombotic consequences in patients with adenomyosis who developed disseminated intravascular coagulation (DIC) [15,17].
However, adenomyosis is not a rare disease; thus, proof of a link between adenomyosis and clinically significant coagulopathy could not be derived merely from case reports. Most case reports come from the Far East (Japan, China and Korea) and some feature significantly enlarged uteri, which raises a question as to whether these individuals had unique features. The articles themselves have not addressed this feature or the possibility that a mass effect compressing the pelvic vessels increases thrombotic risk. It is worth the mention that whilst adenomyosis is associated with uterine enlargement, massive uterine enlargement is more likely to be encountered in women with fibroids. The vast majority of the reports did not include a detailed description of adenomyosis, of concomitant pathology or of the use of medication that could increase the risk of thrombosis. Nevertheless, awareness of a possible association in women with significantly elevated CA125 is warranted [31].

3.2. Vasculopathies and Adenomyosis

We identified 11 relevant publications under this heading and 7 other articles reported on cases of ischemic stroke or infarction.
In 2000, Hickey and Fraser [32] summarized evidence that disruption to both the regulation of endometrial vascular growth and of its function has been found to be associated with disturbances to menstrual bleeding. Dysregulation primarily occurs via local factors, and in the case of adenomyosis, its presence is commonly evidenced by menstrual disturbance, while alterations to vascular distribution and structure suggest altered angiogenesis.

3.2.1. Vascular Involvement in Adenomyosis

The presence of endometrial tissue in myometrial vessels was identified first during the menstrual period (e.g., [33]) and subsequently also in non-menstruating uteri. Sahin et al. [34] identified intravascular endometrial tissue in 14/277 hysterectomy specimens from women outside the menstrual phase. All had extensive adenomyosis. They suggested that as perivascular cells proliferate, they may impinge on endothelially intact vascular lumina and become intraluminal. Meenakshi and McCluggage [35] identified vascular involvement in 54/434 (12.4%) uteri with adenomyosis. This ranged from the single- to multiple-vessel involvement of endometrial stroma and, sometimes, glands. In most cases the endothelial lining was intact. There is a positive correlation between endometrial angiogenesis and menstrual disorders, including in women with adenomyosis [36].
COX-2 expression in the endometrium did not vary during the menstrual cycle in the control group or in patients with endometrial polyps but increased during the secretory phase in patients with adenomyosis. There was also an increased expression of MMP-2 in stromal cells and of micro-vessel density (MVD) in adenomyosis foci throughout the cycle [37]. The expression of vascular endothelial growth factor (VEGF), but not of hypoxia-inducible factor-1alpha (HIF-α) and MVD, was increased in the eutopic endometrium in adenomyosis [38]. In the ectopic endometrium the increase in VEGF expression exceeded that of the eutopic mucosa and was accompanied by that of HIF-1α, especially in epithelial cells, and of MVD [38]. Annexin-A2 (ANXA2), a protein that plays a role in regulating cell growth and in signal transduction pathways, was very significantly up-regulated in the ectopic endometrium of women with adenomyosis compared with its eutopic counterpart. Of relevance is the observation that overexpression of ANXA2 was highly correlated with markers of epithelial–mesenchymal transition (EMT) [39]. Levels of IL-22 and its receptors IL-22R1 and IL-10R2 in both the eutopic and ectopic endometrium in women with adenomyosis were significantly higher than in controls [40]. Recombinant human IL-22 (rhIL-22) increased IL-22R1 and IL-10R2 levels, promoted the invasiveness of endometrial stromal cells (ESCs), inhibited the expression of metastasis suppressor gene CD82, and stimulated the secretion of IL-8, RANTES (regulated on activation normal T cell expressed and secreted) chemokine, IL-6 and VEGF from ESCs.

3.2.2. Clinical Implications

Targeting abnormal vasculature associated with uterine pathologies could be pursued within therapeutics [32]. This includes blocking dysregulated estrogen-responsive proteins such as ANXA2 in adenomyosis, which would reduce the latter’s proangiogenic capacity [39]. Another potential strategy is inhibiting the crosstalk between vascular endothelial cells and endometrial stromal cells through blocking IL-22 expression [40]. Inhibiting the increased expression of IL-22 receptors IL-22R1 and IL-10R2 in venous endothelial cells (VECs) in ectopic tissue from women with adenomyosis represents another potential treatment option. Administration of rhIL-22 led to an elevation of human umbilical vein endothelial cells (HUVECs) without modifying apoptosis [41].
Berberine (BBR), an isoquinoline-derivative alkaloid, was shown to significantly inhibit the proliferation and viability of eutopic and ectopic ESCs, with only a minor effect on normal endometrial stromal cells, thus offering a potential therapeutic effect [42].

