The Potential Link Between Uterine Fibroids and Cancer Risk: A Comprehensive Review

Abstract

Objectives:

The reproductive health and quality of life of women are profoundly affected by uterine fibroids, which are benign tumors of the myometrium. By reviewing the existing literature, speculating on possible causes, and drawing attention to gaps in our understanding, this review seeks to delve into the complex system of links between uterine fibroids and cancer susceptibility. Future research on women’s health could benefit from considering the findings of this review, alongside emerging evidence, to inform clinical decision-making.

Mechanism:

This review examines the epidemiology and clinical relevance of uterine fibroids, which are widespread and significantly affect women’s health. This review explores the molecular causes and pathophysiology of uterine fibroids with a focus on genetic, epigenetic, and hormonal factors. It also evaluates the correlation between fibroids and various cancers, such as endometrial cancer and leiomyosarcoma, while addressing the challenges of distinguishing benign from malignant tumors and the potential causes of malignant transformation.

Findings in Brief:

Uterine fibroids are typically benign, but they have the potential to become malignant in certain cases. Therefore, early diagnosis and effective treatment methods, including histopathology, cancer biomarkers, and advanced imaging techniques, are crucial for identifying and managing malignant transformation. Patient education is vital for empowering individuals to recognize the early signs and symptoms of uterine fibroids, leading to timely medical consultation and better management outcomes.

Conclusions:

This review emphasizes the need for continued research to refine our understanding of the relationship between uterine fibroids and cancer risk with the aim of enhancing diagnostic and therapeutic strategies to improve patient outcomes.

Graphical abstract

Keywords

uterine fibroids / gynecological cancer risk / leiomyosarcoma / endometrial cancer / fibroid malignant transformation

1. Introduction: Understanding Uterine Fibroids

1.1 Background and Epidemiology

Uterine fibroids, also known as uterine leiomyomas, are benign smooth muscle tumors of the uterus with unclear precise causes [1]. They are among the most common gynecological conditions, affecting 20–40% of women globally [2]. In the United States alone, nearly 11 million women are diagnosed with fibroids, with an increased prevalence among African American women [3]. A study has reported that the prevalence can reach 33.9% in certain populations, especially among women who have not yet given birth [4].

Although benign, uterine fibroids can significantly affect a woman’s quality of life by causing heavy menstrual bleeding, pelvic pain, urinary frequency, constipation, and infertility [5]. Approximately 70–75% of women with fibroids experience these symptoms [5]. Fibroids are the leading cause of hysterectomy, emphasizing their severe effects on reproductive health [6]. During pregnancy, fibroids are present in 1–10% of cases, with complications occurring in 10–40% of cases [7].

The exact cause of uterine fibroids remains unknown, but several factors contribute to their development, including genetic predisposition, hormonal influences (estrogen and progesterone), epigenetic modifications, and inflammation [8]. Women with a family history of fibroids, a high body mass index (BMI), and elevated estrogen levels are at an increased risk [9]. Additionally, environmental factors such as early menarche, nulliparity, and exposure to endocrine disruptors may also contribute to fibroid formation [10].

Understanding the epidemiology of fibroids, including their common diagnosis through clinical evaluation and ultrasonography, provides a foundation for discussing treatment options [11]. Magnetic resonance imaging (MRI) provides detailed visualization and is used to assess fibroid size, location, and characteristics in complex cases [12]. In some instances, histopathological examination is required to differentiate fibroids from malignant tumors such as leiomyosarcoma [13].

These treatments, tailored to symptoms, size, and location, include: (i) medical therapy, hormonal treatments such as gonadotropin-releasing hormone (GnRH) agonists, and selective progesterone receptor modulators (SPRMs) help reduce fibroid size and symptoms [14, 15]. (ii) Minimally invasive procedures such as uterine artery embolization (UAE), high-intensity focused ultrasound (HIFU), and MRI-guided focused ultrasound surgery (MRgFUS) are emerging as effective nonsurgical alternatives [11]. (iii) Surgical intervention: myomectomy is preferred in women who wish to preserve fertility, whereas hysterectomy remains the definitive treatment in severe cases [16].

1.2 Clinical Importance of Fibroids

Uterine fibroids significantly affect women’s health, particularly those aged 35–39 [17]. The most common symptoms were irregular menstrual bleeding, pelvic pressure, and infertility [18]. In some cases, fibroids contribute to pregnancy complications, menstrual disturbances, and chronic pelvic pain [19].

The management of fibroids involves a combination of medical, surgical, and minimally invasive treatments. SPRMs and low-dose mifepristone have shown effectiveness in reducing symptoms [14, 15]. Modern imaging techniques such as MRI and transvaginal ultrasound play a crucial role in diagnosis and treatment planning [20, 21].

Fibroids can also affect fertility, alter the uterine environment, and affect implantation success in assisted reproductive technologies [22]. Furthermore, their association with other benign gynecological conditions and cancers underscores the need for early detection and personalized treatment strategies [1].

Beyond physical symptoms, fibroids can significantly affect quality of life, leading to pain, fatigue, emotional distress, and limitations in daily activities [23, 24]. Psychological effects, including stress, anxiety, and reduced sexual well-being, further highlight the importance of comprehensive patient care [25, 26].

Timely diagnosis and evidence-based treatment are essential for mitigating fibroid-related complications. With a range of available pharmacological, interventional, and surgical options, personalized management strategies can help improve health outcomes and overall well-being [27, 28].

The effect on women’s health may be substantial because of the wide variety of clinical presentations that comprise common symptoms and problems of uterine fibroids. Depending on the variables, including the size and location of the uterine fibroids, one may encounter a variety of symptoms. Discomfort in the pelvis, heavy or painful periods, an increase in the frequency with which one needs to urinate, and problems with reproduction, such as infertility, problems during pregnancy, or miscarriage, are common symptoms [29, 30, 31]. Medical intervention may be necessary if complications related to uterine fibroids progress to critical stages. Urinary retention, hydronephrosis due to obstructive uropathy, sarcomatous alterations (infrequent instances), hyaline or red degeneration of fibroids, and severe anemia requiring blood transfusions are some of the consequences of uterine fibroids [32]. Fibroids, in addition to the difficulties associated with pregnancy, also represent hazards to newborn health and obstetric issues. These complications include fetal malposition, premature delivery, placenta previa, postpartum hemorrhage, and neonatal morbidity [33, 34]. Physical pain, mental anguish, and limitations in everyday activities that may result from uterine fibroids include excessive menstrual flow, abnormal uterine hemorrhage, infertility, lower abdominal pain, iron-deficiency anemia, and other related conditions. Fibroids may affect a person’s general health in addition to their bulk symptoms, including abdominal fullness, constipation, and increased urine frequency. The aforementioned information is summarized in Fig. 1 for further clarity.

2. Pathophysiology and Molecular Mechanisms

2.1 Genetic and Epigenetic Factors as well as Cellular and Molecular Pathways

Recent research has highlighted a strong genetic and epigenetic link between uterine fibroids and malignancies, particularly leiomyosarcoma and endometrial cancer [35, 36, 37]. Several gene mutations have been implicated in the development and malignant transformation of fibroids. Mediator complex subunit 12 (MED12) mutations, found in up to 70% of fibroids, are also frequently detected in leiomyosarcomas, suggesting a shared tumorigenic pathway [38, 39]. Additionally, mutations in HMGA2, COL4A5-A6, and FH are associated with fibroid growth and may contribute to cancer susceptibility [40, 41]. FH mutations are linked to hereditary leiomyomatosis and renal cell carcinoma (HLRCC), reinforcing the genetic overlap between fibroids and malignancy [42].

Both fibroids and many gynecological cancers exhibit common changes in DNA methylation and histone modification patterns, which can affect gene expression [36, 43]. Hypermethylation of tumor suppressor genes and hypomethylation of oncogenes contribute to fibroid growth and may facilitate malignant transformation [36]. Additionally, silencing of key apoptotic and cell cycle regulatory genes through epigenetic mechanisms has been linked to tumor progression [37]. Dysregulation of microRNAs (miRNAs) plays a crucial role in fibroid progression and is potentially associated with malignancy. Specific miRNAs involved in cell proliferation, extracellular matrix remodeling, and apoptosis have been found to be altered in both fibroids and uterine sarcomas [44]. Furthermore, fibroids and gynecological cancers share dysregulation in key oncogenic pathways such as Wnt/\beta-catenin, PI3K/AKT/mTOR, and MAPK/ERK, which are essential for tumor development [45, 46].

Although fibroids are typically benign, chromosomal instability and the accumulation of genetic mutations may contribute to their rare but significant malignant transformation [8]. Research indicates that fibroids exhibiting increased genomic alterations have molecular similarities to aggressive uterine sarcomas [47]. This evidence suggests that although uncommon, the potential for malignant progression should not be overlooked.

Understanding the genetic and epigenetic links between fibroids and cancer is essential to identify high-risk individuals, improve early detection, and develop targeted therapies. Further research into molecular markers and genomic instability will help clarify the mechanisms underlying fibroid-associated malignancies [48].

2.2 Cellular and Molecular Pathways

The development of uterine fibroids and their potential malignant transformation involve multiple hormonal, genetic, and signaling pathways, many of which are also implicated in cancer progression [49]. Key pathways include estrogen and progesterone signaling, oncogenic regulators such as HMGA2, and cell proliferation pathways such as PI3K/AKT/mTOR, Wnt/\beta-catenin, and MAPK/ERK [50, 51, 52]. HMGA2, a known oncogene, is frequently overexpressed in uterine fibroids and has been linked to abnormal cell growth and genomic instability [53]. HMGA2 has also been implicated in various malignancies, further supporting the genetic overlap between fibroids and cancer [54]. Fibroids exhibit abnormal activation of multiple cancer-associated pathways: (i) PI3K/AKT/mTOR signaling promotes cell survival, proliferation, and metabolic adaptation, which are the hallmarks of many tumors [50], (ii) Wnt/\beta-catenin signaling regulates cell differentiation and tissue homeostasis; however, when disrupted, it contributes to fibroid growth and potential malignancy [46], and (iii) MAPK/ERK signaling drives cell proliferation and extracellular matrix production, which are key features of fibroid pathophysiology [55].

Estrogen and progesterone play central roles in the pathogenesis of fibroids by promoting cell proliferation and inhibiting apoptosis [8]. Fibroid tissues contain elevated levels of estrogen receptors (ER) and progesterone receptors (PR), leading to enhanced hormonal responsiveness [56]. This hormone-driven proliferation shares similarities with hormone-sensitive cancers, particularly endometrial and breast cancer [57].

Excessive extracellular matrix (ECM) deposition is a defining characteristic of fibroids and contributes to tumor stiffness and abnormal tissue growth [54]. Dysregulation of transforming growth factor-beta (TGF-\beta) signaling further enhances fibrotic changes and supports an environment conducive to tumor progression [58]. The interplay between hormonal regulation, oncogenic activation, and proliferative signaling pathways highlights the complex molecular landscape of fibroids and their potential link to malignancy. Future research targeting these pathways may lead to novel therapeutic strategies for fibroids and associated cancers [59].

As illustrated in Fig. 2, complex genetic and cellular connections are highlighted by the molecular landscape of uterine fibroids, which shows that there are major common pathways involved in cancer formation. Studies have shown that the Wnt/\beta-catenin signaling pathway is vital for the development of fibroid tumors and the advancement of cancer, with abnormal activation leading to the growth and transformation of cells [45, 46]. This pathway provides evidence for the possible pathways via which fibroid growth may affect the development of tumors in the surrounding tissues. Genetic research has revealed strong hereditary links between uterine fibroids and other diseases. Genome-wide association research has found a high degree of genetic linkage between the two disorders [8]. The same genetic background between fibroid growth and cancer progression indicates shared molecular pathways. Inflammation is another important link between fibroids and cancer. Fibroids may cause chronic inflammation, which in turn can stimulate inflammatory cytokines and growth factors, leading to cancer by promoting angiogenesis [29]. The fact that somatic mutations, especially in MED12 and similar genes, influence cellular signaling networks and may act as cancer risk indicators further supports this link [47]. Additional similarities have been uncovered by gene expression analysis, which shows that fibroids have altered the expression of genes important for cell cycle control and apoptosis, two fundamental mechanisms in cancer biology [48]. These results indicate that there may be a substantial overlap between the biological processes of uterine fibroids and those of cancer growth, highlighting the need for further investigation into these complex molecular interactions.

