literature review on uterine fibroid treatment

• Search Menu
• Sign in through your institution
• Advance Articles
• Thematic Issues
• ENDO Meeting Abstracts
• Clinical Practice Guidelines
• Endocrine Reviews
• Endocrinology
• Journal of the Endocrine Society
• The Journal of Clinical Endocrinology & Metabolism
• JCEM Case Reports
• Molecular Endocrinology (Archives)
• Endocrine Society Journals
• Author Guidelines
• Submission Site
• Open Access
• Why Publish with the Endocrine Society?
• Notice about Predatory Publishing
• Advertising & Corporate Services
• Reprints, ePrints, Supplements
• About Endocrine Reviews
• Editorial Board
• Author Resources
• Reviewer Resources
• Rights & Permissions
• Member Access
• Terms and Conditions
• Journals on Oxford Academic
• Books on Oxford Academic

Article Contents

Epidemiology, risk/protective factors, driver mutations, and tumor-initiating stem cells, environmental exposure and pathogenesis of uterine fibroids, key pathways contributing to uterine fibroids formation, malignant transformation of uterine fibroids, future perspectives, acknowledgments, additional information, data availability.

• < Previous

Comprehensive Review of Uterine Fibroids: Developmental Origin, Pathogenesis, and Treatment

• Article contents
• Figures & tables
• Supplementary Data

Qiwei Yang, Michal Ciebiera, Maria Victoria Bariani, Mohamed Ali, Hoda Elkafas, Thomas G Boyer, Ayman Al-Hendy, Comprehensive Review of Uterine Fibroids: Developmental Origin, Pathogenesis, and Treatment, Endocrine Reviews , Volume 43, Issue 4, August 2022, Pages 678–719, https://doi.org/10.1210/endrev/bnab039

• Permissions Icon Permissions

Uterine fibroids are benign monoclonal neoplasms of the myometrium, representing the most common tumors in women worldwide. To date, no long-term or noninvasive treatment option exists for hormone-dependent uterine fibroids, due to the limited knowledge about the molecular mechanisms underlying the initiation and development of uterine fibroids. This paper comprehensively summarizes the recent research advances on uterine fibroids, focusing on risk factors, development origin, pathogenetic mechanisms, and treatment options. Additionally, we describe the current treatment interventions for uterine fibroids. Finally, future perspectives on uterine fibroids studies are summarized. Deeper mechanistic insights into tumor etiology and the complexity of uterine fibroids can contribute to the progress of newer targeted therapies.

Developmental exposure to EDCs in early life reprograms myometrial stem cells, thus increasing the risk of uterine fibroids development.

Several risk factors such as age, race, obesity, parity, hypertension, vitamin D deficiency, and diet in late life can trigger uterine fibroids pathogenesis.

Pathogenic exon 2 mutations in MED12 promote uterine fibroids formation and disrupt CDK8/19 kinase activity.

Several vital pathways and mechanisms such as sex hormones, ECM, Wnt/β-catenin, TGF-β, growth factors, epigenetic and epitranscriptomic regulation, YAP/TAZ, Rho/ROCK, and DNA damage repair pathways contribute to the development of uterine fibroids.

Fertility therapy is highly needed for the treatment of patients with uterine fibroids.

Uterine fibroid lesions were initially known as the “uterine stone.” In the second century AD, they were called scleromas. The term fibroid was first introduced in the 1860s. Uterine fibroids are the most common pelvic tumors among women of reproductive age, affecting more than 70% of women worldwide, particularly women of color ( 1-3 ). Uterine fibroids are heterogeneous in composition and size among women and within the same individual, and vary in number between individuals ( 4-14 ). In addition, the fibroid pseudocapsule presents as a fibro-neurovascular structure surrounding a uterine fibroid, separating it from normal peripheral myometrium ( 15-18 ). Although benign, uterine fibroids are associated with significant morbidity; they are the primary indication for hysterectomy, and a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor ( 19 , 20 ). Accordingly, the annual USA health care costs associated with uterine fibroids have been estimated at ~$34 billion ( 21 ). Uterine fibroids thus represent significant societal health and financial burden.

Risk Factors and Epidemiology

The prevalence of uterine fibroids is increasing in some populations, such as in African American women ( 22 ). However, its reported incidence is likely to be an underestimation, as many tumors are asymptomatic or slightly symptomatic and therefore remain undiagnosed ( 1 ). In addition, approximately only 25% to 30% of women report the clinical symptoms of uterine fibroids ( 5 ).

The most important and frequently reported risk factor for uterine fibroids is race, disproportionately impacting African American women ( Figs. 1 and 2 ). Other risk factors include older age, premenopausal state, nonparity, family history of uterine fibroids, hypertension, food additives, and frequent consumption of soybean milk. On the other hand, protective factors for uterine fibroids include combined oral contraception or injectable medroxyprogesterone acetate in the depot form, smoking in women of low mass, and parity ( 1 ). Other important risk factors include obesity ( 23-25 ), vitamin D deficiency ( 26-28 ), excessive vitamin E levels ( 29 ), altered reproductive tract microbiome ( 30 ), exposure to endocrine-disrupting chemicals (eg, organophosphate esters and plasticizers) ( 31 , 32 ), and various early-life adverse environmental exposures ( 33 ). Individual and environmental risk factors associated with tobacco smoking and alcohol abuse can also contribute to the formation of uterine fibroids ( 34 , 35 ). More risk factors are associated with a higher probability of uterine fibroid formation and development ( 1 , 23 ).

Developmental origin of fibroids from myometrial stem cells. Intrauterine and early-life adverse environmental exposure to endocrine-disrupting chemicals may act as the early hit to induce normal myometrial stem cells’ reprogramming by hijacking epigenomic plasticity. The plasticity of the developing epigenome is susceptible to epigenomic changes in myometrial stem cells following later-life adverse exposures, thereby leading to mutations and their transformation into tumor-initiating stem cells. The development and growth of fibroids are mainly characterized by abnormal cell proliferation, inhibited apoptosis, DNA instability, excessive deposition of ECM, and other critical biological pathways. Abbreviations: ECM, extracellular matrix; MED12, RNA polymerase II transcriptional mediator complex subunit 12; ncRNAs, non-coding RNA.