3.2.3. Reports of Cases of Increased Coagulability in Adenomyosis

We identified five case reports of various vascular complications attributed to the presence of adenomyosis. The first report from 1991 briefly outlined the history of a patient with adenomyosis who suffered from thrombosis, apparently due to the intravascular invasion of endometriotic tissue [6]. A second article described the case of a woman with hereditary hyper-homocysteinemia, previous myomectomy and repeated DVT leading to the occlusion of the femoral vein and menorrhagia. Adenomyosis was confirmed upon hysterectomy but was not linked to thrombosis [7].
One publication reported a case of adenomyosis complicated by an episode of acute DIC that occurred during menstruation. There were no known predisposing factors, and anticoagulation therapy and supplementation of coagulation factors resulted in rapid improvement [8].
Another report summarized the case of a patient with severe adenomyosis who, following pregnancy termination, suffered from acute, non-septic DIC [18]. There was no evidence of infection, and the hypothesis was formulated that the occurrence of a hemorrhage in the adenomyotic tissue after termination caused inflammation and the release of numerous microthrombi and necrosis in adenomyosis, leading to hypercoagulation, massive fibrinolysis and DIC [18]. It is important to reiterate that most case reports come from the Far East, and many have features that suggest either advanced or atypical disease. Many of the case reports have not included histological confirmation, and none them have included a full description of adenomyosis.

3.3. Cerebral Complications

Whether there is a link between cerebral complications and adenomyosis is contentious. Only case reports or very small series have been published, and all come from the Far East. The published literature does not contain any objective proof of a causal relationship between adenomyosis and vascular complications, except for the elevation of some non-specific markers.
Yamanaka et al. [16] suggested that there was an increased risk of thrombotic disorders in women with adenomyosis with a uterine volume ≥100 cubic centimeters who had elevated soluble fibrin (SF) (a marker of coagulation) and DD (a marker of both coagulation and fibrinolysis), but there was no increased risk found in women without activated fibrinolysis. Nevertheless, their conclusion should be taken with caution as the study lacked a control group.
We identified case reports of cerebral infarction in women with adenomyosis and intracranial venous thrombosis (Table 2).

3.3.1. Ischemic Stroke/Infarction

In an early report, adenomyosis with raised D-dimer and CA125 levels were believed to be contributory to an increased risk of thromboembolism [47]. The 59-year-old postmenopausal woman who was receiving HRT had multiple hyperintense cerebral and cerebellar lesions and aortic valve thrombi.
A case of a nonbacterial thrombotic endocarditis complicated by cerebral infarction in a woman with adenomyosis was reported in Japan. She presented mitral valve vegetation upon transesophageal echocardiography and a highly elevated CA125 (901 U/mL). The vegetation reduced after treatment by intravenous unfractionated heparin [48].
Three cases of ischemic stroke during menstruation in patients with adenomyosis have been reported [52]. All had elevated CA-125, CA-19-9, and D-Dimer levels during menstruation but these markedly decreased afterwards. The strokes were attributed to nonbacterial thrombotic endocarditis, stenosis of the cerebral arteries associated with a hypercoagulable state, and the presence of hyper-viscous mucinous proteins in the adenomyotic lesions [52].
In recent years, attention has been paid to the existence of specific risk factors for stroke in women. A comprehensive review of the association between adenomyosis and ischemic stroke by Yan et al. [59] listed fifteen reports of cases involving patients ranging from 34 to 59 years old. All cases were from Japan, China and Korea. The specific indications for an early diagnosis were fatigue and dizziness during menstruation [59]. Ischemic stroke can occur as part of systemic thromboembolism involving multiple organs and can recur, leading to neurological deterioration. MRI shows multiple hyper-intensive spots in the adenomyotic foci. Elevated soluble fibrin and DD levels during menstruation might indicate a higher risk of thrombotic disorders [59].
In a retrospective study of 470 consecutive women with common non-cancerous gynecologic diseases, 37 had ischemic stroke and 2 had transient ischemic attack (TIA) [63]. Cases were divided based on the etiology of the stroke into the conventional stroke mechanism: CSM (large artery atherosclerosis, small vessel occlusion, cardioembolism, and other determined etiology), or non-CSM (lesions related to hypercoagulability). Six cases were associated with adenomyosis, and the majority had cryptogenic stroke. Adenomyosis was present in one case in the CSM group (15%) and in 5 cases (25%) in the non-CSM group. The study concluded that hyper-coagulability in adenomyosis may play a role in the pathogenesis of ischemic stroke/TIA.