3. Classification and Types of Uterine Fibroids

Uterine fibroids are classified on the basis of their location, histological features, and clinical impact. While most fibroids are benign, certain subtypes exhibit genetic and molecular alterations that suggest a potential link to malignancy [60, 61].

3.1 Major Types of Fibroids and Clinical Relevance

Uterine fibroids, the most common benign tumors in women of reproductive age, are classified into distinct types based on their location, each with unique clinical implications that affect symptoms, fertility, and treatment strategies. Submucosal fibroids are located beneath the uterine lining and protrude into the endometrial cavity, often leading to heavy menstrual bleeding and fertility complications [17]. Their proximity to the endometrium has raised concerns regarding the potential interactions between endometrial hyperplasia and carcinogenesis [62]. Intramural fibroids are found within the uterine muscle, which may distort the uterine cavity and cause pelvic pain, abnormal bleeding, and pregnancy complications [63]. Although typically benign, their growth patterns and genetic features warrant further study regarding malignant potential [64]. Subserosal fibroids are located on the outer uterine surface and exert pressure on the surrounding organs, causing urinary and bowel symptoms, but have minimal reproductive impact [65]. Rare and atypical fibroids including parasitic fibroids, broad ligament fibroids, and giant cervical fibroids exhibit unusual growth patterns that can mimic malignancies, complicating diagnosis [66, 67].

3.2 Histological Variants and Cancer Risk

Certain fibroid subtypes exhibit molecular and histopathological features that require careful differentiation from uterine sarcomas. Cellular and atypical fibroids display increased mitotic activity, which can be mistaken for malignant tumors [60]. Fumarate hydratase-deficient (FH-d) fibroids, a rare variant, have been linked to HLRCC, reinforcing a genetic connection with malignancy [68]. Intravascular leiomyomatosis (IVL), although benign, exhibits aggressive growth patterns, occasionally infiltrating blood vessels and mimicking malignancies [69, 70].

3.3 Clinical Implications and Management

While most fibroids are non-cancerous, distinguishing them from uterine sarcomas remains a significant diagnostic challenge [71, 72]. Histopathological examination is the gold standard for ruling out malignancies. Novel molecular markers and imaging techniques are being explored to improve early detection of high-risk fibroid subtypes [73, 74]. Although uterine fibroids are generally benign, certain subtypes share genetic and molecular characteristics with other malignancies. Advances in genetic profiling and biomarker research will enhance risk stratification and guide personalized treatment strategies [75, 76].

Table 1 provides a condensed categorization of uterine fibroids with details of their location, characteristics, symptoms, impact on fertility, and available treatment choices.

4. The Link Between Uterine Fibroids and Cancer

4.1 Overview of the Association

Although uterine fibroids are typically benign and have not been directly linked to an increased risk of uterine or ovarian cancer, research continues to explore their potential associations with other cancers, such as thyroid and breast cancer, owing to shared hormonal factors and the possibility of misdiagnosis. Uterine fibroids are primarily benign; however, distinguishing them from malignant tumors such as leiomyosarcomas remains a clinical challenge. Histopathological analysis plays a crucial role in differentiating benign fibroids from cancerous uterine sarcomas because imaging alone is often insufficient [1]. Although most fibroids do not undergo malignant transformation, a study has indicated that fibroids and certain gynecological malignancies share common genetic risk loci, suggesting potential overlapping molecular pathways [77]. Additionally, hormonal influences, particularly estrogen and progesterone, not only drive fibroid growth but may also contribute to cancer progression by promoting abnormal cell proliferation [78]. Understanding these molecular and hormonal mechanisms is essential for developing targeted screening strategies and improving early detection of malignancies in target patients. The shared risk factors between uterine fibroids and gynecological malignancies, including obesity and hormonal imbalances, suggest a potential underlying connection that warrants further investigation into their association with cancer risk [79]. Uterine fibroids may make detection and treatment more difficult when gynecological malignancies are present. Delays in cancer detection may occur if fibroids obstruct imaging or clinical examinations. Healthcare practitioners should consider these issues when identifying patients with uterine fibroids, healthcare practitioners should consider these problems [80].

4.2 Mechanisms of Malignant Transformation

The transformation of benign fibroids into malignant tumors is a multifaceted process. Gene mutations play a crucial role in this transformation, with specific alterations, such as those in MED12, potentially causing benign fibroids to become malignant leiomyosarcomas [81, 82]. Hormonal factors are essential for the growth and transformation of uterine fibroids. Estrogen and progesterone are key hormones involved in this process. If there is a hormonal imbalance, fibroids have the potential to develop into malignant tumors owing to disruptions in cell proliferation and differentiation [83].

Uterine sarcomas are one of many cancers with improperly active cellular signaling pathways, including PI3K/AKT/mTOR. Increased cell proliferation, survival, and malignant transformation are caused by deregulation of these pathways in uterine fibroids [84]. Uterine fibroids and gynecological malignancies may have a common etiology, including alterations in miRNA expression patterns. By affecting gene regulation, cell proliferation, and tumor development, altered expression of specific miRNAs may exacerbate the malignant transformation of fibroids [36].

Environmental endocrine disrupters, including phthalates, are potential causes of the development and progression of uterine fibroids. The combination of hereditary and hormonal variables with specific environmental exposures may increase the likelihood of cancer development [85]. Uterine fibroids and gynecological malignancies share several common pathogenic mechanisms, including genetic alterations, inflammatory processes, and hormonal imbalances. These overlapping pathways suggest that disruptions in hormone regulation, particularly those involving estrogen and progesterone, could contribute to both fibroid development and gynecological cancer progression. Therefore, understanding hormonal influences on fibroids and their potential link to malignancies is critical for improving both diagnostic and therapeutic approaches [86].

4.3 Risk Factors for Malignancy in Fibroids

The potential for malignant transformation of uterine fibroids is influenced by multiple risk factors, including genetic predisposition, hormonal imbalances, and lifestyle choices. Understanding these factors is crucial for assessing individual risk profiles and for improving early detection strategies.

Genetic predisposition plays a significant role in the development and progression of fibroids. Studies have indicated that individuals with a family history of fibroids or gynecological malignancies may have a heightened risk of fibroid-related cancers [87, 88]. Additionally, mutations in key genes such as MED12 have been associated with both benign and malignant uterine tumors, suggesting a potential genetic link between fibroid growth and cancer development [81, 82]. Hormonal dysregulation, particularly involving estrogen and progesterone, is strongly linked to fibroid development and possible malignant transformation. Prolonged exposure to elevated levels of these hormones may stimulate abnormal cellular proliferation in the uterus, thereby increasing the risk of fibroid-related malignancies [89, 90]. Furthermore, environmental endocrine disruptors such as phthalates have been implicated in altering hormonal pathways, potentially contributing to fibroid growth and cancer susceptibility [85].

Several modifiable lifestyle factors may affect the risk of developing fibroid malignancy. For instance, obesity is associated with increased estrogen production from adipose tissue, which may promote fibroid growth and influence cancer progression [78, 91]. Additionally, reproductive history, including nulliparity, early menarche, and late menopause, has been linked to prolonged hormonal exposure, further elevating the risk [92]. Other environmental factors such as tobacco use, excessive alcohol consumption, and exposure to endocrine-disrupting chemicals may exacerbate fibroid progression and malignancy potential [93, 94, 95].

Metabolic disorders, including insulin resistance and diabetes, have been correlated with an increased prevalence of uterine fibroids, and may contribute to their malignant transformation [78, 91]. These conditions often create a pro-inflammatory and hyperestrogenic environment, fostering fibroid growth and a complicated disease.

Uterine fibroids may increase or shrink in size due to hormonal shifts that occur during menopause and perimenopause, which are two stages of the aging process. With the changing uterine milieu that accompanies advancing maternal age, the risk of malignancies associated with fibroids increases [96]. The possible risk factors for malignancy in fibroids are shown in Fig. 3.

4.4 Integration of Hormonal and Inflammatory Mechanisms

The association between uterine fibroids and cancer risk involves complex endocrine pathways. Fibroid cells express aromatase, leading to local estrogen production that affects both fibroid growth and the surrounding tissues [97], which can influence the development of hormone-sensitive cancers. This relationship is particularly evident in postmenopausal women, where the presence of fibroids is associated with altered hormone levels, which may contribute to endometrial cancer risk [98]. In obese individuals, increased estrogen production from adipose tissue further complicates this hormonal landscape, potentially elevating the risks for both fibroid growth and hormone-sensitive cancers [99].

Chronic inflammation plays a crucial role in the progression of malignancies. Uterine fibroids demonstrate elevated levels of inflammatory markers, particularly tumour necrosis factor alpha (TNF-\alpha) and specific interleukins, which can promote cell proliferation while inhibiting apoptosis [100]. The inflammatory environment creates several important effects: (i) altered myometrial inflammation can affect progenitor cell activity, potentially increasing tissue susceptibility to malignant transformation [101]; (ii) local immune responses are modified, leading to increased oxidative stress and potential DNA damage [100]; and (iii) pro-inflammatory cytokines from visceral fat may amplify the inflammatory state [102].

Recent studies have demonstrated important therapeutic implications. While some hormonal therapies, such as GnRH agonists and SPRMs, can effectively manage fibroid symptoms, their long-term effects on cancer risk require further investigation [103]. The relationship between oxidative stress and fibroid formation may also influence cancer risk via molecular mechanisms [104]. These findings have led to increased interest in less invasive treatment approaches, given the potential cancer risks associated with certain surgical interventions [77, 105, 106].

5. Types of Cancer Associated With Uterine Fibroids

Fig. 4 shows a schematic of the potent cancer types linked to uterine fibroids.

5.1 Endometrial Cancer

Research has examined the relationship between uterine fibroids and endometrial cancer, and some studies have suggested an association. Specifically, a genetic study indicated that women with a history of uterine fibroids may have an increased risk of developing endometrial cancer. However, this relationship remains complex and is influenced by various factors, including hormonal pathways, and potential misdiagnosis. Further investigation is necessary to clarify the nature of this association and its implications for women’s health [77]. Endometrial cancer is common in postmenopausal women having a higher BMI, higher levels of human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125), coupled fibroids, and thickening endometrial linings, according to research [98]. There may be a correlation between a family history of endometriosis or fibroids and an increased risk of endometrial or ovarian cancer [1]. Although fibroids were once considered harmless lumps, recent genetic research has linked them to changes in endometrial function and endometrial cancer development [77]. Furthermore, it has been shown that fibroids may induce mechanical deformation of the endometrial cavity, which can lead to changes in gamete and embryo transit and subsequent embryo implantation [107].

Research has also shown that fibroids may affect the receptivity and peristalsis of the endometrium, the ability of sperm to migrate, and even the implantation of embryos [108]. In individuals receiving assisted reproductive technologies, fibroids near the endometrium have also been associated with a lower live birth rate [109]. There may be a link between fibroids and endometrial cancer because they cause endometrial damage and make implantation more difficult [110]. Uterine fibroids are characterized by a complex interplay between genetic, hormonal, and environmental variables, which may be summarized as the pathophysiology of the condition. Based on molecular studies, fibroids may modify endometrial receptivity, peristalsis, sperm migration, and embryo implantation [107]. Live birth rates in women with assisted reproductive technologies are lower when fibroids are present near the endometrial cavity [109].

In addition, the presence of fibroids has been associated with changes in the expression of genes in the endometrium, including a reduction in the expression of Homebox (HOX) gene, which may harm reproduction [111]. Fibroids may negatively affect the endometrium because their regulation is abnormal with respect to growth factors and cytokines [112]. Additionally, fibroids have the potential to alter endometrial chemical composition, disrupt inflammatory and autophagy levels, and cause abnormal angiogenesis, all of which may affect endometrial receptivity and function [113]. Research has shown that endometrial fibroid tumors that develop in the uterus as a result of fibroids are associated with an increased risk of endometrial cancer [114]. The similar etiology, clinical features, and pathological parameters of endometrial cancer and uterine fibroids lend credence to the idea that the two diseases are related [1]. The endometrial thickness may be increased by fibroids, affecting fertility [115].