Risk factors for uterine fibroids that mainly affect inflammation, DNA damage pathways, and genetic instability. External and internal factors, such as EDC exposure, hyper-responsiveness to sex steroid hormones, obesity, vitamin D deficiency, and altered reproductive tract microbiome, contribute to chronic systemic inflammation. The inflammatory environment, EDC exposure, and vitamin D deficiency promote DNA damage and the accumulation of mutations. Consequently, these genetic events may activate the pathways involved in cell proliferation, the inhibition of apoptosis, and ECM remodeling, ultimately leading to the development and growth of fibroids. Abbreviations: E2, estrogen; EDCs, endocrine-disrupting chemicals; MED12 , RNA polymerase II transcriptional mediator complex subunit 12; P4, progesterone.

These points require some additional comments. Epidemiologists understand that they must study women from the community to eliminate bias and have a prospective study design with a large sample size and low loss to follow-up to enable the measurement of age-specific incidence and other risk factor-related pathogenesis of uterine fibroids ( 36 ). Improvement of awareness and education for uterine fibroids in the community will help to better understand the risk factors of this diseases. Notably, data from uterine fibroid research in underrepresented groups are lacking ( 37 ). On the other hand, epidemiological studies may reflect both the natural and false effects of a selected factor on the investigated outcome. Findings may be subject to different explanations because they may occur due to random errors, biases, or confounding, which may produce false results. These factors need to be considered at both the design and analysis stage of a study to minimize them. Notably, the same instruments for health outcomes evaluation in exposed and unexposed groups should be applied to avoid misclassification or bias. Studies without including confounding variables from the onset or without matching by age, race, and other factors should always be treated with caution ( 38 ).

Increasing age is a significant risk factor for uterine fibroids, especially among women at the premenopausal stage and those ≥ 40 years of age ( 24 , 39 , 40 ). For instance, 60% of African American women aged 35–49 years reported uterine fibroids, whereas 80% of those aged ≥ 50 have uterine fibroids. Among White women, 40% of those aged ≤ 35 years and 70% aged ≥ 50 years developed uterine fibroids ( 3 ). These tumors have not been detected in prepubertal girls, and only sporadic cases have been reported in adolescents. However, the factor(s) involved in their development at such an early age is unknown. Due to the slight difference in biochemical pathways, uterine fibroids in young women do not exhibit typical uterine fibroid biology. In several cases, adolescent patients had a translocation between chromosomes 12 and 14, which is a confirmed risk factor for uterine fibroids ( 41 , 42 ). Women at the menopausal stage have shrunk uterine fibroid lesions and decreased sex hormones. Notably, the use of hormonal replacement therapy may cause these lesions to regrow and may induce the first clinical symptoms of uterine fibroids ( 43 ).

Race and ethnicity

Populations of different races/ethnicities vary in the risk of developing uterine fibroids. The United States Census recognized 5 racial categories (White or European; Black or African American; Asian American; American Indian/Alaska Native; and Native Hawaiian/Pacific Islander) as well as people of 2 or more races ( https://www.census.gov/topics/population/race/about.html . Accessed July, 2021). In addition, the Census Bureau also classified Hispanic or Non-Hispanic as ethnicity. Medical records and self-report were used and demonstrated that Black women, the largest racial minority in the United States, are most likely out of any racial category to develop uterine fibroids ( 3 , 5 , 44-46 ). The severity of uterine fibroid–derived symptoms also tended to be greater among African American women ( 47 ). Uterine fibroids are 3 times more common in African American women and 2 times more common in Hispanic women compared with White women.( 3 , 46 ). The more common occurrence of uterine fibroids in African American women may be attributed to higher concentrations of steroid hormones in African American women and may also be due to gene polymorphism, including the catechol-Ο-methyltransferase (COMT) encoding gene ( 48 ). However, the etiology of the increased incidence of uterine fibroids in African American women has not been fully elucidated. Additionally, the relationship between the higher incidence of uterine fibroids and more severe manifestations of disease may be due to vitamin D deficiency in African American women ( 49 , 50 ). African American women are diagnosed with vitamin D deficiency at a rate of 5 to 10 times more than that of White women. It is thought that the limited absorption of ultraviolet (UV) radiation, which is essential for vitamin D metabolism, may be the reasoning for this discovery ( 50 ).

Furthermore, the African American population experiences higher levels of racial discrimination ( 51 , 52 ) and there are multiple ways by which perceived racism can affect health ( 53 ). A positive association between self-reported experiences of racial discrimination and the incidence of uterine fibroids was demonstrated in a large follow-up study of the cohort of the Black Women’s Health Study ( 54 ). In this sense, Vines et al have found an association with the presence of uterine fibroids among the African American women in the high-stress intensity group ( 55 ).

Discrimination is thought to negatively influence physical wellbeing through the stress response ( 56 , 57 ). The hypothesis that stress led to uterine fibroid pathogenesis could be explained by the fact that disturbance of the hypothalamic–pituitary–adrenal axis and the subsequent release of stress biomarkers such as cortisol and epinephrine ( 58 ) have been linked with increased uterine fibroid risk ( 59 ). In addition, stress also may provoke fluctuations in estrogen and progesterone hormone levels ( 60 , 61 ), both important in uterine fibroid development. Furthermore, it is also biologically plausible that the higher uterine fibroid risk observed in African American women is associated with the systemic inflammation provoked by stress-related factors ( Fig. 2 ) ( 62 ). To date, studies on the role of stress in uterine fibroid development among women of various race/ethnic groups are limited. In this sense, more studies that examine perceived racism as a chronic stressor linked to occurrence of uterine fibroids are needed to fully understand these dependencies.

Obesity is directly related to increased energy consumption and reduced physical activity ( 63 ). Currently, obesity is the fifth leading cause of death ( 64 ). Several studies have found obesity as a significant risk factor for uterine fibroids development ( 23 , 65 ), which has been attributed to the metabolic functions of adipose tissues. Adipose tissues produce and release various cytokines and growth factors involved in regulating diverse physiological and pathological processes, including immunity and inflammation ( 66 ). Adrenal androgens are mostly metabolized by aromatase in adipose tissues to estrogens ( 67-69 ). Obesity and particularly excess visceral fat may be complemented with the reduced production of the sex hormone–binding globulin (SHBG), which binds circulating hormones, disrupting the hormonal activity toward sensitive tissues, and thereby influencing the delicate hormonal balance in the body ( 70 ).