3.3.2. Cerebral Vasa Thrombosis

We identified 7 publications, all from the Far East, reporting a possible causal association between cerebral vascular thromboses and adenomyosis.
One case report was on a woman with massive adenomyosis who developed cerebral venous thrombosis (CVT) leading to seizures and loss of consciousness. She had a localized, high-intensity region in the left frontal lobe, as determined upon MRI, abrupt termination of the anterior half of the superior sagittal sinus and a filling defect in part of the left transverse sinus. She had elevated CA-125 and D-Dimer levels. There was no recurrence following resection of the adenomyotic mass [46].
Aiura et al. [54] reported a case of middle cerebral artery occlusion and recurrent cerebral infarction. The woman had heavy uterine bleeding, adenomyosis, a left ovarian tumor, multiple uterine myomas, and old and new bilateral renal infarctions. She developed left hemiparesis, dysarthria and a pulmonary thromboembolism. She underwent endovascular thrombectomy, hysterectomy and ovariectomy. D-Dimers and tumor markers rapidly returned to normal. There were no further ischemic events at 15 months post-hysterectomy. The clinical picture resembled Trousseau’s syndrome, or cancer-associated thrombosis.
A report by Yadav et al. [58] described a 42-year-old woman with a history of menorrhagia secondary to adenomyosis, for which she received a progestin-only pill (with poor compliance). She developed a sudden onset of headaches and seizures and was identified to have a left cortical hematoma with surrounding edema in the temporo-occipital region secondary to cerebral venous sinus thrombosis. She declined a hysterectomy and was commenced on a progestin-only pill, resulting in symptomatic control and no recurrence over the two months of follow-up.
The case by Zhao et al. [53] is of a 34-year-old woman who complained of headache, fever and left limb weakness during the menstrual phase. MRI showed restriction in the middle-right cerebral artery distribution. She was diagnosed with acute infarction in the right basal ganglia and the subcortical region of the right frontotemporal lobe. Two additional cases of cerebral venous sinus thrombosis (CVST) in young women with adenomyosis were reported by Li et al. [60]. Their literature review identified 25 cases of stroke in women with adenomyosis; however, only 3 were related to CVST. Li et al. pointed to the coexistence in these patients of HMB, anemia and CA-125 elevation [59].

3.4. Cardiac Pathology

Our search identified four publications that suggested a connection between cardiac complications and adenomyosis.
A study of the metabolic parameters and cardiometabolic risk in women with adenomyosis included 96 premenopausal women with an imaging-based diagnosis of adenomyosis and 97 controls. The adenomyosis group had a higher prevalence of raised systolic blood pressure, low HDL-cholesterol and central obesity [65]. One study reported a case of non-bacterial thrombotic endocarditis associated with a hypercoagulable state in a woman with adenomyosis [48].
Soeda et al. [45] reported on a 47-year-old woman with menorrhagia, severe anemia and diffuse adenomyosis who complained of dizziness, nausea, vomiting, and loss of consciousness after a red blood cell transfusion. MRI showed multiple right cerebellar and bilateral frontal, parietal, and occipital lobe infarcts. She had nonbacterial thrombotic endocarditis (NBTE) affecting the tricuspid and aortic valves. She was started on hormonal and anticoagulant (warfarin) treatment. Kim et al. [49] described a case of a woman with adenomyosis and NBTE who developed multiple embolic cerebral infarcts leading to dysarthria, left perioral sensory change, and left-hand weakness. Infarcts were identified in the cerebellum and precentral gyrus. She had elevated DD, CA19-9, and CA125.