According to genetic studies, endometrial cancer is one of the many cancers that uterine fibroids are associated with. Using Mendelian randomization, Kho et al. [77] showed that uterine fibroids increase the risk of endometrial cancer, demonstrating the significance of genetic variables in gynecological disorders. There seems to be a similar genetic route across many malignancies since Edwards et al. [116] found that genetic variations linked to uterine fibroids were also linked to an elevated risk of glioblastoma and esophageal cancer. In addition, Tai et al. [117] provided more evidence that reproductive characteristics, such as uterine fibroids, are significantly heritable, and that this heritability may extend to cancer risk. Environmental variables such as exposure to heavy metals are also components of this phenomenon [117]. A hormonal link may exist between environmental pollutants, fibroid development, and cancer risk. Johnstone et al. [118] discovered that cadmium levels were correlated with estrogen receptor expression in fibroids. These results highlight the need for ongoing multidisciplinary studies on uterine fibroids and cancer because of the intricate interplay between genetics and environment.

5.2 Leiomyosarcoma

Leiomyosarcoma is a highly uncommon malignant tumor type that develops from abnormalities in the smooth muscle. Although it usually develops independently, there is some evidence that it may, in rare cases, originate from fibroids [119]. Molecular and immunohistochemical techniques have shown that leiomyosarcomas may develop from specific subtypes of leiomyomas, namely the cellular subtype [119]. Although leiomyosarcomas originating from fibroids are relatively rare, they have been reported, particularly in people in their fifth to sixth decades of life [119].

Among hysterectomy specimens from patients older than 60, the incidence of leiomyosarcoma from suspected uterine fibroids may be as high as 1%, with estimates putting the frequency between 0.08% and 0.49% [120, 121]. Although leiomyosarcomas are thought to form from benign fibroids, it is important to consider the possibility of malignant transformation from benign fibroids when older patients present with menorrhagia and suspected uterine fibroids [122]. Leiomyosarcomas are often confused with leiomyomas, making the diagnosis of benign fibroids more difficult. The need for healthcare providers to be more vigilant in preventing the misdiagnosis of leiomyosarcoma as a benign uterine fibroid is highlighted by this diagnostic challenge [123, 124]. Furthermore, it is crucial to obtain a precise diagnosis and handle leiomyosarcoma appropriately to guarantee the best possible results for patients, because it is more aggressive than benign fibroids.

Diagnosis of leiomyosarcoma remains a significant clinical challenge because of its resemblance to benign fibroids. The similarity in imaging characteristics between leiomyosarcomas and fibroids increases the risk of misdiagnosis, potentially leading to delayed treatment and poor patient outcomes [125]. Current imaging techniques, including ultrasonography, often fail to reliably distinguish between the two conditions, and there are no universally accepted diagnostic imaging criteria for leiomyosarcoma [126]. Given its aggressive nature, rapid and accurate identification is crucial to guide appropriate treatment strategies [127]. Accurate and rapid identification of leiomyosarcomas is crucial because of their aggressive nature, as it guides the development of suitable treatment plans, which is a complex process that often requires advanced diagnostic techniques such as immunohistochemistry and molecular profiling to distinguish them from benign conditions such as leiomyomas [128].

A multidisciplinary strategy is necessary for the management of leiomyosarcomas associated with fibroids. The most outstanding prognosis is achieved with surgical resection performed early in the course of leiomyosarcoma, which remains an essential component of cancer management [129, 130]. Conservative treatment options for fibroids must consider the potential dangers of power morcellation in the setting of leiomyosarcoma with serious consideration [131]. Contrast-enhanced ultrasound (CEUS), which contrasts the ultrasound image and surrounding tissue, can also diagnose myometrial and endometrial disorders, including leiomyosarcomas, thus improving minimally invasive treatments [132]. Further investigation into the genetic variations and chromosomal aberrations observed in uterine smooth muscle tumors may lead to the development of diagnostic markers that may differentiate leiomyosarcomas from fibroids [133].

5.3 Other Gynecologic Cancers

Fibroids may occur in association with ovarian or cervical cancers. Fibroids have been linked to ovarian and cervical malignancies in several studies. Dysregulation of endothelin-1 (ET-1), which is associated with hypertension and reproductive diseases, has been linked to endometriosis, ovarian cancer, and cervical cancer [134]. Possible common causative genes have been identified in shared genetic risk areas for endometrial cancer, endometriosis, and uterine fibroids [77].

While the direct correlation between uterine fibroids and gynecological cancers remains under investigation, fibroids have been associated with systemic health conditions such as cardiovascular disease and adverse pregnancy outcomes [135, 136, 137]. The shared underlying mechanisms, including chronic inflammation, hormonal imbalances, and metabolic dysregulation, may contribute to the increased risk of both fibroid-related complications and malignancies​. Additionally, the presence of endometrial polyps alongside fibroids further complicates the gynecological landscape, as polyps themselves have been linked to an increased risk of endometrial cancer​. These interconnected factors suggest that while fibroids are benign, their broader systemic effects could influence cancer susceptibility, warranting further research on their potential oncogenic pathways.

Recent years have seen a plethora of research on cervical cancer and its possible molecular underpinnings, particularly regarding tyrosine phosphoproteomes and estrogen receptor 1 (ER1) mutations [138, 139]. A possible biomarker for disease progression, high sialic acid binding Ig like lectin 9 (SIGLEC9) expression in cervical cancer, has been linked to immune cell infiltration [140]. Increasing research points to cervical cancer screening as an effective method for lowering both the incidence and death rates associated with this disease [141].

5.4 Thyroid Cancer

According to previous studies, there is a strong link between thyroid disorders and uterine fibroids. Additionally, evidence suggests a greater likelihood of thyroid nodules and cancer. Using data from a nationwide health insurance database, Yuk and Kim [142] discovered that fibroid patients had an increased risk of thyroid cancer due to the prevalence of thyroid nodules. Their earlier finding that fibroids increase the risk of benign thyroid disorders in women is consistent with this finding [143]. Guenego et al. [144] reported a correlation between uterine fibroids and differentiated thyroid cancer. They also found that surgical removal of a fibroid increased the likelihood of developing thyroid cancer [144]. This was further corroborated by Li et al. [145], who found that premenopausal women with fibroids had an increased incidence of thyroid nodules. Hormonal and inflammatory variables are pivotal in the processes linking fibroids and thyroid carcinoma; however, this is only partly true. While fibroids raise estrogen levels, which may affect thyroid function, their chronic inflammatory state may encourage the formation of thyroid tumors through inflammatory cytokines [146]. Additional investigations into the standard molecular processes between thyroid illness and uterine fibroids are warranted in light of these results, which indicate a complicated interaction between the two.

5.5 Breast Cancer

Owing to standard hormonal and genetic variables, research has shown a strong association between uterine fibroids and the risk of breast cancer. Owing to the heightened estrogen levels shared by both uterine leiomyomas and breast cancer, population-based research in Taiwan discovered that women with both disorders had a significantly increased risk of developing breast cancer [147]. Using a population-based case-control approach, Tseng et al. [148] further supported these results, indicating that fibroids may accelerate breast tissue carcinogenesis by creating an estrogenic environment. Shen et al. [149] reported a disproportionately high risk of breast cancer among women diagnosed with uterine leiomyoma before the age of 30. Notably, hormonal interactions such as progesterone and estrogen are required for the development of both fibroids and breast cancer [150]. Another potential environmental component that increases the risk of breast cancer in women with fibroids is cadmium (Cd) exposure, which has estrogen-like effects [151]. There has to be further investigation into the common molecular pathways between uterine fibroids and breast cancer, since these related studies show how intricately related the two conditions are.

5.6 Ovarian Cancer

Shen et al. [1] did not find a significant correlation between uterine fibroids and ovarian cancer, suggesting that a direct link remains unconfirmed​. However, other studies have indicated potential associations, such as shared genetic risk regions between uterine fibroids and ovarian cancer, as well as overlapping hormonal and inflammatory pathways. These findings suggest that while no definitive causal relationship has been established, further research is needed to explore the potential mechanisms connecting the two conditions [1]. There may be overlapping molecular pathways between endometrial and ovarian malignancies, since Glubb et al. [152] found shared genetic risk areas for both types of cancer. An increased risk of ovarian cancer may be associated with a strong correlation between uterine fibroids and ovarian cysts, as reported by Wu et al. [153]. Ovarian cancer may develop in women with fibroids because of the hormonal milieu that they create. Ovaries and other tissues may be more susceptible to carcinogenesis due to persistent inflammatory processes and elevated estrogen levels in fibroids. The complicated nature of the link between uterine fibroids and ovarian cancer is highlighted by these results, which underscores the need for further study on this topic.

6. Diagnostic Approaches

6.1 Imaging Techniques

To diagnose fibroids and distinguish them from cancer, various imaging techniques are essential. The location of fibroids relative to other structures and their diagnosis and monitoring are often accomplished via ultrasound, particularly during pregnancy [154]. It is possible to distinguish between benign, malignant, and ambiguous adnexal masses using ultrasound and MRI [155]. One of the most important functions of MRI is to help identify uterine fibroids by revealing their size and location and distinguishing them from other benign and malignant entities such as leiomyosarcoma [156]. In addition, adenomyosis and uterine fibroids may be accurately diagnosed using transvaginal ultrasound with strain elastography, and the findings are similar to those of MRI-based diagnoses [157].

When it comes to relatively simple clinical situations, gray-scale ultrasonography is used for uterine fibroid diagnosis, while MRI is used for more complicated instances [157]. Broad ligament fibroids can be better identified with ultrasound because imaging technology allows visible separation of the tumor from its surrounding components [158]. Because most fibroids do not cause symptoms and are commonly discovered accidentally during regular ultrasound examinations, this diagnostic tool is vital when a woman is expecting a child [159]. When fibroids exhibit unusual symptoms, a combination of MRI and ultrasound may help rule out cancer [160]. HIFU has garnered much attention as a non-invasive treatment for symptomatic fibroids. HIFU is thought to eliminate fibroids by inducing coagulative necrosis in the desired tissue. The need for precise imaging and subsequent pathological confirmation is further underscored by the fact that histological investigation plays a pivotal role in establishing diagnoses, even when degraded leiomyomas imitate cancer.

To better identify and define intracavitary diseases, Doppler ultrasonography is a helpful supplement to B-mode ultrasonography for evaluating uterine malignancies. Improved diagnostic accuracy and patient treatment may be achieved by integrating Doppler ultrasonography into standard practice for women with perimenopausal and postmenopausal hemorrhage, according to Nguyen and Nguyen [161].

6.2 Biomarkers for Malignant Transformation

To identify possible biomarkers that indicate that fibroids have transformed into malignant tumors, a study has investigated molecular markers that distinguish benign fibroids from leiomyosarcomas. This demonstrates the importance of G-protein coupled receptor 55 (GPR55) expression in cancer development; thus, lowering GPR55 expression in fibroids may prevent leiomyosarcoma [162]. The presence of driver mutations linked to leiomyomas in some leiomyosarcomas raises the possibility of a connection between benign leiomyomas and their malignant progression [163]. In addition, it distinguishes between several forms of uterine smooth muscle tumors, such as leiomyoma, atypical leiomyoma, and leiomyosarcoma, and emphasizes the need to locate biomarkers in order to obtain a correct diagnosis and prognosis [164]. To distinguish benign fibroids from possible cancers, another study has examined the molecular features of fibroids; they have also addressed the rarity of fibroid malignant transformation and the need for precise imaging and diagnostic methods [165]. This has led to the discovery of MED12 variants as possible diagnostic indicators for uterine cancer and benign tumors, providing new information on the molecular mechanisms underlying fibroid transformation [166]. Identifying possible indicators to distinguish uterine leiomyosarcomas from leiomyomas is crucial, and the authors stressed the need for individualized treatment plans based on molecular markers [167]. Researchers have suggested that growth factor signaling may play a role in advancing uterine leiomyomas, which might indicate a connection between the two processes [168].

6.3 Histopathological Examination

Histopathological examination is the gold standard for distinguishing benign and malignant uterine fibroids. This method is critical for ensuring accurate diagnosis, guiding therapeutic decisions, and providing optimal postsurgical care [169]. Fibroids are classified into various subtypes based on histopathological characteristics, including common leiomyomas and rare variants, such as mitotically active, cellular, atypical, and myxoid fibroids, some of which may have malignant potential [170]. Precise classification is essential for differentiating benign fibroids from leiomyosarcomas, thereby reducing misdiagnoses that could lead to inappropriate treatment [171]. Histopathology also plays a key role in distinguishing fibroids from other conditions that present similar clinical features, such as gastrointestinal stromal tumors [172]. In cases where fibroids exhibit severe cystic degeneration, histopathological assessment can effectively rule out malignancy [173]. Additionally, intraoperative histological testing is valuable for confirming diagnoses, particularly retroperitoneal fibroids [174]. Given the potential for misclassification of benign and malignant leiomyosarcomas, histopathological evaluation remains indispensable for achieving precise diagnosis and effective treatment planning [175].