Each kilogram of excessive body weight is correlated with an increased risk of uterine fibroids development ( 71 , 72 ). A study conducted in the United States found that women diagnosed with uterine fibroids are heavier than those without uterine fibroids ( 72 ). Moreover, an increase in the body mass index (BMI) by one unit ( 23 ), higher waist-to-hip ratios, and body fat percentage exceeding 30% ( 73 ) increase the risk for uterine fibroids. Abdominal visceral fat also enhances this risk ( 65 ). A recent meta-analysis of 22 studies, including 325 899 participants, and 19 593 cases, found a positive association between obesity and the risk or prevalence of fibroids ( 74 ).

Obesity is most prevalent among African Americans compared with other racial and ethnic populations in the United States, contributing to the higher risk of developing uterine fibroids in the African American population ( 25 ). Uterine fibroids occur more frequently in obese postmenopausal women and those who have undergone hormonal replacement therapy ( 75 ). Furthermore, obese women diagnosed with type 2 diabetes are more likely to develop uterine fibroids ( 75 ), and this observation has been related to elevated concentrations of insulin-like growth factor (IGF-1) ( 76 ). Insulin resistance plays a role in the development of uterine fibroids in obese women.

Main epidemiological studies demonstrated an inverse association between parity and uterine fibroids, suggestive of a protective effect ( 77 ). Nulliparous women are more commonly affected by uterine fibroids than multiparous women ( 44 ). Each subsequent child may lower the risk of this pathology ( 74 ). These study analyses were based on USA data, which need further investigation related to the difference in race and ethnicity in other countries. Steroid hormone exposure during pregnancy and dramatic remodeling of the uterine tissues after each pregnancy may be attributable to a decrease in uterine fibroid formation ( 77 , 78 ).

Hypertension

There is a direct correlation between arterial hypertension and uterine fibroids ( 44 , 79 , 80 ). Increased diastolic blood pressure is associated with a higher risk of uterine fibroids, regardless of use of antihypertensive drugs ( 79 ). Women suffering from hypertension are 5 times more likely to develop uterine fibroids ( 81 ), and earlier diagnosis of hypertension is a significant factor. The formation of lesions is attributed to the chronic destruction of the myometrium due to increased blood flow and cytokines secreted by injured myometrial cells ( 79 ).

Vitamin D deficiency and diet

Vitamin D is a collective term for fat-soluble steroid compounds with pleiotropic solid influence in the human body ( 82 , 83 , 84 ) Vitamin D is synthesized in the human skin from 7-dehydrocholesterol upon exposure to sunlight. Then, it is transported by the vitamin D-binding protein to the liver and kidneys, where it is converted to 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)D] ( 83 ), respectively, and ultimately carried to the target tissues ( 85 ).

Age, race, health, and even clothing affect the rate at which vitamin D is produced in the skin ( 86 ). Endogenous vitamin D production from sun exposure is influenced by climate, namely, reduced and/or inefficient sunlight absorption may cause vitamin D deficiency ( 86 ). The synthesis of vitamin D decreases with age ( 82 , 86 ). Of note, individuals with darker skin pigmentation and complexion need longer sun exposure to produce adequate amounts of vitamin D ( 87 ). Approximately 80% of African American women have vitamin D deficiency, compared with only 20% of Caucasian women ( 88 ). The higher risk of vitamin D deficiency in African Americans has been attributed to due to darker skin pigmentation and decreased access to solar radiation, resulting in increased risk for uterine fibroids ( 89 ).

Adequate vitamin D can also be ensured through diet or supplementation ( 90 ). The most stable form in circulating blood, 25(OH)D, is used to assess vitamin D levels in individuals ( 91 ). However, different organizations have different classifications for 25(OH)D levels. According to the Endocrine Society, vitamin D deficiency is defined as 25(OH)D serum concentrations ≤20 ng/mL; insufficient , between 21 and 29 ng/mL; and sufficient , ≥30 ng/mL ( 92 ). Meanwhile, the United States Institute of Medicine (IOM) defines the sufficient 25(OH)D serum level as ≥20 ng/mL ( 93 ). ( 94 )

Some experts consider low 25(OH)D serum concentrations as a marker of poor health ( 90 ). Conversely, increased concentrations of vitamin D have been associated with reduced prolonged menstruation cycle ( 95 ), infertility, hyperandrogenism, insulin resistance, and polycystic ovary syndrome (PCOS) ( 96 ). Furthermore, abnormal vitamin D levels tend to change the maternal-fetal vascular system and may cause abnormal pregnancy development, dysregulated metabolism, and disrupted placental function ( 97 ).

The role of vitamin D in the pathogenesis of uterine fibroids has been investigated ( 26 ). Three main studies demonstrated that vitamin D levels are much lower in the sera of uterine fibroid patients, suggesting the vitamin D may be linked to the pathogenesis of uterine fibroids. ( 98-100 ).

Lifestyle factors, such as diet and level of physical activity influence the formation of uterine fibroids. Women consuming more green vegetables, fruit, and fish than red meat are less commonly diagnosed with uterine fibroids ( 27 , 49 , 101 ). Of note, African American women consume lesser amounts of fruits, vegetables, vitamins, and minerals compared with White women ( 102 , 103 ). Diets rich in citrus fruits markedly reduced the risk of uterine fibroids ( 104 ). ( 88 , 105 , 106 ).

Protective Factors

The use of oral and injectable contraceptives can reduce the risk of developing uterine fibroids ( 44 ). Hormonal contraception protected women from developing clinical symptoms of uterine fibroids ( 107 ). However, using oral contraceptives at adolescence may be considered a risk factor for developing symptomatic uterine fibroids later in life, whereas using them after adolescence reduces the risk ( 44 , 108-110 ). Contraceptives increase estrogen and progesterone concentrations in the body, indicating that mechanisms other than hormonal levels are involved in the development of uterine fibroids ( 5 ).

Some substances of plant origin can prevent cell division and formation of fibrosis while modulating hypercritical pathways involved in the development of uterine fibroids ( 111 ). The use of phytochemicals in the prevention and treatment of uterine fibroids has been investigated and showed promising options ( 111-113 ). However, some substances that had been considered potentially helpful have been associated with adverse effects. For example, elevated vitamin E concentration in the serum may be an risk factor for uterine fibroids in Caucasian women. Vitamin E can function as a ligand for estrogen receptors (ERs) due to its structural determinants ( 29 ).