3.5. Renal Pathology

We identified two case reports that dealt with renal pathology complicating DIC. The first case, by Son et al. [10], was of acute kidney injury (AKI) in a 40-year-old woman with adenomyosis. Renal affection was the result of menstruation-related disseminated intravascular coagulation, which the authors attributed to myometrial injury resulting from a heavy intra-myometrial menstrual flow.
The second case report, by Yoo et al. [13], was of a woman with significant adenomyosis and menometrorrhagia who presented with DIC. This was successfully treated with hysterectomy and blood product transfusions.

4. Adenomyosis and Abnormal Uterine Bleeding

Adenomyosis has been identified to be one of the structural causes of abnormal uterine bleeding (AUB). We recently reviewed this topic [66] and concluded that—despite the large volume of studies—available information does not provide conclusive evidence of a link. The study design in most studies was unsuitable. There was a lack of proper characterization of the study population, there were no agreed diagnostic criteria for adenomyosis, and there was no detailed assessment of menstrual blood loss. In addition, it must be borne in mind that symptoms of adenomyosis, including AUB, can occur in the presence of other pathologies. The incidence of concomitant pathology, such as endometriosis, leiomyomas, endometrial hyperplasia and carcinoma is high. A study involving 710 premenopausal women undergoing hysterectomy for adenomyosis reported that only 4.5% had no symptoms, while dysmenorrhea was the most common complaint [67].
An important issue in evaluating the possible role of adenomyosis in causing vascular complications is the presence of a state of hypercoagulability in women with adenomyosis. This topic has been extensively investigated by Liu et al. [3], who observed the presence of a clinically relevant difference in coagulability between patients with adenomyosis-associated heavy menstrual bleeding (ADM-HMB) and women without adenomyosis. They concluded that precautionary, prophylactic measures may be advisable in order to reduce the risk of thrombotic events in ADM-HMB patients, especially those with excessive menstrual blood loss. In addition, the data suggest that anti-thrombotic/anti-coagulation therapies may hold therapeutic potential. Yet, these agents may increase bleeding. It is important to reiterate that the vast majority of case reports contain incomplete descriptions of the extent of the disease and of confounding factors that can increase the risk of vascular events. These include both local factors such as the presence or absence of concomitant pathology, and the use of steroids or other drugs that can increase coagulation. On the other hand, some of the described features, such as giant adenomyosis and very high CA125 levels, raise questions regarding the general applicability of these drugs to more typical cases. There are no controlled studies that compare thrombotic events in women with and without adenomyosis, and the available data suggest that such studies may be hindered by the need for a large cohort and long-term follow-up. CA125 is recognized to increase coagulability, but it is unclear if the mildly elevated levels noted in some women with adenomyosis have a significant clinical impact. Anemia results from excessive menstrual bleeding in adenomyosis and can result in a deranged coagulation profile. It is possible to hypothesize that increased coagulability is a bodily response that is aimed at limiting bleeding, or a result of its high association with inflammation. This is an area that warrants further investigation

5. Conclusions

It is extremely difficult to draw a firm conclusion on the pathogenetic role of adenomyosis in causing vascular complications, first and foremost because available evidence consists mostly of case reports. To begin with, contrary to common belief, we have recently documented that available studies do not provide conclusive evidence of a link between adenomyosis and abnormal uterine bleeding [3].
With regards to the hypercoagulable state and adenomyosis, there is evidence that platelets play a role in the pathogenesis and pathophysiology of adenomyosis [2,19,27]. In addition, there are case reports that show increased coagulability as a feature of adenomyosis. However, case reports are insufficient evidence of an association.
In this review, we compiled available evidence of vascular complications associated with adenomyosis; predominantly, these manifest as venous thromboembolism, ischemic stroke, and cerebral vasa thrombosis. Overall, these complications have been reported as single cases or short series, contrasting the high incidence of adenomyosis in women. This goes against the argument for the existence of a causative link. Thus, the strength of this study and the associations it discusses is that is continues to ask the question of whether there are causative links, except perhaps in a minority of cases with special features. In very rare instances these complications can also involve cardiac and renal pathology. In view of these complications, along with numerous reports of its association with depression and adenomyosis, as in the case of endometriosis, adenomyosis may be viewed as a disease with possible systemic manifestations [68].