7. Prevention and Early Detection

Early detection and prevention play a crucial role in reducing the incidence of uterine fibroids and their potential complications. Identifying modifiable risk factors and implementing targeted screening strategies can help mitigate disease progression and improve patient outcomes [176].

Preventive measures include lifestyle modifications, hormonal regulation, and early medical interventions. One study has suggested that vitamin D deficiency may be a risk factor for fibroid development, indicating that maintaining adequate vitamin D levels may be beneficial [176]. Additionally, managing hypertension and cardiovascular risk factors is essential as they have been linked to fibroid progression [177]. Pharmacological approaches, such as GnRH agonists and SPRMs, may help reduce fibroid size and symptoms, potentially lowering long-term risks [178].

Regular gynecological checkups and imaging techniques, including ultrasound and MRI, are essential for early detection and monitoring of fibroid growth [81]. Screening is particularly important for high-risk populations such as women with early menarche, nulliparity, obesity, or a family history of fibroids [176]. Additionally, fibroid screening during pregnancy can help identify patients at risk for adverse obstetric outcomes [11].

Educating patients about fibroid symptoms, risk factors, and treatment options is crucial for early diagnosis and management [179]. Increased health literacy can help patients make informed decisions, improve treatment outcomes, and reduce disparities in care [180]. Awareness programs should emphasize the importance of early medical interventions, particularly for women at higher risk [181, 182].

8. Future Research Directions

8.1 Areas Requiring Further Research

Although numerous studies have explored the link between uterine fibroids and cancer, critical gaps remain in the understanding of the mechanisms underlying fibroid malignancy risk [183]. Although research has identified genetic mutations, hormonal influences, and inflammatory pathways as key factors, their exact contributions to fibroid transformation require further investigation [184]. One area that requires further exploration is the role of oxidative stress in fibroid development and its potential link to malignancy. Oxidative stress markers have been associated with multiple gynecological disorders; however, their specific impact on fibroid progression remains unclear [184]. Additionally, while fibroids significantly affect women’s quality of life, more research is needed to assess their long-term effects on reproductive health and overall well-being [185]. Another unresolved question concerns the precise cause of the fibroid formation. Although risk factors such as genetic predisposition, hormonal imbalances, and environmental influences have been identified, the underlying mechanisms driving fibroid growth remain partially understood [186, 187]. The role of dietary factors in fibroid pathogenesis and progression remains an emerging area of study [188, 189]. Addressing these knowledge gaps will help to refine preventive strategies, improve diagnostic accuracy, and develop more effective treatments for fibroid-related complications.

8.2 Potential Areas for Future Study

Many ideas for future research on uterine fibroids have been proposed, all of which have the potential to further our knowledge of the problem and lead to new treatments. A more thorough investigation of the molecular processes underlying the development and progression of uterine fibroids is necessary to fully explore this promising area. Finally, to end these benign tumors, researchers must understand the complex biochemical processes that lead to their formation. By doing so, they may identify prospective targets for more targeted and accurate treatment [188]. Understanding the effects of uterine fibroids on fertility and pregnancy outcomes is crucial to elucidate their involvement in diminishing endometrial receptivity [108]. Research on the connection between diet and uterine fibroids is a promising new field. By studying the potential effects of dietary components on growth and development, we may find dietary treatments that can improve nutritional status and help prevent or manage fibroids [189]. To better understand the role of vitamin D in the development of uterine fibroids and identify targets for targeted treatment, it may be worthwhile to investigate the immunohistochemical expression of vitamin D receptors in these tumors [190]. New treatment methods and improvements in the medical management of uterine fibroids should be the primary focus of research into potential new medicines. Research into the effectiveness of novel pharmacological treatments, such as SPRMs, may lead to less intrusive methods for treating fibroids [191]. Moreover, the fibroid management area benefits significantly from investigating the feasibility of transcervical radiofrequency and high-intensity focused ultrasound ablation as less-invasive therapeutic techniques for uterine fibroids [192, 193].

9. Conclusions

The complicated association between uterine fibroids and the risk of developing cancer was investigated in this study. Particular attention has been paid to the conditions associated with cancer, including endometrial cancer, thyroid cancer, ovarian cancer, breast cancer, and leiomyosarcoma. Important discoveries emphasize the complex relationship between hormonal, genetic, and epigenetic variables in the production of fibroids, and their possible involvement in the progression of the disease to cancer. Despite the continued importance of histological analysis and other cutting-edge diagnostic technologies, many questions remain regarding how to distinguish benign from malignant tumors. Future studies should focus on the molecular processes of cancer transformation, the development of more accurate diagnostic tools, and the creation of tailored treatment strategies. Women diagnosed with uterine fibroids will be better cared for clinically as a result of these initiatives and other changes in screening processes and patient education.

References

[1] Shen F, Liu Y, Lin L, Zhao M, Chen Q. Association of benign gynaecological diseases and risk of endometrial and ovarian cancers. Journal of Cancer. 2020; 11: 3186–3191. https://doi.org/10.7150/jca.39626.

[2] Li W, Jiang Z, Deng X, Xu D. Long-term follow-up outcome and reintervention analysis of ultrasound-guided high intensity focused ultrasound treatment for uterine fibroids. International Journal of Hyperthermia. 2020; 37: 1046–1051. https://doi.org/10.1080/02656736.2020.1807617.

[3] Lou Z, Huang Y, Li S, Luo Z, Li C, Chu K, et al. Global, regional, and national time trends in incidence, prevalence, years lived with disability for uterine fibroids, 1990–2019: an age-period-cohort analysis for the global burden of disease 2019 study. BMC Public Health. 2023; 23: 916. https://doi.org/10.1186/s12889-023-15765-x.

[4] Olotu JE, Okon M. Anatomical location of uterine fibroids among women attending a tertiary health facility in a southern Nigerian population. GSC Biological and Pharmaceutical Sciences. 2021; 14: 7–15. https://doi.org/10.30574/gscbps.2021.14.2.0029.

[5] Wang Y, Zhang S, Li C, Li B, Ouyang L. Minimally invasive surgery for uterine fibroids. Ginekologia Polska. 2020; 91: 149–157. https://doi.org/10.5603/GP.2020.0032.

[6] Jin YC, Ji TH, Yuan X, Sun Y, Sun YJ, Wu J. Bioinformatic analysis identifies potential key genes in the pathogenesis of uterine leiomyoma. European Journal of Gynaecological Oncology. 2021; 42: 50.

[7] Ruiz J. Arrest of labor secondary to large uterine fibroid. Clinical Case Reports. 2024; 12: e8806. https://doi.org/10.1002/ccr3.8806.

[8] Moravek MB, Bulun SE. Endocrinology of uterine fibroids: steroid hormones, stem cells, and genetic contribution. Current Opinion in Obstetrics & Gynecology. 2015; 27: 276–283. https://doi.org/10.1097/GCO.0000000000000185.

[9] Khammas AS, Mohammed SS, Salih SQ, Abubakar D. Prevalence and Risk Factors of Sonographically Detected Uterine Fibroid among Iraqi Women in Medical Baghdad City, Baghdad, Iraq. Borneo Journal of Medical Sciences (BJMS). 2022; 16: 3–14. https://doi.org/10.51200/bjms.v16i2.3334.

[10] Shen Y, Wu Y, Lu Q, Ren M. Vegetarian diet and reduced uterine fibroids risk: A case-control study in Nanjing, China. The Journal of Obstetrics and Gynaecology Research. 2016; 42: 87–94. https://doi.org/10.1111/jog.12834.

[11] Langton CR, Harmon QE, Upson K, Baird DD. Soy-Based Infant Formula Feeding and Uterine Fibroid Development in a Prospective Ultrasound Study of Black/African-American Women. Environmental Health Perspectives. 2023; 131: 17006. https://doi.org/10.1289/EHP11089.

[12] Kwas K, Nowakowska A, Fornalczyk A, Krzycka M, Nowak A, Wilczyński J, et al. Impact of Contraception on Uterine Fibroids. Medicina (Kaunas, Lithuania). 2021; 57: 717. https://doi.org/10.3390/medicina57070717.

[13] Stewart EA, Cookson CL, Gandolfo RA, Schulze-Rath R. Epidemiology of uterine fibroids: a systematic review. BJOG. 2017; 124: 1501–1512. https://doi.org/10.1111/1471-0528.14640.

[14] Kriplani A, Mukherjee B, Gupta S, Singh I, Pandey S, Singh A, et al. An expert consensus on the medical management of uterine fibroids and complementing surgical management with focus on low dose mifepristone. International Journal of Clinical Obstetrics and Gynaecology. 2024; 8: 48–51. https://doi.org/10.33545/gynae.2024.v8.i3a.1452.

[15] Bestel E, Donnez J. The potential of selective progesterone receptor modulators for the treatment of uterine fibroids. Expert Review of Endocrinology & Metabolism. 2014; 9: 79–92. https://doi.org/10.1586/17446651.2014.862495.

[16] Fu Y, Fan Y, Fan W, Lv Y, Ai S, Yu C. Efficacy and safety of traditional Chinese herbal formula combined with western medicine for uterine fibroid: A protocol for systematic review and meta-analysis. Medicine. 2020; 99: e22039. https://doi.org/10.1097/MD.0000000000022039.

[17] Sarıdoğan E, Sarıdoğan E. Management of fibroids prior to in vitro fertilization/intracytoplasmic sperm injection: A pragmatic approach. Journal of the Turkish German Gynecological Association. 2019; 20: 55–59. https://doi.org/10.4274/jtgga.galenos.2018.2018.0148.

[18] Podder MR, Podder R, Shivkumar PV. Demographic parameters of women with uterine fibroids presenting as abnormal uterine bleeding. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2018; 7: 2915–2920. http://dx.doi.org/10.18203/2320-1770.ijrcog20182906.

[19] Khyade RL. A study of menstrual disturbance in cases of fibroid uterus. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2017; 6: 2494–2497.

[20] Mukthadira, Hira M, Sharma NK, Rahman AM, Razzaque MA, Hossain MZ, et al. Role of Transvaginal Ultrasonography in the evaluation of Uterine Fibroids: a regional observation in Bangladesh. Community Based Medical Journal. 2018; 7: 17–23. https://doi.org/10.3329/cbmj.v7i2.55451.

[21] Allam EA, Mounir SG, Dalia S. The Role of Magnetic Resonance Imaging in Evaluation of Leiomyoma after Uterine Artery Embolization. The Medical Journal of Cairo University. 2019; 87: 4175–4184.

[22] Moon JW, Kim CH, Kim JB, Kim SH, Chae HD, Kang BM. Alterations in uterine hemodynamics caused by uterine fibroids and their impact on in vitro fertilization outcomes. Clinical and Experimental Reproductive Medicine. 2015; 42: 163–168. https://doi.org/10.5653/cerm.2015.42.4.163.

[23] Ain QU, Noor H, Shahid S, Bibi H, Akbar H, Zulfiqar L, et al. Assessment of Uterine Fibroids in Pre and Post Menopausal Women by Transabdominal Ultrasound. Journal of Health and Rehabilitation Research. 2024; 4: 1444–1447. https://doi.org/10.61919/jhrr.v4i2.1026.

[24] Thampi A, Lakshman A, Cheriyan SM, Sharaf S, Thomas RP, Shenoy TH. Uterine Leiomyoma: Clinical Manifestations and Perceived Impact on Women’s Health Life. Asian Journal of Pharmaceutical and Clinical Research. 2023; 16: 21–24. https://doi.org/10.22159/ajpcr.2023.v16i4.46515.

[25] Vines AI, Ta M, Esserman DA. The association between self-reported major life events and the presence of uterine fibroids. Womens Health Issues. 2010; 20: 294–298. https://doi.org/10.1016/j.whi.2010.03.009.

[26] Venugopal N, Jacob N, Nallasamy V, Ramanathan S. Awareness and knowledge of uterine fibroid among women in Kerala, India. International Journal of Public Health Science (IJPHS). 2022; 11: 877–883. http://doi.org/10.11591/ijphs.v11i3.21269.