In addition, the consumption of milk and other dairy products may influence the development of uterine fibroids. An increased risk of uterine fibroids was associated with consumption of milk or soybeans ( 114 ). Other prospective cohort studies have yielded controversial results. One study reported no clear association with overall dairy consumption, whereas another study found that yogurt consumption and calcium intake from foods reduced the risk of uterine fibroid development ( 115 ). Moreover, some of the risk factors are described in the environmental exposure section.

Uterine Fibroids Driver Mutations

Within the past decade, the application of rapidly advanced genomic technologies, including high-throughput sequencing methodologies, has led to the identification of recurrent and largely mutually exclusive genetic alterations (so-called drivers ) responsible for the formation of uterine fibroids. Among these, somatic mutations in the Xq13 gene encoding the RNA Polymerase II (Pol II) mediator subunit MED12 are the most prevalent, occurring in 45–90% cases of uterine fibroids depending upon patient ethnicity ( 8 , 116-128 ). A proportionally smaller fraction of uterine fibroids has been attributed to genetic alterations leading to the overexpression of HMGA2 , disruption of the COL4A5-COL4A6 locus, and biallelic loss of FH encoding the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase ( 117 , 129 ) . Additionally, recurrent deletions and rearrangements involving chromosomes 6p21, 7q22, 22q, and 1p have been observed in patients with uterine fibroids. However, these mutations generally co-occur with other genetic alterations, suggesting that they represent secondary driver events restricted to a subpopulation of tumor cells ( 121 , 130-133 ). Altogether, the identification of different fibroids driver mutations has permitted the genetic stratification of these tumors into at least 4 molecular subtypes ( 129 , 134 , 135 ). Interestingly, transcriptome-wide gene expression profiling studies of different uterine fibroid subtypes have revealed that distinct driver mutations are generally characterized by unique gene expression signatures, indicative of distinct pathways to tumorigenesis. This suggests that MED12 mutation–positive and MED12 mutation–negative uterine fibroids are likely unrelated by driver mutations occurring in a common MED12 -dependent pathway ( 129 , 134 ). There are 4 main driver mutations discovered in uterine fibroids.

High-frequency MED12 mutations have been observed in tumors from women of diverse racial and ethnic origins, including those of North American, European, African, Asian, and Middle Eastern descent, thus implicating MED12 as a dominant universal driver of uterine fibroids ( 8 , 118-128 ). Nonetheless, data from a recent meta-analysis indicates that MED12 mutations occur more frequently in women of African as opposed to non-African descent ( 136 ). Regarding uterine fibroid–linked mutations in MED12, are all located within exons 1 or 2, and most are missense mutations with a smaller proportion corresponding to small in-frame deletions and insertions ( 118 , 129 , 137 ). Exon 2 mutations are far more frequent than those in exon 1, with the latter accounting for ~1% to 2% of pathogenic alterations reported in uterine fibroids ( 10 , 129 ). Although missense mutations in exon 2 are distributed throughout the coding sequence, most are clustered in codons 36, 43, and 44, suggesting the importance of their corresponding and evolutionarily highly conserved amino acid residues ( 7 , 8 , 118 , 121 , 128 ). Notably, in addition to uterine fibroids, MED12 exon 2 mutations are also found at similarly high frequency (~80%) in breast fibroepithelial tumors, and to a lesser extent (~5%) of chronic lymphocytic leukemias ( 138-144 ).

In addition to their high frequency occurrence, several additional findings suggest that MED12 mutations are true drivers of fibrotic transformation. First, predominant monoallelic expression of mutant MED12 has been observed almost uniformly in MED12 mutation–positive uterine fibroids, indicating a pathogenic requirement for a functionally altered MED12 allele ( 7 , 129 , 137 ). Second, targeted expression of a MED12 mutant transgene ( c. 131G>A; p.G44D) in the uterine mesenchyme of mice was sufficient to induce uterine fibroid formation, providing direct genetic proof of disease causality ( 145 ).

Combined molecular and clinical analyses have been applied to identify relationships between MED12 mutation status and tumor characteristics as well as patient clinical variables. These analyses have consistently revealed that MED12 mutations are associated with smaller tumor size, conventional tumor histology, and increased tumor number within the uterus ( 7 , 123 , 146-152 ). While most of these studies have been underpowered to detect associations with additional clinical features, a comparatively larger analysis including 750 fibroid tumors from 244 hysterectomy patients confirmed these associations and additionally found MED12 mutations to be positively correlated with subserosal (compared to intramural) location and inversely correlated with parity ( 10 ). No associations were observed between MED12 mutations and patient infertility, smoke consumption, BMI, history of pelvic inflammatory disease and chlamydia, hypertension, thyroid disorder, diabetes, oral contraceptive use, or family history of uterine fibroids ( 10 ). The observation that MED12 mutation–positive uterine fibroids are associated with a subserous location was subsequently confirmed in another large retrospective study that included 361 tumors from 234 myomectomy patients whose median age of 34 years also revealed that the MED12 mutation frequency in uterine fibroids from fertile-age women is comparable to that found in perimenopausal women ( 153 ). Altogether, these analyses support the relevance of MED12 driver mutations in the pathogenesis and clinical presentation of uterine fibroids.

The noted association between MED12 mutations and smaller tumor size has been variously ascribed to underlying study bias (ie, early clinical intervention in response to the combinatorial burden of multiple co-existing MED12 -mutant tumors) or inherent biological differences in the growth properties of MED12 mutation–positive and MED12 mutation–negative tumors in situ . While the underlying basis for this association remains unknown, the notion that MED12 mutation–positive and MED12 mutation–negative tumors might exhibit unique growth features is supported by studies showing a clear distinction in the ability of primary cells from either tumor type to survive monolayer culture in vitro. Thus, while primary cells from MED12 mutation–negative uterine fibroids were shown capable of survival and maintenance for many passages under normal culture conditions, those derived from MED12 mutation–positive tumors were shown to be rapidly lost within the first several passages ( 154 ). Interestingly, while passaging of cells was noted to accelerate the loss of MED12–mutated cells from cultures, cell loss was nonetheless still observed in confluent cells absent passaging, revealing an apparent requirement for a niche-derived soluble factor(s) or matrix component(s) that is lacking in vitro ( 155 ). These novel findings reveal inherently unique growth requirements, and possible therapeutic vulnerabilities, for cells from MED12 mutation–positive uterine fibroids, and further suggest that alternative models will be required to overcome what currently constitutes a significant barrier to mechanistic studies concerning the molecular basis of MED12 in the pathogenesis of uterine fibroids.