Author Contributions

Conceptualization, M.H., S.-W.G. and G.B.; methodology, I.R., P.B. and M.H.; validation, P.B. and G.B.; writing—original draft preparation, M.H., G.B. and S.-W.G.; writing—review and editing, G.B., M.H. and S.-W.G. All authors have read and agreed to the published version of the manuscript.

Funding

Grant 82071623 from the National Natural Science Foundation of China (S.-W.G.) and grant SHDC2020CR2062B from Shanghai Shanking Centre for Hospital Development (S.-W.G.).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data presented in this study are derived from the publications listed in the list of references.

Conflicts of Interest

The authors declare no conflicts of interest.

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Reprodmed 06 00038 g001
Figure 1. Flow chart summarizing the paper selection process.
Figure 1. Flow chart summarizing the paper selection process.
Reprodmed 06 00038 g001
Table 1. Studies reporting on deranged coagulation and/or DVT in women with adenomyosis. DVT: deep-vein thrombosis; CA125: cancer antigen 125; DIC: disseminated intravascular coagulation.
Table 1. Studies reporting on deranged coagulation and/or DVT in women with adenomyosis. DVT: deep-vein thrombosis; CA125: cancer antigen 125; DIC: disseminated intravascular coagulation.
ReferenceCountryStudy TypeSynopsis
Lin et al. (2022) [5]ChinaComparative trialCoagulation parameters in premenopausal women with adenomyosis (n = 229), fibroids (n = 265) and controls (n = 142). Adenomyosis correlated with lower Hb levels, higher platelet count, and longer prothrombin time. Patients of adenomyosis group were older and had bigger uteri.
Kupryjańczyk (1991) [6]PolandCase reportDetails not available.
Nawroth et al. (2001) [7]GermanyCase report37-year-old with hyperhomocysteinemia, previous myomectomy. Past DVT on three occasions resulted in post-thrombotic syndrome with persistent femoral vein occlusion and collateral circulation. Adenomyosis on subtotal hysterectomy, not linked to coagulopathy.
Nakamura et al. (2002) [8]JapanCase reportAcute DIC in a 32-year-old with adenomyosis admitted with severe dysmenorrhea and gingival bleeding during menstruation. Treated medically. Deranged coagulation parameters the following cycle. MRI suggested intramural hemorrhage in large adenomyosis. Discharged on GnRH analogs.
Akira et al. (2009) [9]JapanCase report34-year-old with adenomyosis treated with GnRHa admitted with DVT. Was subsequently maintained on low-dose buserelin acetate.
Son et al. (2010) [10]KoreaCase reportAcute kidney injury and DIC. A 40-year-old woman received GnRH for ovulation induction.
Uterus to L4/umbilicus. CA125 = 16,684 U/mL. Suggested that GnRH increased tissue tactor and adenomyosis growth.
Takeda et al. (2010) [11]JapanCase report40-year-old admitted with DIC 7 years after laparoscopic myomectomy. Had multiple intra-myometrial mass lesions with intra-tumoral hemorrhage. Histology: low-grade endometrial stromal sarcoma coexistent with adenomyosis.
Ohashi et al. (2011) [12]JapanCase report51-year-old with adenomyosis admitted with anemia, thrombocytopenia and acute renal failure. Renal biopsy showed acute tubular necrosis believed to be secondary to DIC. Uterus was to the level of umbilicus. Micro-hemorrhage by MRI was not found on histology.
Yoo et al. (2012) [13]KoreaCase reportDIC in patient with 9 m adenomyotic lesion. Massive intralesional hemorrhage. Microscopic adenomyosis with dilated blood vessels containing multiple thrombi.
Okuda et al. (2013) [14]JapanCase report38-year-old with massive pulmonary embolism receiving oral contraceptive pill for adenomyosis.
Zhang et al. (2013) [15]ChinaCase reportDIC after D&C for missed abortion in a patient with adenomyosis. Required subtotal hysterectomy.