[27] Ezzedine D, Norwitz ER. Are Women With Uterine Fibroids at Increased Risk for Adverse Pregnancy Outcome? Clinical Obstetrics and Gynecology. 2016; 59: 119–127. https://doi.org/10.1097/GRF.0000000000000169.

[28] Martin J, Ulrich ND, Duplantis S, Williams FB, Luo Q, Moore RC. Obstetrical Outcomes of Ultrasound Identified Uterine Fibroids in Pregnancy. American Journal of Perinatology. 2016; 33: 1218–1222. https://doi.org/10.1055/s-0036-1593389.

[29] Don EE, Middelkoop MA, Hehenkamp WJK, Mijatovic V, Griffioen AW, Huirne JAF. Endometrial Angiogenesis of Abnormal Uterine Bleeding and Infertility in Patients with Uterine Fibroids-A Systematic Review. International Journal of Molecular Sciences. 2023; 24: 7011. https://doi.org/10.3390/ijms24087011.

[30] Prasad S, Sethi S. Study to Compare the Efficacy and Safety of Ulipristal Acetate and Mifepristone as Medical Treatment of Uterine Fibroid. International Journal of Medical and Biomedical Studies. 2019; 3: 200–205. https://doi.org/10.32553/ijmbs.v3i9.569.

[31] Koga K, Fukui M, Fujisawa M, Suzukamo Y. Impact of diagnosis and treatment of uterine fibroids on quality of life and labor productivity: The Japanese online survey for uterine fibroids and quality of life (JOYFUL survey). The Journal of Obstetrics and Gynaecology Research. 2023; 49: 2528–2537. https://doi.org/10.1111/jog.15758.

[32] Disi ES. Sciatica in Early Pregnancy With Coexisting Uterine Leiomyoma and Tarlov Cyst: A Case Report. Cureus. 2022; 14: e27855. https://doi.org/10.7759/cureus.27855.

[33] Vyas PS, Kim SW, Castellano JM, Bal JK, Plewniak KM. Uterine Fibroid-Induced Compressive Neuropathy of Lumbar Plexus and Obturator Nerve. CRSLS. 2023; 10: e2023.00034. https://doi.org/10.4293/CRSLS.2023.00034.

[34] Wang S, Wang XT, Liu RH, Liu M, Wu YR, Huang XY, et al. Dydrogesterone has no effect on uterine fibroids when used to prevent miscarriage in pregnant women with uterine fibroids. Ginekologia Polska. 2017; 88: 679–685. https://doi.org/10.5603/GP.a2017.0121.

[35] Aghogho ET, Iru NM, Simeon AN, Mike EI, Tudjegbe OM. Knowledge and Perception Towards Uterine Fibroids among Ante-Natal Clinic Attendees in Two Sub-Urban Communities in Delta State, Nigeria. Dutse Journal of Pure and Applied Sciences. 2023; 9: 290–301. https://dx.doi.org/10.4314/dujopas.v9i4a.27.

[36] George JW, Fan H, Johnson B, Carpenter TJ, Foy KK, Chatterjee A, et al. Integrated Epigenome, Exome, and Transcriptome Analyses Reveal Molecular Subtypes and Homeotic Transformation in Uterine Fibroids. Cell Reports. 2019; 29: 4069–4085.e6. https://doi.org/10.1016/j.celrep.2019.11.077.

[37] Katz TA, Yang Q, Treviño LS, Walker CL, Al-Hendy A. Endocrine-disrupting chemicals and uterine fibroids. Fertility and Sterility. 2016; 106: 967–977. https://doi.org/10.1016/j.fertnstert.2016.08.023.

[38] Kubinova K, Tesarova M, Hansikova H, Vesela K, Kuzel D, Mara M. Fumarate hydratase gene mutation in two young patients with sporadic uterine fibroids. The Journal of Obstetrics and Gynaecology Research. 2013; 39: 410–414. https://doi.org/10.1111/j.1447-0756.2012.01939.x.

[39] Mäkinen N, Mehine M, Tolvanen J, Kaasinen E, Li Y, Lehtonen HJ, et al. MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas. Science. 2011; 334: 252–255. https://doi.org/10.1126/science.1208930.

[40] Mehine M, Kaasinen E, Heinonen HR, Mäkinen N, Kämpjärvi K, Sarvilinna N, et al. Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers. Proceedings of the National Academy of Sciences of the United States of America. 2016; 113: 1315–1320. https://doi.org/10.1073/pnas.1518752113.

[41] Bertsch E, Qiang W, Zhang Q, Espona-Fiedler M, Druschitz S, Liu Y, et al. MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma. Modern Pathology: an Official Journal of the United States and Canadian Academy of Pathology, Inc. 2014; 27: 1144–1153. https://doi.org/10.1038/modpathol.2013.243.

[42] Uimari O, Subramaniam KS, Vollenhoven B, Tapmeier TT. Uterine Fibroids (Leiomyomata) and Heavy Menstrual Bleeding. Frontiers in Reproductive Health. 2022; 4: 818243. https://doi.org/10.3389/frph.2022.818243.

[43] Yang Q, Nair S, Laknaur A, Ismail N, Diamond MP, Al-Hendy A. The Polycomb Group Protein EZH2 Impairs DNA Damage Repair Gene Expression in Human Uterine Fibroids. Biology of Reproduction. 2016; 94: 69. https://doi.org/10.1095/biolreprod.115.134924.

[44] Cardozo ER, Foster R, Karmon AE, Lee AE, Gatune LW, Rueda BR, et al. MicroRNA 21a-5p overexpression impacts mediators of extracellular matrix formation in uterine leiomyoma. Reproductive Biology and Endocrinology: RB&E. 2018; 16: 46. https://doi.org/10.1186/s12958-018-0364-8.

[45] Ko YA, Jamaluddin MFB, Adebayo M, Bajwa P, Scott RJ, Dharmarajan AM, et al. Extracellular matrix (ECM) activates β-catenin signaling in uterine fibroids. Reproduction. 2018; 155: 61–71. https://doi.org/10.1530/REP-17-0339.

[46] Li F, Wang J, Liu W. Search for key genes, key signaling pathways, and immune cell infiltration in uterine fibroids by bioinformatics analysis. Medicine. 2023; 102: e33815. https://doi.org/10.1097/MD.0000000000033815.

[47] Turunen M, Spaeth JM, Keskitalo S, Park MJ, Kivioja T, Clark AD, et al. Uterine leiomyoma-linked MED12 mutations disrupt mediator-associated CDK activity. Cell Reports. 2014; 7: 654–660. https://doi.org/10.1016/j.celrep.2014.03.047.

[48] Buyukcelebi K, Chen X, Abdula F, Elkafas H, Duval AJ, Ozturk H, et al. Engineered MED12 mutations drive leiomyoma-like transcriptional and metabolic programs by altering the 3D genome compartmentalization. Nature Communications. 2023; 14: 4057. https://doi.org/10.1038/s41467-023-39684-y.

[49] Bulun SE. Uterine fibroids. The New England Journal of Medicine. 2013; 369: 1344–1355. https://doi.org/10.1056/NEJMra1209993.

[50] Amjad E, Asnaashari S, Sokouti B. Induction of mTOR signaling pathway in the progression of papillary thyroid cancer. Meta Gene. 2020; 24: 100704. https://doi.org/10.1016/j.mgene.2020.100704.

[51] Amjad E, Asnaashari S, Sokouti B. The role of associated genes of Wnt signaling pathway in chronic obstructive pulmonary disease (COPD). Gene Reports. 2020; 18: 100582. https://doi.org/10.1016/j.genrep.2019.100582.

[52] Amjad E, Asnaashari S, Jahanban-Esfahlan A, Sokouti B. The role of MAPK, notch and Wnt signaling pathways in papillary thyroid cancer: Evidence from a systematic review and meta-analyzing microarray datasets employing bioinformatics knowledge and literature. Biochemistry and Biophysics Reports. 2024; 37: 101606. https://doi.org/10.1016/j.bbrep.2023.101606.

[53] Unachukwu U, Chada K, D’Armiento J. High Mobility Group AT-Hook 2 (HMGA2) Oncogenicity in Mesenchymal and Epithelial Neoplasia. International Journal of Molecular Sciences. 2020; 21: 3151. https://doi.org/10.3390/ijms21093151.

[54] Jayes FL, Liu B, Feng L, Aviles-Espinoza N, Leikin S, Leppert PC. Evidence of biomechanical and collagen heterogeneity in uterine fibroids. PloS One. 2019; 14: e0215646. https://doi.org/10.1371/journal.pone.0215646.

[55] Shen Z, Li S, Sheng B, Shen Q, Sun LZ, Zhu H, et al. The role of atorvastatin in suppressing tumor growth of uterine fibroids. Journal of Translational Medicine. 2018; 16: 53. https://doi.org/10.1186/s12967-018-1430-x.

[56] Botía CP, Camarasa SC, Baixauli FR, Sánchez AC. Uterine Fibroids Review: Understanding Their Origins to Better Understand Their Future Treatments. Journal of Tumor Research. 2017; 3: 2. http://dx.doi.org/10.35248/2684-1258.17.3.130.

[57] Yu L, Moore AB, Dixon D. Receptor tyrosine kinases and their hormonal regulation in uterine leiomyoma. Seminars in Reproductive Medicine. 2010; 28: 250–259. https://doi.org/10.1055/s-0030-1251482.

[58] Ciebiera M, Włodarczyk M, Wrzosek M, Męczekalski B, Nowicka G, Łukaszuk K, et al. Role of Transforming Growth Factor β in Uterine Fibroid Biology. International Journal of Molecular Sciences. 2017; 18: 2435. https://doi.org/10.3390/ijms18112435.

[59] Rafique S, Segars JH, Leppert PC. Mechanical Signaling and Extracellular Matrix in Uterine Fibroids. Seminars in Reproductive Medicine. 2017; 35: 487–493. https://doi.org/10.1055/s-0037-1607268.

[60] Flake GP, Moore AB, Sutton D, Flagler N, Clayton N, Kissling GE, et al. The Life Cycle of the Uterine Fibroid Myocyte. Current Obstetrics and Gynecology Reports. 2018; 7: 97–105. https://doi.org/10.1007/s13669-018-0241-7.

[61] Flake GP, Moore AB, Sutton D, Kissling GE, Horton J, Wicker B, et al. The natural history of uterine leiomyomas: light and electron microscopic studies of fibroid phases, interstitial ischemia, inanosis, and reclamation. Obstetrics and Gynecology International. 2013; 2013: 528376. https://doi.org/10.1155/2013/528376.

[62] Santalla-Hernández A, Manzanares S, Naveiro-Fuentes M, López-Criado MS, Fernández-Parra J. Obstetric outcome after ultrasound guided transvaginal radiofrequency ablation of uterine myomas. Obstetrics & Gynecology International Journal. 2023; 14: 160–164. http://doi.org/10.15406/ogij.2023.14.00715.

[63] Saridogan E, Deguara CS. Office Hysteroscopic Treatment of Uterine Fibroids. Current Obstetrics and Gynecology Reports. 2016; 5: 106–109. https://doi.org/10.1007/s13669-016-0152-4.

[64] Buhur A, Öncü N. Comparison of Laparoscopic and Open Myomectomy in a Tertiary Hospital: A Retrospective Cohort Study. Comprehensive Medicine. 2024; 16: 112–117. http://doi.org/10.14744/cm.2024.68442.

[65] Zhao R, Wang X, Zou L, Li G, Chen Y, Li C, et al. Adverse obstetric outcomes in pregnant women with uterine fibroids in China: A multicenter survey involving 112,403 deliveries. PloS One. 2017; 12: e0187821. https://doi.org/10.1371/journal.pone.0187821.

[66] Sood A, Gupta RG, Mishra GV, Khandelwal S, Suryadevara M. Wandering Fibroid in a Post Menopausal Woman From Rural India: A Case Report. Cureus. 2023; 15: e42734. https://doi.org/10.7759/cureus.42734.

[67] Singh L, Gupta T, Kumari S, Gupta S. True broad ligament fibroid mimicking ovarian mass in a postmenopausal woman. International Journal of Reproduction Contraception Obstetrics and Gynecology. 2019; 8: 2910–2912. http://dx.doi.org/10.18203/2320-1770.ijrcog20193067.