An extenuating factor in rapid loss of MED12-mutant cells from culture may relate to the recent observation that MED12 mutation–positive uterine fibroids, compared with MED12 mutation–negative tumors, exhibit apparently greater cellular heterogeneity. In this regard, prior studies have revealed that uterine fibroids, while clonally derived, are nonetheless heterogeneous in their cellular composition, consisting predominantly of smooth muscle cells and fibroblasts, along with smaller numbers of vascular smooth muscle cells, vascular endothelial cells, and immune cells ( 156 , 157 ). Significantly, recent work has shown that MED12 -mutant tumors, compared with MED12 -WT (HMGA-overexpressing) tumors, harbor significantly more collagen-producing tumor-associated fibroblasts (TAFs) that also contribute significantly to excessive levels of extracellular matrix (ECM) observed in MED12 -mutant tumors ( 158 ). Notably, only smooth muscle cells, but not TAFs, carry MED12 mutations, suggesting antecedent divergence from a common progenitor before cell type–specific mutation acquisition or, alternatively, an extratumoral origin for TAFs. Interestingly, this work also showed that within MED12-mutant tumors, smooth muscle cells grow in response to progesterone, which has no effect on TAFs that instead grow in response to estrogen ( 158 ). The observation that MED12 mutation–positive uterine fibroids comprise similar ratios of smooth muscle cells and TAFs that respond differently to steroid hormones could explain the intriguing observation that estrogen alone can attenuate regression, but not promote growth, of progesterone-dependent MED12-mutant tumor xenografts ( 159 ). The high ratio of TAFs could also explain the rapid disappearance of MED12 -mutant smooth muscle cells from primary cultures of uterine fibroids. Thus, growth-deficient MED12-mutant cells could be overwhelmed by TAFs, for which standard culture conditions were originally optimized. Ultimately, the number of heterogenous cell types within MED12 mutation–positive uterine fibroids and the degree to which they are clonally related remains to be firmly established, and newer technologies, including single-cell RNA sequencing, could help to resolve these outstanding issues.

The molecular basis by which pathogenic mutations in MED12 drive uterine fibroid formation is presently unclear, but dysregulation of RNA Pol II-driven gene expression is implicated. Mediator is a conserved multiprotein interface found between gene-specific transcription factors and Pol II ( 137 ) and channels regulatory signals from activator and repressor proteins to affect changes in gene expression programs that control diverse physiological processes, including cell growth, homeostasis, development, and differentiation. Structurally, Mediator is comprised of a 26-subunit core that binds tightly to Pol II in the so-called holo-enzyme ( 137 ). MED12, MED13, CycC, and CDK8 (or its paralog CDK19) comprise a 4-subunit “kinase” module that variably associates with the core Mediator ( 137 ).( 137 ). Notably, the kinase module is a major ingress of signal transduction through the Mediator, and MED12-dependent CDK8 activation is required for the nuclear transduction of signals initiated by multiple oncogenic pathways, with which MED12 is biochemically and genetically linked ( Fig. 3 ) ( 137 ). Furthermore, MED12 is a target of oncogenic mutation in colon, prostate, and renal cell carcinomas ( 119 , 160 , 161 ). However, these mutations predominantly occur in the MED12 C-terminus and thus lie distant from fibroids-linked mutations that cluster in the N-terminus, suggesting distinct tumorigenic mechanisms ( 162 ).

Role of MED12 mutation in the pathogenesis of fibroids. Two mutually compatible models are demonstrating that fibroids driver mutations in MED12 trigger myometrial stem cell transformation and fibroids formation through altered signaling. In the first model (A), MED12 mutations in exon 2 disrupt the CDK8 T-loop conformation to affect Mediator kinase activity and the phosphorylation of downstream targets, including those that control myometrial stem cell fate and/or function. In the second model (B), MED12 mutations alter gene expression programs that control myometrial stem cell fate and/or function through kinase-independent mechanisms, such as MED12 interactions with transcriptional regulatory proteins ( 173 ). The 2 models are not mutually exclusive, and both scenarios could contribute to fibroids pathogenesis. Shown here is the 4-subunit Mediator kinase module comprising MED13, MED12, CycC, and CDK8/19 that variably associates with a core Mediator, which is collectively composed of 26 different subunits arranged into 3 structurally defined domains, ie, Head, Middle, and Tail. The structure of the core Mediator is from Clark et al ( 137 ), whereas that of the kinase module is from Li et al ( 167 ). Abbreviations: CDK8/19, cyclin-dependent kinase 8/19; CycC, cyclin C; MED12/13, RNA polymerase II transcriptional mediator complex subunit 12/13; MMSC, myometrial stem cell; UFs, uterine fibroids.

Uterine fibroid–linked mutations in MED12 are all located within exons 1 or 2, most of which are missense mutations, and a smaller proportion include in-frame deletions and insertions ( 118 , 129 , 137 ). Particularly, those occurring in exon 2 are far more frequent than those in exon 1, with the latter accounting for ~6% of pathogenic alterations reported in uterine fibroids ( 129 ). Although missense mutations in exon 2 are distributed throughout the coding sequence, most are clustered in codons 36, 43, and 44, suggesting the importance of their corresponding and evolutionary highly conserved amino acid residues ( 7 , 8 , 118 , 121 , 128 ).

Within the Mediator kinase module, MED12 is known to activate CycC-CDK8, and the mechanistic basis has recently been clarified ( 128 , 163-167 ). Thus, MED12 binds directly to CDK8, leading to structural reconfiguration and stabilization of the CDK8 activation (T)-loop in a manner critically dependent upon MED12 residues recurrently mutated in uterine fibroids ( 167 ). These observations suggest that uterine fibroid driver mutations in MED12 could alter T-loop conformation and disrupt CDK8 kinase activity ( Fig. 3 ) ( 167 ). Indeed, pathogenic exon 2 mutations in MED12 have been confirmed to disrupt CDK8/19 kinase activity both in vitro and in clinically relevant patients with uterine fibroids ( 128 , 129 , 165 , 166 ). Collectively, these studies reveal a common molecular defect associated with uterine fibroid–linked mutations in MED12 and implicate the aberrant Mediator-associated CDK8/19 kinase activity in the pathogenesis of uterine fibroids. Mechanistically, Mediator kinase activity has been implicated in diverse cellular processes ranging from controlling transcription factor half-life and RNA Pol II activity to regulating chromatin chemistry and functional status ( 137 , 168 , 169 ). Accordingly, its disruption as a direct consequence of uterine fibroid mutations in MED12 could have broad implications for the dysregulation of gene expression programs that collectively contribute to tumor formation. Nonetheless, MED12 has also been shown to regulate transcription in a CDK8-independent manner ( 170-173 ), although this function is largely mediated through the MED12 C-terminus that lies spatially distant from N-terminal residues mutated in uterine fibroids ( Fig. 3 ). Because MED12 mutations have been linked to pathways directly implicated in uterine fibroid pathology, including the Wnt/β-catenin, protein kinase B/mammalian target of rapamycin (AKT/mTOR), progesterone receptor, focal adhesion, extracellular matrix, angiogenic, and HIF1α pathways, among others ( 7 , 134 , 137 , 174-176 ), the relative contribution of CDK8 to MED12-dependent regulation of these pathways and the extent to which altered Mediator kinase activity contributes to their dysregulation will be an important area of future investigation.