Yamanaka et al. (2016) [16]JapanProspective case series(n = 8) tested daily from day 1 to 5 of menstruation: thrombin–antithrombin complex (TAT), soluble fibrin (SF), D-dimer (DD), and plasmin–α2–plasmin inhibitor complex (PIC).
Extensive adenomyosis comes with potential risks of infarction and thrombosis and exacerbates menorrhagia via activation of coagulation and fibrinolysis during menstruation.
Cernogoraz et al. (2019) [17]ItalyCase reportDIC related to menstruation. Uterus: 758 g multiple intramural macroscopic thrombi. Microscopic diffuse adenomyosis and diffuse hemorrhage and microthrombi in smaller vessels.
Kimura et al. (2020) [18]JapanCase report37-year-old, aseptic DIC 3 days after surgical termination of pregnancy at 6 weeks. Treated with nafamostat mesylate. Assumed to be triggered by bleeding within adenomyosis.
Hong et al. (2020) [19]SingaporeRetrospective series5 out of 41 women admitted to hospital with adenomyosis had pulmonary embolism. In 4, PE was believed to be triggered by adenomyosis. Mean uterine size: 506 ± 216 g.
Zhang et al. (2020) [20]ChinaRetrospective comparative studyWomen with adenomyosis (n = 111) and fibroids (n = 115). In adenomyosis, APTT was longer [(30.4 ± 3.1), vs. (29.6 ± 2.5) s, respectively], and TT was shorter [(14.2 ± 1.2), (14.6 ± 1.0) s, respectively].
Niu et al. (2021) [21]ChinaCase report and review37-year-old with adenomyosis developed DIC 4 days following suction evacuation at 8 weeks for unwanted pregnancy.
Zhang et al. (2022) [22]ChinaCase report38 year old (Moyamoya disease) developed acute cerebral infarction. Underwent adenomyosis upon laparoscopic hysterectomy. Myoamoya disease leads to progressive stenosis or occlusion of cerebral arteries. Incidence higher in Japan, China and Korea.
Zong et al. (2024) [23]ChinaCase report50-year-old with adenomyosis with leg DVT after long-distance travel. Elevated CA 125 (401.5 U/mL). CA125 levels were normal after hysterectomy.
Table 2. Studies reporting on cerebral infarction ischemic or embolic stroke or cerebral venous thrombosis in women with adenomyosis. HRT: hormone replacement therapy.
Table 2. Studies reporting on cerebral infarction ischemic or embolic stroke or cerebral venous thrombosis in women with adenomyosis. HRT: hormone replacement therapy.
ReferenceCountryStudy TypeSynopsis
Yamashiro et al. (2012) [43]JapanCase report42-year-old CA125 1750 U/mL.
Yamashiro et al. (2012) [44]Japan4 Case reportsAge 45, 44, 50 and 42. Multiple cerebral infarcts in cortical and subcortical areas, 2 also had emboli in finger or kidneys. Elevated coagulation markers. Received GnRHa.
Soeda et al. (2011) [45]JapanCase reportNon-bacterial thrombotic endocarditis and cerebral, renal and splenic infarcts.
50-year-old, MRI pelvic mass (size of unborn head- reaching L3). Received GnRHa CA125 = 1579 U/mL. Histology: adenomyosis with hemorrhage in hyperplastic glands.
Nishioka et al. (2014) [46]JapanCase report47-year-old, cerebral venous thrombosis in giant adenomyosis.
Hijikata et al. (2016) [47]JapanCase report59-year-old on HRT. Aortic valve thrombus. CA125 = 334 U/mL. Adenomyosis diagnosed by ultrasound. Article suggested measuring CA125 in women with adenomyosis taking HRT.
Uchino et al. (2018) [48]JapanCase reportNon-bacterial endocarditis and cerebral infarction in 48-year-old. CA125 901 U/mL. Giant adenomyosis 10 × 10 cm reaching L5 with multiple hemorrhages in myometrium.
Kim et al. (2018) [49]KoreaCase reportCerebral infarct, elevated CA125 and CA19-9. Huge adenomyosis.
Aso et al. (2018) [50]JapanCase report44 y old, Hb 10.3 g/dL, CA125 = 2115 U/mL. CA19.9 1824 U/mL.
Elevated CA125. Multiple cerebral infarcts. GnRH reduced CA125 and CA19.9, Infarcts recurred after discontinuing GnRHa but no recurrence after hysterectomy.