[68] Alkhrait S, Ali M, Kertowidjojo E, Romero IL, Hathaway F, Madueke-Laveaux OS. Investigating Fumarate Hydratase-Deficient Uterine Fibroids: A Case Series. Journal of Clinical Medicine. 2023; 12: 5436. https://doi.org/10.3390/jcm12175436.

[69] Tan Y, Han J, Wang Z, Yan J, Dong L, Liu R. Different clinical diagnosis end up in the same pathological diagnosis of intravascular leiomyomatosis: Two case reports. Medicine. 2024; 103: e36887. https://doi.org/10.1097/MD.0000000000036887.

[70] Liu J, Wang Z. Advances in the Preoperative Identification of Uterine Sarcoma. Cancers. 2022; 14: 3517. https://doi.org/10.3390/cancers14143517.

[71] Trelborg KF, Bjørn AM. Spontaneous expulsion of a large vaginal mass–a case of complete ejection of a detached fibroma in statu nascendi. Danish Journal of Obstetrics and Gynaecology. 2023; 1: 42–45. https://doi.org/10.56182/djog.v1i1.20.

[72] Nava HJ. Highly Cellular Leiomyoma Mixed With a Focus of Adenomyosis. Cureus. 2022; 14: e28129. https://doi.org/10.7759/cureus.28129.

[73] Laganà AS, Romano A, Vanhie A, Bafort C, Götte M, Aaltonen LA, et al. Management of Uterine Fibroids and Sarcomas: The Palermo Position Paper. Gynecologic and Obstetric Investigation. 2024; 89: 73–86. https://doi.org/10.1159/000537730.

[74] Vázquez Ruvalcaba A, García AGG, Cornejo MYL, Palacios AAM, Vespero FH. Shifting paradigms in uterine fibroids treatment: insights from current therapeutic approaches. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2023; 12: 2582–2589. https://doi.org/10.18203/2320-1770.ijrcog20232317.

[75] Fuldeore MJ, Soliman AM. Patient-reported prevalence and symptomatic burden of uterine fibroids among women in the United States: findings from a cross-sectional survey analysis. International Journal of Women’s Health. 2017; 9: 403–411. https://doi.org/10.2147/IJWH.S133212.

[76] Jeong HG, Lee MJ, Lee JR, Jee BC, Kim SK. The Largest Uterine Leiomyoma Removed by Robotic-Assisted Laparoscopy in the Late Reproductive Age: A Case Report. Journal of Menopausal Medicine. 2021; 27: 37–41. https://doi.org/10.6118/jmm.20028.

[77] Kho PF, Mortlock S, Endometrial Cancer Association Consortium, International Endometriosis Genetics Consortium, Rogers PAW, Nyholt DR, et al. Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus. Human Genetics. 2021; 140: 1353–1365. https://doi.org/10.1007/s00439-021-02312-0.

[78] Guare LA, Das J, Caruth L, Setia-Verma S. Social Determinants of Health and Lifestyle Risk Factors Modulate Genetic Susceptibility for Women’s Health Outcomes. Proceedings of the Pacific Symposium. 2025; 30: 296–313. https://doi.org/10.1142/9789819807024_0022.

[79] Mohan A, Kumar V, Brahmachari S, Pandya B. A Study on Clinico-Pathological Profile of Breast Cancer Patients and Their Correlation With Uterine Fibroids Using Hormone Level and Receptor Status Assessment. Breast Cancer: Basic and Clinical Research. 2022; 16: 11782234221090197. https://doi.org/10.1177/11782234221090197.

[80] Ikechebelu JI, Okpala BC, Eleje GU, Nwachukwu CE, Nwajiaku LA, Nnoruka M. Delayed presentation of giant uterine fibroids in a Nigerian private specialist health facility. SAGE Open Medical Case Reports. 2021; 9: 2050313X211063137. https://doi.org/10.1177/2050313X211063137.

[81] Segars JH, Parrott EC, Nagel JD, Guo XC, Gao X, Birnbaum LS, et al. Proceedings from the Third National Institutes of Health International Congress on Advances in Uterine Leiomyoma Research: comprehensive review, conference summary and future recommendations. Human Reproduction Update. 2014; 20: 309–333. https://doi.org/10.1093/humupd/dmt058.

[82] Datir SG, Bhake A. Management of Uterine Fibroids and Its Complications During Pregnancy: A Review of Literature. Cureus. 2022; 14: e31080. https://doi.org/10.7759/cureus.31080.

[83] Li Q, Zhong J, Yi D, Deng G, Liu Z, Wang W. Assessing the risk of rapid fibroid growth in patients with asymptomatic solitary uterine myoma using a multivariate prediction model. Annals of Translational Medicine. 2021; 9: 370. https://doi.org/10.21037/atm-20-4559.

[84] Makker A, Goel MM, Mahdi AA, Bhatia V, Das V, Agarwal A, et al. PI3K/Akt/mTOR signaling & its regulator tumour suppressor genes PTEN & LKB1 in human uterine leiomyomas. The Indian Journal of Medical Research. 2016; 143: S112-S119. https://doi.org/10.4103/0971-5916.191808.

[85] Kim HJ, Kim SH, Oh YS, Heo SH, Kim KH, Kim DY, et al. Effects of Phthalate Esters on Human Myometrial and Fibroid Cells: Cell Culture and NOD-SCID Mouse Data. Reproductive Sciences. 2021; 28: 479–487. https://doi.org/10.1007/s43032-020-00341-0.

[86] Lapresa-Alcalde MV, Ruiz-Navarro MJ, Sancho de Salas M, Cubo AM. A Review and Follow-Up of Uterine Smooth Muscle Tumours of Uncertain Malignant Potential (STUMP): A Case Series and Literature Review. Diseases. 2023; 11: 99. https://doi.org/10.3390/diseases11030099.

[87] Giri A, Edwards TL, Hartmann KE, Torstenson ES, Wellons M, Schreiner PJ, et al. African genetic ancestry interacts with body mass index to modify risk for uterine fibroids. PLoS Genetics. 2017; 13: e1006871. https://doi.org/10.1371/journal.pgen.1006871.

[88] Swain D, Yadav C, Kumari J, Rani M, Rongmei PD, Khurana SK. Predictors and symptomatic burden of uterine fibroids among women in South-Eastern India: a cross-sectional survey analysis. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2019; 8: 524–530. https://doi.org/10.18203/2320-1770.ijrcog20190278.

[89] Shen Y, Xu Q, Ren M, Feng X, Cai Y, Gao Y. Measurement of phenolic environmental estrogens in women with uterine leiomyoma. PloS One. 2013; 8: e79838. https://doi.org/10.1371/journal.pone.0079838.

[90] Mariama D, Daouda C, Keneme B, Alfousseyni G, Mbacke S. Implication of the Cytochrome P-450c17α ( CYP17α ) Gene in the Tumor Progression of Uterine Fibroids in Senegalese Women. International Journal of Genetics and Genomics. 2021; 9: 67–77. https://doi.org/10.11648/j.ijgg.20210904.12.

[91] Pandey S, Singh H. Pharmacological Activity and Effectiveness of Electrohomoeopathy Medicine on Uterine Fibroids Individuals. International Journal of Innovative Research in Medical Science. 2021; 6: 649–655. https://doi.org/10.23958/ijirms/vol06-i10/1239.

[92] Urkendovna AS, Aruzhan A, Karina S. Uterine Fibroids: Retrospective Study with Analysis of Different Risk Factors. International Journal of Women’s Health and Wellness. 2023; 9: 152. http://doi.org/10.23937/2474-1353/1510152.

[93] Wise LA, Palmer JR, Harlow BL, Spiegelman D, Stewart EA, Adams-Campbell LL, et al. Risk of uterine leiomyomata in relation to tobacco, alcohol and caffeine consumption in the Black Women’s Health Study. Human Reproduction (Oxford, England). 2004; 19: 1746–1754. https://doi.org/10.1093/humrep/deh309.

[94] Katz TA, Yang Q, Treviño LS, Walker CL, Al-Hendy A. Endocrine-disrupting chemicals and uterine fibroids. Fertility and Sterility. 2016; 106: 967–977. https://doi.org/10.1016/j.fertnstert.2016.08.023.

[95] Chiaffarino F, Cipriani S, Ricci E, La Vecchia C, Chiantera V, Bulfoni A, et al. Alcohol consumption and risk of uterine myoma: A systematic review and meta analysis. PLoS One. 2017; 12: e0188355. https://doi.org/10.1371/journal.pone.0188355.

[96] Templeman C, Marshall SF, Clarke CA, DeLellis Henderson K, Largent J, Neuhausen S, et al. Risk factors for surgically removed fibroids in a large cohort of teachers. Fertility and Sterility. 2009; 92: 1436–1446. https://doi.org/10.1016/j.fertnstert.2008.08.074.

[97] Uimari O, Järvelä I, Ryynänen M. Do symptomatic endometriosis and uterine fibroids appear together? Journal of Human Reproductive Sciences. 2011; 4: 34–38. https://doi.org/10.4103/0974-1208.82358.

[98] Zhang L, Lai H, Lin Q. Analysis of risk factors and construction and validation of a predictive model for determining the risk of endometrial cancer in postmenopausal patients with abnormal uterine bleeding. European Journal of Gynaecological Oncology. 2023; 44: 39–45. http://doi.org/10.22514/ejgo.2023.077.

[99] Sommer EM, Balkwill A, Reeves G, Green J, Beral DV, Coffey K, et al. Effects of obesity and hormone therapy on surgically-confirmed fibroids in postmenopausal women. European Journal of Epidemiology. 2015; 30: 493–499. https://doi.org/10.1007/s10654-015-0016-7.

[100] Gong L, Liu M, Shi H, Huang Y. Uterine fibroids are associated with increased risk of pre-eclampsia: A case-control study. Frontiers in Cardiovascular Medicine. 2022; 9: 1011311. https://doi.org/10.3389/fcvm.2022.1011311.

[101] Orciani M, Caffarini M, Biagini A, Lucarini G, Delli Carpini G, Berretta A, et al. Chronic Inflammation May Enhance Leiomyoma Development by the Involvement of Progenitor Cells. Stem Cells International. 2018; 2018: 1716246. https://doi.org/10.1155/2018/1716246.

[102] Sun K, Xie Y, Zhao N, Li Z. A case-control study of the relationship between visceral fat and development of uterine fibroids. Experimental and Therapeutic Medicine. 2019; 18: 404–410. https://doi.org/10.3892/etm.2019.7575.

[103] Nieman LK, Blocker W, Nansel T, Mahoney S, Reynolds J, Blithe D, et al. Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study. Fertility and Sterility. 2011; 95: 767–772.e2. https://doi.org/10.1016/j.fertnstert.2010.09.059.

[104] AlAshqar A, Lulseged B, Mason-Otey A, Liang J, Begum UAM, Afrin S, et al. Oxidative Stress and Antioxidants in Uterine Fibroids: Pathophysiology and Clinical Implications. Antioxidants (Basel, Switzerland). 2023; 12: 807. https://doi.org/10.3390/antiox12040807.

[105] Chen J, Chen W, Zhang L, Li K, Peng S, He M, et al. Safety of ultrasound-guided ultrasound ablation for uterine fibroids and adenomyosis: A review of 9988 cases. Ultrasonics Sonochemistry. 2015; 27: 671–676. https://doi.org/10.1016/j.ultsonch.2015.05.031.

[106] Mascaretti S, Ferrari F, Miccoli A, Arrigoni F, Fascetti E, Barile A, et al. Feasibility of Magnetic Resonance-Guided Focus Ultrasound Surgery (MRgFUS) in the Uterine Fibroid Treatment: Evaluation of the Treatment Radicalization in Single and Multiple Fibroids Correlated to Clinical Outcome. Clinical and Experimental Obstetrics & Gynecology. 2018; 45: 84–87. https://doi.org/10.12891/ceog3828.2018.

[107] Horne AW, Critchley HOD. The effect of uterine fibroids on embryo implantation. Seminars in Reproductive Medicine. 2007; 25: 483–489. https://doi.org/10.1055/s-2007-991046.

[108] Narula S, Harris A, Tsaltas J. A Review of the Molecular Basis for Reduced Endometrial Receptivity in Uterine Fibroids and Polyps. Journal of Endometriosis and Pelvic Pain Disorders. 2017; 9: 239–244. https://doi.org/10.5301/jeppd.5000304.