Finally, the molecular basis for the high-frequency occurrence of MED12 exon 2 mutations in uterine fibroids is not presently understood. Either of 2 alternative scenarios can be posited. First, high-frequency MED12 exon 2 mutations might simply reflect the selection of clustered mutations among disparate others arising randomly throughout the MED12 gene through errors of replication, particularly if these mutations similarly impact an important biological function of MED12 in the myometrium. As described previously, all uterine fibroid driver mutations in MED12 disrupt Mediator-associated CDK8/19 kinase activity, and it is perhaps notable that Mediator kinase has been implicated in the control of stem cell plasticity and fate determination. For example, a developmentally programmed reduction in CDK8 expression is associated with naïve pluripotency during animal development in vivo, and chemical inhibition of CDK8/19 was recently shown sufficient to revert primed pluripotent stem cells to a naïve pluripotent state in vitro ( 177 , 178 ). Furthermore, CDK8 has been implicated in cancer stem cell self-renewal and tumorigenicity in colon and brain cancer ( 179 , 180 ). Finally, within the uterus, it was recently shown that Mediator kinase subunits are enriched in myometrial stem cells (MMSCs), and further, that chemical inhibition of CDK8/19 in MMSCs led to reduced phosphorylation of stem cell-enriched transcription factors and altered expression of myogenic genes. Thus, it seems possible that MED12 exon 2 mutations, through disruption of Mediator kinase activity, could provide a selective advantage to myometrial stem/progenitor cells by altering their growth and/or differentiative trajectory, leading to the formation of uterine fibroid stem cells that, in turn, seed and sustain monoclonal tumor growth.

An alternative hypothesis to explain the high-frequency occurrence of MED12 exon 2 mutations invokes a sequence- or structure-specific basis for clustered mutagenesis through error-prone repair of site-specific DNA damage. Replication fork arrest as occurs, for example, on repeat and satellite sequences or noncanonical B-DNA, is often processed through DNA double-strand break intermediates, which are prone to erroneous repair and punctual mutagenesis (or chromosomal rearrangements) ( 181 ). Accordingly, such error-prone sequences, should they reside in the vicinity of MED12 exon 2, might favor the occurrence of high-frequency somatic mutations found in uterine fibroids. However, the genomic sequence within and flanking MED12 exon 2 is characterized by neither particularly high GC content nor repeat motifs characteristic of replication-resistant DNA, perhaps arguing against replication-dependent site-specific mutagenesis as a basis for the high-frequency occurrence of MED12 mutations. Nonetheless, it was recently noted that this region does harbor a 16-bp sequence with significant homology to a putative terminator-based hairpin sequence within the tRNA gene cluster of Staphylococcus aureus , a common component of the uterine microbiota ( 182 ). On this basis, it was hypothesized that MED12 hot-spot mutations arise through site-specific mutagenesis brought on by replication-dependent processing of aberrant R-loops produced by insertion of S. aureus RNA with the homologous DNA sequence in MED12 ( 182 ). Although speculative, this intriguing hypothesis nonetheless does invoke a direct link between host and microbiome that together form a complex interrelationship prone to homeostatic disruption and the development of human disease ( 183 , 184 ). While the genic basis for high-frequency MED12 mutations in uterine fibroids thus remains obscure, it is nonetheless clear that once incurred, these mutations interact with additional environmental components including hormonal, angiogenic, and growth regulatory factors to drive tumor progression.

The high mobility group A (HMGA) family includes related HMGA1 and HMAG2 non-histone chromosomal proteins that regulate transcription by altering chromatin structure. The HMGA non-histone proteins bind to the AT-rich enhancers or promoters’ minor groove and introduce structural alterations in chromatin. One of the most commonly observed cytogenetic abnormalities (8%-10%) in uterine fibroids is a translocation involving chromosomes 12 and 14, which disrupts a putative regulatory sequence typically 5′ of the HMGA2 gene ( 185 , 186 ). In addition, the expression levels of HMGA2 are elevated in uterine fibroids compared to myometrium with 12q15 rearrangements ( 187 , 188 ). Uterine fibroids with HMGA2 aberrations displayed significant upregulation of proto-oncogene pleomorphic adenoma gene 1 ( PLAG1 ), suggesting that HMGA2 triggered the pathogenesis of uterine fibroids through PLAG1 activation ( 189 ).

Mutations in fumarate hydratase ( FH ) on chromosome 1 in band q42 were found in uterine fibroids ( 190 , 191 ). Heterozygous germline mutations in the FH gene caused a syndrome known as hereditary leiomyomatosis and renal cell carcinoma (HLRCC) ( 192 ). FH deficiency, accounting for up to 1.6% of uterine fibroids, alters the expression profiles of fibroids, most strikingly increasing the expression of genes involved in glycolysis ( 132 ) as well as activating nuclear factor erythroid 2 related factor 2 (NRF2) target genes ( 189 ).

COL4A5/COL4A6

Similar to the FH deficiency subtype, COL4A5/COL4A6 deletions are a rare subtype constituting about 2% of uterine fibroids ( 193 ). Integrated data analysis reveals insulin receptor substrate-4 ( IRS4 ), a gene located adjacent to COL4A5 , as the most uniquely expressed gene in this uterine fibroid subtype ( 189 ).