Okazaki et al. (2018) [51]Japan2 casesCerebral infarction in women aged 42 and with CA125 395 U/mL, and women aged 50 with CA125 143 U/mL.
Yin et al. (2018) [52]China3 casesAdenomyosis with elevated CA125, and D-dimer. Stroke linked to hypercoagulable state and hyper-viscosity due to mucinous proteins leading to nonbacterial thrombotic endocarditis (NBTE) and stenosis of the cerebral arteries.
Zhao et al. (2020) [53]ChinaCase report34-year-old presented with fever. CA125 = 937.7 U/mL.
Adenomyosis reaching L5, on estradiol acetate and dydrogesterone. Fever may have a role.
Aiura et al. (2021) [54]JapanCase reportMiddle cerebral artery occlusion in a 48-year-old.
CA125 = 3536 u/mL CA19.9 892 u/mL. Histology: adenomyosis, endometriosis and fibroid. Tumor markers regressed after hysterectomy. Developed PE 3 days after hysterectomy but no recurrence of ischemic attacks.
Yasuda et al. (2022) [55]JapanCase reportMultiple cerebral infarcts during menstruation in a 47-year-old. Hysterectomy but not Edoxaban prevented recurrence.
Arai et al. (2022) [56]JapanCase report50-year-old, CA125 = 999 U/mL. Recurrent cerebral infarction. Massive adenomyosis, given GnRH. No recurrence after hysterectomy.
Tamura et al. (2022) [57]JapanCase report46-year-old. Multiple cerebral infarcts middle cerebral and DVT. Large adenomyosis reaching L4. CA125 1477 U/mL.
Yadav et al. (2022) [58]NepalCase report42-year-old with menorrhagia and adenomyosis. Admitted with left cortical hematoma, venous sinus thrombosis, anemia, CA125 155 U/mL. Treated with progesterone-only pill with no recurrence.
Yan et al. (2022) [59]ChinaCase report49-year-old, 4 episodes of stroke that occurred at time of menstruation. Elevated CA125.
Li et al. (2023) [60]China2 Case reportsTwo cases of cerebral venous sinus thrombosis and adenomyosis. One had normal CA125, second had CA125 312.4 U/mL.
Morishima et al. (2023) [61]JapanCase report42-year-old, multiple cerebral infarcts during two menstrual episodes. CA125 293 U/mL. Adenomyosis. No recurrence after hysterectomy.
Seo (2023) [62]KoreaCase report47-year-old, Hb 3.4 g/dL. CA125 = 48 U/mL, CA19-9= 49.2 U/mL. Globally hypertrophied uterus and adenomyosis on ultrasound. Multiple cerebellar and cerebral infarcts. Had non-bacterial thrombotic endocarditis. No recurrence after hysterectomy.
Yamashiro et al. (2023) [63]JapanMulticenter retrospective studyConsecutive women (age 20–59) with ischemic stroke/transient ischemic attack (TIA) in 10 stroke centers between 2017 and 2019. A total of 39 out of 470 women with stroke/TIA: 24 had fibroids, 9 endometriosis, 6 adenomyosis.
Chi et al. (2024) [64]ChinaCase report46-year-old with adenomyosis and fibroids developed multiple hemorrhagic cerebral infarcts. Treated with GnRHa.
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Habiba, M.; Ruscito, I.; Bianchi, P.; Guo, S.-W.; Benagiano, G. Is Adenomyosis Associated with Systemic Vascular Complications? Reprod. Med. 2025, 6, 38. https://doi.org/10.3390/reprodmed6040038

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Habiba M, Ruscito I, Bianchi P, Guo S-W, Benagiano G. Is Adenomyosis Associated with Systemic Vascular Complications? Reproductive Medicine. 2025; 6(4):38. https://doi.org/10.3390/reprodmed6040038

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Habiba, Marwan, Ilary Ruscito, Paola Bianchi, Sun-Wei Guo, and Giuseppe Benagiano. 2025. "Is Adenomyosis Associated with Systemic Vascular Complications?" Reproductive Medicine 6, no. 4: 38. https://doi.org/10.3390/reprodmed6040038

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Habiba, M., Ruscito, I., Bianchi, P., Guo, S.-W., & Benagiano, G. (2025). Is Adenomyosis Associated with Systemic Vascular Complications? Reproductive Medicine, 6(4), 38. https://doi.org/10.3390/reprodmed6040038

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