[109] Levens ED, Stegmann BJ, Feinberg EC, Larsen FW. Ultrasonographic characteristics of the endometrium among patients with fibroids undergoing ART. Fertility and Sterility. 2008; 89: 1005–1007. https://doi.org/10.1016/j.fertnstert.2007.03.096.

[110] Mailli L, Auyoung EY, Angileri SA, Ameli-Renani S, Ratnam L, Das R, et al. Predicting the Fibroid-Migratory Impact of UAE: Role of Pre-embolization MRI Characteristics. Cardiovascular and Interventional Radiology. 2020; 43: 453–458. https://doi.org/10.1007/s00270-019-02348-w.

[111] Guven S, Kart C, Unsal MA, Odaci E. Intramural leoimyoma without endometrial cavity distortion may negatively affect the ICSI - ET outcome. Reproductive Biology and Endocrinology: RB&E. 2013; 11: 102. https://doi.org/10.1186/1477-7827-11-102.

[112] Doherty L, Mutlu L, Sinclair D, Taylor H. Uterine fibroids: clinical manifestations and contemporary management. Reproductive Sciences. 2014; 21: 1067–1092. https://doi.org/10.1177/1933719114533728.

[113] Don EE, Mijatovic V, Huirne JAF. Infertility in patients with uterine fibroids: a debate about the hypothetical mechanisms. Human Reproduction. 2023; 38: 2045–2054. https://doi.org/10.1093/humrep/dead194.

[114] Fortuny J, Sima C, Bayuga S, Wilcox H, Pulick K, Faulkner S, et al. Risk of endometrial cancer in relation to medical conditions and medication use. Cancer Epidemiology, Biomarkers & Prevention: a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2009; 18: 1448–1456. https://doi.org/10.1158/1055-9965.EPI-08-0936.

[115] Rajani PW, Rajaratnam A. Histopathological Evaluation of Endometrium in Perimenopausal Women With Fibroids. Journal of Safoms. 2018; 6: 88–90. http://doi.org/10.5005/jp-journals-10032-1146.

[116] Edwards TL, Giri A, Hellwege JN, Hartmann KE, Stewart EA, Jeff JM, et al. A Trans-Ethnic Genome-Wide Association Study of Uterine Fibroids. Frontiers in Genetics. 2019; 10: 511. https://doi.org/10.3389/fgene.2019.00511.

[117] Tai AS, Lin RT, Lin YC, Wang CH, Lin SH, Imoto S. Genome-wide causal mediation analysis identifies genetic loci associated with uterine fibroids mediated by age at menarche. Human Reproduction. 2022; 37: 2197–2212. https://doi.org/10.1093/humrep/deac136.

[118] Johnstone EB, Louis GMB, Parsons PJ, Steuerwald AJ, Palmer CD, Chen Z, et al. Increased urinary cobalt and whole blood concentrations of cadmium and lead in women with uterine leiomyomata: Findings from the ENDO Study. Reproductive Toxicology. 2014; 49: 27–32. https://doi.org/10.1016/j.reprotox.2014.06.007.

[119] Kun EH, Tsang YT, Lin S, Pan S, Medapalli T, Malpica A, et al. Differences in gynecologic tumor development in Amhr2-Cre mice with KRAS G12D or KRAS G12V mutations. Scientific Reports. 2020; 10: 20678. https://doi.org/10.1038/s41598-020-77666-y.

[120] Beyan E, Kanmaz AG, İnan AH, Karataşlı V, Tutar SO, Alan M, et al. Evaluation of occult uterine leiomyosarcomas. Ginekologia Polska. 2019; 90: 433–437. https://doi.org/10.5603/GP.2019.0075.

[121] Practice Committee of American Society for Reproductive Medicine in collaboration with Society of Reproductive Surgeons. Myomas and reproductive function. Fertility and Sterility. 2008; 90: S125–S130. https://doi.org/10.1016/j.fertnstert.2008.09.012.

[122] Padilla O, Arya S, Noble LS, Plavsic SK. Saline infusion sonography: tips and tricks for improved visualization of the uterine cavity. Donald School Journal of Ultrasound in Obstetrics & Gynecology. 2018; 12: 32–51. http://doi.org/10.5005/jp-journals-10009-1550.

[123] MacKenzie D, Jr, Watters AK, To JT, Young MW, Muratori J, Wilkoff MH, et al. ALT Positivity in Human Cancers: Prevalence and Clinical Insights. Cancers. 2021; 13: 2384. https://doi.org/10.3390/cancers13102384.

[124] Smith J, Zawaideh JP, Sahin H, Freeman S, Bolton H, Addley HC. Differentiating uterine sarcoma from leiomyoma: BET1T2ER Check! The British Journal of Radiology. 2021; 94: 20201332. https://doi.org/10.1259/bjr.20201332.

[125] Harry VN, Narayansingh GV, Parkin DE. Uterine Leiomyosarcomas: A Review of the Diagnostic and Therapeutic Pitfalls. The Obstetrician & Gynaecologist. 2007; 9: 88–94. https://doi.org/10.1576/toag.9.2.088.27309.

[126] Naeem M, Murrium SK, Qayyum S, Abidin MZU, Khan WS. Diagnostic Accuracy of Ultrasound in Differentiation Uterine Leiomyosarcoma From Uterine Leiomyoma: A Systematic Review. Pakistan Journal of Medical & Health Sciences. 2021; 15: 2836–2839. https://doi.org/10.53350/pjmhs2115112836.

[127] Aden D, Zaheer S, Singh S, Ranga S. Epithelioid Leiomyosarcoma of the Uterus and the Diagnostic Challenge in Diagnosing it on Small Biopsy. Journal of Mid-life Health. 2022; 13: 241–243. https://doi.org/10.4103/jmh.jmh_36_22.

[128] Huang J, Chen Y, Li Z, Chen M, Huang D, Zhu P, et al. A bibliometric analysis of literatures on uterine leiomyosarcoma in the last 20 years. Frontiers in Oncology. 2024; 14: 1343533. https://doi.org/10.3389/fonc.2024.1343533.

[129] Valery JR, Tan W, Cortese C. Renal leiomyosarcoma: a diagnostic challenge. Case Reports in Oncological Medicine. 2013; 2013: 459282. https://doi.org/10.1155/2013/459282.

[130] Cuppens T, Annibali D, Coosemans A, Trovik J, Ter Haar N, Colas E, et al. Potential Targets’ Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas-an ENITEC Group Initiative. Clinical Cancer Research: an Official Journal of the American Association for Cancer Research. 2017; 23: 1274–1285. https://doi.org/10.1158/1078-0432.CCR-16-2149.

[131] Odejinmi F, Agarwal N, Maclaran K, Oliver R. Should we abandon all conservative treatments for uterine fibroids? The problem with leiomyosarcomas. Women’s Health. 2015; 11: 151–159. https://doi.org/10.2217/whe.14.71.

[132] Stoelinga B, Juffermans L, Dooper A, de Lange M, Hehenkamp W, Van den Bosch T, et al. Contrast-Enhanced Ultrasound Imaging of Uterine Disorders: A Systematic Review. Ultrasonic Imaging. 2021; 43: 239–252. https://doi.org/10.1177/01617346211017462.

[133] Liegl-Atzwanger B, Heitzer E, Flicker K, Müller S, Ulz P, Saglam O, et al. Exploring chromosomal abnormalities and genetic changes in uterine smooth muscle tumors. Modern Pathology: an Official Journal of the United States and Canadian Academy of Pathology, Inc. 2016; 29: 1262–1277. https://doi.org/10.1038/modpathol.2016.107.

[134] Wallace K, Chatman K, Porter J, Scott J, Johnson V, Moseley J, et al. Enodthelin 1 is elevated in plasma and explants from patients having uterine leiomyomas. Reproductive Sciences. 2014; 21: 1196–1205. https://doi.org/10.1177/1933719114542018.

[135] Laughlin-Tommaso SK, Fuchs EL, Wellons MF, Lewis CE, Calderon-Margalit R, Stewart EA, et al. Uterine Fibroids and the Risk of Cardiovascular Disease in the Coronary Artery Risk Development in Young Adult Women’s Study. Journal of Women’s Health. 2019; 28: 46–52. https://doi.org/10.1089/jwh.2018.7122.

[136] Li H, Hu Z, Fan Y, Hao Y. The influence of uterine fibroids on adverse outcomes in pregnant women: a meta-analysis. BMC Pregnancy and Childbirth. 2024; 24: 345. https://doi.org/10.1186/s12884-024-06545-5.

[137] Kınay T, Öztürk Başarır Z, Fırtına Tuncer S, Akpınar F, Kayıkçıoğlu F, Koç S. Prevalence of endometrial polyps coexisting with uterine fibroids and associated factors. Turkish Journal of Obstetrics and Gynecology. 2016; 13: 31–36. https://doi.org/10.4274/tjod.36043.

[138] Robinson-Bennett BL, Deford J, Diaz-Arrastia C, Levine L, Wang HQ, Hannigan EV, et al. Implications of tyrosine phosphoproteomics in cervical carcinogenesis. Journal of Carcinogenesis. 2008; 7: 2. https://doi.org/10.1186/1477-3163-7-2.

[139] Yang XM, Wu ZM, Huang H, Chu XY, Lou J, Xu LX, et al. Estrogen receptor 1 mutations in 260 cervical cancer samples from Chinese patients. Oncology Letters. 2019; 18: 2771–2776. https://doi.org/10.3892/ol.2019.10612.

[140] Wu Y, Huang W, Xie Y, Wang C, Luo N, Chen Y, et al. Siglec-9, a Putative Immune Checkpoint Marker for Cancer Progression Across Multiple Cancer Types. Frontiers in Molecular Biosciences. 2022; 9: 743515. https://doi.org/10.3389/fmolb.2022.743515.

[141] Leung SS, Leung I. Cervical cancer screening: knowledge, health perception and attendance rate among Hong Kong Chinese women. International Journal of Women’s Health. 2010; 2: 221–228. https://doi.org/10.2147/ijwh.s10724.

[142] Yuk JS, Kim JM. Uterine fibroids increase the risk of thyroid goiter and thyroid nodules. Scientific Reports. 2022; 12: 6620. https://doi.org/10.1038/s41598-022-10625-x.

[143] Hellwege JN, Jeff JM, Wise LA, Gallagher CS, Wellons M, Hartmann KE, et al. A multi-stage genome-wide association study of uterine fibroids in African Americans. Human Genetics. 2017; 136: 1363–1373. https://doi.org/10.1007/s00439-017-1836-1.

[144] Guenego A, Mesrine S, Dartois L, Leenhardt L, Clavel-Chapelon F, Kvaskoff M, et al. Relation between hysterectomy, oophorectomy and the risk of incident differentiated thyroid cancer: The E3N cohort. Clinical Endocrinology. 2019; 90: 360–368. https://doi.org/10.1111/cen.13899.

[145] Li S, Li W, Sheng B, Zhu X. Relationship between thyroid disorders and uterine fibroids among reproductive-age women. Endocrine Journal. 2021; 68: 211–219. https://doi.org/10.1507/endocrj.EJ20-0340.

[146] Braganza MZ, Berrington de González A, Schonfeld SJ, Wentzensen N, Brenner AV, Kitahara CM. Benign breast and gynecologic conditions, reproductive and hormonal factors, and risk of thyroid cancer. Cancer Prevention Research. 2014; 7: 418–425. https://doi.org/10.1158/1940-6207.CAPR-13-0367.

[147] Chuang SC, Wu GJ, Lu YS, Lin CH, Hsiung CA. Associations between Medical Conditions and Breast Cancer Risk in Asians: A Nationwide Population-Based Study in Taiwan. PloS One. 2015; 10: e0143410. https://doi.org/10.1371/journal.pone.0143410.

[148] Tseng JJ, Chen YH, Chiang HY, Lin CH. Increased risk of breast cancer in women with uterine myoma: a nationwide, population-based, case-control study. Journal of Gynecologic Oncology. 2017; 28: e35. https://doi.org/10.3802/jgo.2017.28.e35.

[149] Shen TC, Hsia TC, Hsiao CL, Lin CL, Yang CY, Soh KS, et al. Patients with uterine leiomyoma exhibit a high incidence but low mortality rate for breast cancer. Oncotarget. 2017; 8: 33014–33023. https://doi.org/10.18632/oncotarget.16520.