Additionally, a small number of mutually exclusive drive mutations were recently identified. Germline mutations in SRCAP members YEATS4 and ZNHIT1 predispose women to uterine fibroids. The fibroids bearing these mutations exhibited defective deposition of the histone variant H2A.Z ( 194 ). Moreover, an integrative computational approach (decomposition and classification of genomic tensors) can discriminate normal and uterine fibroid subtype ( 195 ), suggesting that the inclusion of epigenetic features can help better understand the state and complexity of uterine fibroids.

Conversion of Myometrial Stem Cells to Uterine Fibroid Stem Cells

The human myometrium is the muscular wall of the uterus that is formed by an intricate network of smooth muscle fibers dispersed throughout an extracellular matrix of connective tissue. This process contributes to the normal tonicity of the uterus. Increasing evidence supports the hypothesis that uterine fibroids originate from stem cells in the myometrium, although the specific cell of origin has not yet been identified ( 196 , 197 ). Stem cells derived from the myometrium and uterine fibroids have been isolated, and tumor-initiating cells in fibroids have been identified ( 198-201 ). Moreover, the markers used to enrich putative mesenchymal stem cells are similarly enriched for MMSCs from myometrium and uterine fibroids ( 202 ). Notably, MED12 mutations are only found in uterine fibroid stem cells and not in MMSCs ( 203 ). In addition, distinct MED12 mutations have been detected in different uterine fibroid tumors derived from the same uterus ( 7 ), indicating that the emergence of each mutation might be an independent event. The prevailing model for fibroid pathogenesis invokes the genetic transformation of a single MMSC into a tumor-initiating cell that seeds and sustains clonal tumor growth through endocrine, autocrine, and paracrine growth factors and hormone receptor signaling ( 204 ).

Several factors have been proposed as the origin of tumor-initiating cells, including genomic instability, inflammatory microenvironment, cell fusion, lateral gene transfer, and developmental environmental insult ( 205 , 206 ). The adverse effect of developmental environmental insult may cause the deregulation of multiple developmental processes, including the disruption of stem cell niche, developmental reprogramming, and altered stem cell characteristics. Somatic stem/progenitor cells from various hormone-supported tissues remained susceptible to endocrine-disrupting chemicals (EDCs) ( 206 , 207 ). In uterine fibroids, developmental exposure to EDCs impaired the biological characteristics of MMSCs in an Eker rat model with Tsc2 mutation. This model spontaneously develops uterine fibroids with 63% incidence. However, early-life exposure to EDCs, such as diethylstilbestrol (DES), increased the penetrance of the Tsc2 mutation, resulting in 100% incidence ( 208 ).

The impact of environmental exposure to MMSCs that increase susceptibility to uterine fibroid development have been investigated using the same model. The more MMSCs in the DES-exposed myometrium have been observed than those exposed to vehicle. In addition, MMSCs from 5-month-old DES rats exhibited increased proliferation rates compared to MMSCs from age-matched control rats ( 206 ). These results suggest that developmental exposure to EDCs targets MMSCs and alters their characteristics, which may underlie reprogramming of epigenome and initiation of hormone-dependent uterine fibroid pathogenesis ( Fig. 1 ).

Early and late epigenome and environment interactions can potentially impact uterine function and increase the risk of uterine fibroids ( Fig. 1 ) by shaping the developing epigenome of target genes ( 209 ). This epigenomic reprogramming may remain transcriptionally and phenotypically silent until triggered by a later life event, such as exposure to risk factors. For example, during a critical developmental window of the liver, exposure to BPA induced epigenomic reprogramming at specific genes and chromatin states in the neonatal liver to accelerate acquiring an adult epigenetic signature. Although it persists until adulthood, much of this reprogramming remained transcriptionally silent until a later-life challenge with a Western-style diet high in fat, fructose, and cholesterol, which disrupted metabolic function and significantly elevated serum cholesterol and lipid levels ( 209 ). Further studies on stem cells from reproductive organs may contribute to a better understanding of the genome-environment interaction leading to reproductive diseases, including uterine fibroids.

The occurrence of MED12 driver mutations and how they interact synergistically with other implicated pathways in uterine fibroids remain largely unknown. Therefore, the further investigation is highly needed to elucidate the mechanism of interplay between hormones, environments, DNA repair system, and other factors in the occurring of MED12 mutations.

Direct, Intensive, and Adverse Environmental Exposure

Air pollution.

Air pollution is one of the leading causes of death. Exposure to air pollutants affects vital cellular mechanisms and is intimately linked with the etiology of many chronic diseases such as chronic obstructive pulmonary disease and asthma ( 210-212 ). Particulate matter (PM) is a class of pollutants that comprises a complex combination of small-sized particles and gaseous components, such as organic chemicals, smoke, soot, sulfates, nitrates, acidic components, dust particles, and soil. The United States Environmental Protection Agency considers PM the pollutant category with the most significant impact factor on human health ( 213-215 ). Air pollution, including PM2.5, results in infertility, menstrual irregularity, and endometriosis ( 216 ). In addition, chronic exposure to PM2.5 is associated with the incidence of clinically symptomatic uterine fibroids ( 216 ). A 10-year cohort-based case-control study that included 11 028 Taiwanese women diagnosed with uterine fibroids suggested that exposure to PM2.5 and O 3 may increase the risk of developing uterine fibroids ( 217 ). However, only limited research has investigated the relationship between air pollution and uterine fibroid development; therefore, more studies are needed to confirm these findings in other populations.

Alcohol consumption

Heavy alcohol consumption is a risk factor for uterine fibroids ( 35 ). The Nurses’ Health Study II revealed the positive association between current alcohol consumption and risk of uterine fibroids ( 35 , 218 ). The Black Women Health Study concluded that uterine fibroids risk among African American women is positively correlated with past and current alcohol intake ( 219 ). In a study involving 133 000 female teachers and school administrators, drinking at least 20 g of alcohol per day was significantly associated with an increased risk for uterine fibroids ( 220 ). Another cross-section study on premenopausal Japanese women supported this causal risk factor for uterine fibroids and reported that mean alcohol intake is significantly higher among women with fibroids than those without ( 221 ). Moreover, a study of 1146 premenopausal African American and Caucasian women showed that current alcohol intake in Caucasian women is associated with an increased risk of uterine fibroids compared to African Americans and nondrinkers. Although no correlation between alcohol intake and uterine fibroid risk in African Americans was found, the relationship of current and past drinking history and uterine fibroid size was generally similar among African American and White women ( 35 ).