[150] Wise LA, Radin RG, Rosenberg L, Adams-Campbell L, Palmer JR. History of uterine leiomyomata and incidence of breast cancer. Cancer Causes & Control: CCC. 2015; 26: 1487–1493. https://doi.org/10.1007/s10552-015-0647-8.

[151] Ye S, Chung HW, Jeong K, Sung YA, Lee H, Park SY, et al. Blood cadmium and volume of uterine fibroids in premenopausal women. Annals of Occupational and Environmental Medicine. 2017; 29: 22. https://doi.org/10.1186/s40557-017-0178-8.

[152] Glubb DM, Thompson DJ, Aben KKH, Alsulimani A, Amant F, Annibali D, et al. Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers. Cancer Epidemiology, Biomarkers & Prevention: a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2021; 30: 217–228. https://doi.org/10.1158/1055-9965.EPI-20-0739.

[153] Wu BJ, Wei W, Hu CY, Zhang XJ, Zhong F. Investigation on factors related to uterine fibroids in rural women of northern Anhui province. The Journal of Obstetrics and Gynaecology Research. 2021; 47: 3279–3287. https://doi.org/10.1111/jog.14899.

[154] Chandran SS, Samal S. Antepartum myomectomy: a possible procedure for successful outcome. International Journal of Reproduction, Contraception, Obstetrics and Gynecology. 2017; 3: 818–819. https://doi.org/10.5455/2320-1770.ijrcog20140947.

[155] Khanduri S, Pathak V, Surbhi, Gupta A, Goswami S, Dwari K, et al. Reliable Diagnosis of Adenomyosis and Uterine Fibroids Using Transvaginal Ultrasonography With Strain Elastography. International Journal of Radiology and Diagnostic Imaging. 2023; 6: 17–21. https://doi.org/10.33545/26644436.2023.v6.i3a.338.

[156] Kubik-Huch RA, Weston M, Nougaret S, Leonhardt H, Thomassin-Naggara I, Horta M, et al. European Society of Urogenital Radiology (ESUR) Guidelines: MR Imaging of Leiomyomas. European Radiology. 2018; 28: 3125–3137. https://doi.org/10.1007/s00330-017-5157-5.

[157] Khan AT, Shehmar M, Gupta J. Uterine Fibroids: Current Perspectives. International Journal of Women S Health. 2014; 6: 95–114. https://doi.org/10.2147/IJWH.S51083.

[158] Singh P, Gupta M. A Case Series of Fibroids With Atypical Clinical Presentation: A Diagnostic Dilemma. Journal of South Asian Federation of Obstetrics and Gynaecology. 2020; 12: 184–187. https://doi.org/10.5005/jp-journals-10006-1772.

[159] Duc NM, Keserci B. Review of influential clinical factors in reducing the risk of unsuccessful MRI-guided HIFU treatment outcome of uterine fibroids. Diagnostic and Interventional Radiology. 2018; 24: 283–291. https://doi.org/10.5152/dir.2018.18111.

[160] Koul A, Shetty A, Gaffoor N, Murali N, Prasad N. A Tale of 5Ms: Massive Uterine Leiomyoma Mimicking Ovarian Malignancy along with Multiple Fibroids Displaying Multiple Degenerations. Sudan Journal of Medical Sciences. 2023; 18: 104–110. https://doi.org/10.18502/sjms.v18i1.12870.

[161] Nguyen PN, Nguyen VT. Additional value of Doppler ultrasound to B-mode ultrasound in assessing for uterine intracavitary pathologies among perimenopausal and postmenopausal bleeding women: a multicentre prospective observational study in Vietnam. Journal of Ultrasound. 2023; 26: 459–469. https://doi.org/10.1007/s40477-022-00732-w.

[162] Ayakannu T, Taylor AH, Marczylo TH, Konje JC. New Insights of Uterine Leiomyoma Pathogenesis: Endocannabinoid System. Medical Science Monitor Basic Research. 2019; 25: 76–87. https://doi.org/10.12659/MSMBR.914019.

[163] Khamaiseh S, Koivisto-Korander R, Ahvenainen T, Bützow R, Mehine M, Vahteristo P. Abstract 996: Identification of Molecular Biomarkers Differentiating Malignant Uterine Leiomyosarcoma From Benign Leiomyoma. Cancer Research. 2023; 83: 996. https://doi.org/10.1158/1538-7445.AM2023-996.

[164] Zhang Q, Ubago J, Li L, Guo H, Liu Y, Qiang W, et al. Molecular analyses of 6 different types of uterine smooth muscle tumors: Emphasis in atypical leiomyoma. Cancer. 2014; 120: 3165–3177. https://doi.org/10.1002/cncr.28900.

[165] Yang L, Navuluri R. Uterine Fibroids and Adenomyosis: Imaging and Treatment. Contemporary Diagnostic Radiology. 2021; 44: 1–7.

[166] Pérot G, Croce S, Ribeiro A, Lagarde P, Velasco V, Neuville A, et al. MED12 alterations in both human benign and malignant uterine soft tissue tumors. PloS One. 2012; 7: e40015. https://doi.org/10.1371/journal.pone.0040015.

[167] Guo J, Zheng J, Tong J. Potential Markers to Differentiate Uterine Leiomyosarcomas from Leiomyomas. International Journal of Medical Sciences. 2024; 21: 1227–1240. https://doi.org/10.7150/ijms.93464.

[168] Fujisawa C, Castellot JJ, Jr. Matrix production and remodeling as therapeutic targets for uterine leiomyoma. Journal of Cell Communication and Signaling. 2014; 8: 179–194. https://doi.org/10.1007/s12079-014-0234-x.

[169] Rana H, Aithmia R, Pangotra M. Expanded Study on Patterns of Myometrial Lesions in Hysterectomy Specimens: A Retrospective Study of 520 Specimens. International Journal of Research and Review. 2023; 10: 685–690. https://doi.org/10.52403/ijrr.20230889.

[170] Mäkinen N, Vahteristo P, Kämpjärvi K, Arola J, Bützow R, Aaltonen LA. MED12 exon 2 mutations in histopathological uterine leiomyoma variants. European Journal of Human Genetics: EJHG. 2013; 21: 1300–1303. https://doi.org/10.1038/ejhg.2013.33.

[171] Garg P, Bansal R. Neglected case of a huge leiomyoma in an elderly postmenopausal woman: a case report. Journal of Medical Case Reports. 2022; 16: 485. https://doi.org/10.1186/s13256-022-03705-z.

[172] Priyadharshinee G, Sahu TK, Chavadi C. Giant Fibroid Mimicking a Gastrointestinal Stromal Tumor: A Diagnostic Dilemma. Cureus. 2023; 15: e35883. https://doi.org/10.7759/cureus.35883.

[173] Gaur N, Jha MK. Degenerated Fibroid: A Diagnostic Dilemma. International Journal of Reproduction Contraception Obstetrics and Gynecology. 2020; 9: 1766–1768. http://dx.doi.org/10.18203/2320-1770.ijrcog20201265.

[174] Kispotta D, Khess L, Kumari S, Bhagat N. A Rare Case of Retroperitoneal Leiomyoma – A Histopathological Case Report. Pijr. 2021; 10: 9–10.

[175] Knox B, Dobrotwir A, Ades A. Isolated uterine metastasis from a lung adenocarcinoma. BMJ Case Reports. 2019; 12: e232487. https://doi.org/10.1136/bcr-2019-232487.

[176] Igboeli P, Walker W, McHugh A, Sultan A, Al-Hendy A. Burden of Uterine Fibroids: An African Perspective, A Call for Action and Opportunity for Intervention. Current Opinion in Gynecology and Obstetrics. 2019; 2: 287–294. https://doi.org/10.18314/cogo.v2i1.1701.

[177] Mitro SD, Wise LA, Waetjen LE, Lee C, Zaritsky E, Harlow SD, et al. Hypertension, Cardiovascular Risk Factors, and Uterine Fibroid Diagnosis in Midlife. JAMA Network Open. 2024; 7: e246832. https://doi.org/10.1001/jamanetworkopen.2024.6832.

[178] Sohn GS, Cho S, Kim YM, Cho CH, Kim MR, Lee SR, et al. Current medical treatment of uterine fibroids. Obstetrics & Gynecology Science. 2018; 61: 192–201. https://doi.org/10.5468/ogs.2018.61.2.192.

[179] Langton CR, Harmon QE, Baird DD. Family History and Uterine Fibroid Development in Black and African American Women. JAMA Network Open. 2024; 7: e244185. https://doi.org/10.1001/jamanetworkopen.2024.4185.

[180] Evans J. The impact of health literacy on uterine fibroid awareness, diagnosis, and treatment in the United States: a mini literature review. Frontiers in Reproductive Health. 2024; 6: 1335412. https://doi.org/10.3389/frph.2024.1335412.

[181] Stentzel U, Grabe HJ, Schmidt S, Tomczyk S, van den Berg N, Beyer A. Mental health-related telemedicine interventions for pregnant women and new mothers: a systematic literature review. BMC Psychiatry. 2023; 23: 292. https://doi.org/10.1186/s12888-023-04790-0.

[182] Riggan KA, Stewart EA, Balls-Berry JE, Venable S, Allyse MA. Patient Recommendations for Shared Decision-Making in Uterine Fibroid Treatment Decisions. Journal of Patient Experience. 2021; 8: 23743735211049655. https://doi.org/10.1177/23743735211049655.

[183] Zarshenas M, Sorkhenezhad M, Akbarzadeh M. Comparison of Quality and Lifestyle in Women with and Without Uterine Leiomyoma Referred to Gynecology Clinics of Shiraz University of Medical Sciences in 2018. Shiraz E-Medical Journal. 2020; 22: e100815. https://doi.org/10.5812/semj.100815.

[184] Yang Q, Nair S, Laknaur A, Ismail N, Diamond MP, Al-Hendy A. The Polycomb Group Protein EZH2 Impairs DNA Damage Repair Gene Expression in Human Uterine Fibroids. Biology of Reproduction. 2016; 94: 69. https://doi.org/10.1095/biolreprod.115.134924.

[185] Williams VSL, Jones G, Mauskopf J, Spalding J, DuChane J. Uterine fibroids: a review of health-related quality of life assessment. Journal of Women’s Health. 2006; 15: 818–829. https://doi.org/10.1089/jwh.2006.15.818.

[186] McWilliams MM, Chennathukuzhi VM. Recent Advances in Uterine Fibroid Etiology. Seminars in Reproductive Medicine. 2017; 35: 181–189. https://doi.org/10.1055/s-0037-1599090.

[187] Korczynska L, Zeber-Lubecka N, Zgliczynska M, Zarychta E, Zareba K, Wojtyla C, et al. The role of microbiota in the pathophysiology of uterine fibroids - a systematic review. Frontiers in Cellular and Infection Microbiology. 2023; 13: 1177366. https://doi.org/10.3389/fcimb.2023.1177366.

[188] Urkendovna AS, Aruzhan A, Karina S. Uterine Fibroids: Retrospective Study with Analysis of Different Risk Factors. International Journal of Women’s Health and Wellness. 2023; 9: 152. https://doi.org/10.23937/2474-1353/1510152.

[189] Krzyżanowski J, Paszkowski T, Woźniak S. The Role of Nutrition in Pathogenesis of Uterine Fibroids. Nutrients. 2023; 15: 4984. https://doi.org/10.3390/nu15234984.

[190] Markowska A, Kurzawa P, Bednarek W, Gryboś A, Mardas M, Krzyżaniak M, et al. Immunohistochemical Expression of Vitamin D Receptor in Uterine Fibroids. Nutrients. 2022; 14: 3371. https://doi.org/10.3390/nu14163371.

[191] Singh SS, Belland L, Leyland N, von Riedemann S, Murji A. The past, present, and future of selective progesterone receptor modulators in the management of uterine fibroids. American Journal of Obstetrics and Gynecology. 2018; 218: 563–572.e1. https://doi.org/10.1016/j.ajog.2017.12.206.

[192] Garza-Leal J, León IH, Toub D. Pregnancy After Transcervical Radiofrequency Ablation Guided by Intrauterine Sonography: Case Report. Gynecological Surgery. 2014; 11: 145–149. https://doi.org/10.1007/s10397-013-0830-4.

[193] Patel N, Chaudhari K, Patel D, Joshi J. High-Intensity Focused Ultrasound Ablation of Uterine Fibroids: A Review. Cureus. 2023; 15: e44680. https://doi.org/10.7759/cureus.44680.