Although the underlying mechanism is largely unknown, several studies have proposed that alcohol intake increases the levels of steroid hormones in premenopausal women ( 222-224 ). Alcohol intake also altered the growth factors and cytokines, which play a critical role in uterine fibroid pathogenesis. Moreover, alcohol-induced DNA damage might be a contributor. Acetaldehyde, an endogenous and alcohol-derived metabolite, caused DNA damage, particularly double-stranded breaks, that, despite the activation of recombination repair, resulted in chromosomal rearrangements in stem cells ( 225 ). Other studies have reported alcohol-induced mitochondrial DNA damage in lung, brain, and breast cancers ( 226-228 ). More studies are needed to explore alcohol-induced DNA damage in uterine fibroids.

Cigarette smoking

The effect of smoking on uterine fibroids remains controversial ( 229 ). An inverse correlation between smoking and uterine fibroids risk was reported ( 220 , 230 , 231 ). However, this association was not found in other case-control and prospective cohort studies ( 2 , 232 , 233 ). Early studies found that estrone and estradiol levels were reduced in smokers relative to nonsmokers, and cigarette smoking altered the hepatic metabolism of estrogen, thus resulting in lower circulating levels of activated estrogen ( 2 ). However, the components of cigarette smoke may also exert estrogen-related effects on the uterus to promote cell proliferation ( 2 ).

Developmental Exposures

Epidemiological studies and endocrine-disrupting chemical effects.

Various niche factors act on stem cells during development to alter gene expression and induce their proliferation or differentiation for fetus development. During development and tissue maintenance, the highly plastic state of stem/progenitor cells permits the required flexibility for proper tissue formation and repair. Unfortunately, this plasticity also provides an opportunity for aberrant cellular reprogramming via epigenetic mechanisms due to inappropriate exposures to toxins ( 234 ). Developmental adverse exposure can lead to persistent, life-long effects and result in various diseases ( 235-237 ).

EDCs interfere with the body’s endocrine system to produce adverse developmental, reproductive, neurological, and immune effects ( 198 , 238 , 239 ). An increasing number of studies have shown that endocrine disruptors may pose a serious disease risk during development ( 240 ). According to epidemiological and experimental studies, EDCs increased the risk of tumorigenesis, especially in organs susceptible to endocrine regulation. For example, upon exposure to estrogen and progesterone, differentiated myometrial cells secreted wingless-type (WNT) ligands that induced the nuclear translocation of β-catenin in stem/progenitor cells from uterine fibroids. The activation of the β-catenin pathway ultimately enhanced the growth and proliferation of these stem/progenitor cells ( 241 ).

EDCs can exhibit nonmonotonic dose–response curves and produce a pathophysiologic effect even at low doses. Numerous EDCs can interact with nuclear receptors to exert their actions in target cells and tissues ( 242-244 ). For example, the binding of EDCs to nuclear receptors can alter hormonal functions by mimicking the naturally occurring hormones in the body, thereby blocking the binding of endogenous hormones, or by interfering with the production or regulation of hormones and/or their receptors. An EDC may interact with more than one receptor, and multiple EDCs can interact with the same receptor, highlighting the complexity of the response of animals and humans to environmental EDC exposures. Notably, EDCs exposure can increase the risk of uterine fibroids ( Figs. 2 and 4 ). Two extensive prospective studies reported a positive association between developmental exposure to DES, a synthetic and nonsteroid estrogen, and uterine fibroids risk. ( 245 , 246 ). In the Nurses’ Health Study II ( n = 11 831), prenatal exposure to DES increased the risk of uterine fibroids by 13% in women older than 35 years ( 246 ), and exposure during the first trimester of gestation increases the risk by 21%. Large fibroids were more commonly found in those exposed to prenatal DES in the second National Institute of Environmental Health Sciences (NIEHS) uterine fibroid study. In a subset of the NIEHS sister study, the main factors associated with increased risk of uterine fibroids included DES exposure, maternal or gestational diabetes, and monozygotic twins, having risk ratios of 2.02, 1.54, and 1.94, respectively. However, another prospective cohort study, which employed medical records to document exposure, reported no association between prenatal DES exposure and uterine fibroids. Many other EDCs, including parabens, environmental phenols, alternate plasticizers, organophosphate esters, tributyltin, and phthalates, have been associated with uterine fibroids outcomes and their related processes. Phthalates have received increasing attention as they are tightly linked to uterine fibroid prevalence and severity ( 31 , 247-249 ) ( Figs. 1 and 2 ).

Estrogen receptor-mediated signaling pathways in the myometrium. The biosynthesis of natural E2 occurs in the ovary downstream the actions of the LH and the FSH, which are regulated by the GnRH. E2 mediates its biological response through several pathways, which can be classified as genomic and nongenomic. There are 3 main mechanisms of genomic regulation mediated by ER. Firstly, in the classical pathway, E2 ligands passively enter the cells by diffusion. ERα and ERβ are localized in the cytosol and are attached to the chaperon Hsp90, which is released after binding with estrogen. The estrogen-bound receptors form dimers that enter the nucleus and bind to the ERE, specific DNA sequences of the promoters of target genes affecting their transcription. Secondly, the nonclassical pathway involves binding the E2-bound ER to TFs that are already bound to the DNA. The third mechanism is hormone-independent. The ER can regulate E2 responses by activating the signaling of growth factors via the phosphorylation of different serine (118/167) residues on the receptor. In addition to upregulating gene expression, E2 exerts its nongenomic rapid biological actions by interaction with membrane receptors. GPER, a membrane-integrated 7-transmembrane receptor, activates heterotrimeric G-proteins after binding with estrogen to elicit various nongenomic responses, such as calcium signaling, PKC, and cAMP/PKA pathways. Bound-membrane ERs (ERα, ERβ, ER36, and ER46) also activate cytosolic signalings, such as PI3K/Akt and MAPK. In addition, the activation of kinases results in the phosphorylation of specific transcription factors that regulate gene expression. EDCs are exogenous, manufactured chemicals, such as genistein, bisphenol A, and phthalates that mimic natural estrogen molecular and cellular responses, thereby altering the functions of the endocrine system. These chemicals are associated with the developmental origin of fibroids and their pathogenesis. Abbreviations: AC, adenylyl cyclase; AKT, protein kinase B; cAMP, cyclic AMP; CoA, coactivator; E2, estrogen; EDCs, endocrine-disrupting chemicals; EGFR, epidermal growth factor receptor; ER, estrogen receptor; ERE, estrogen-responsive elements; FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; GPER, G-protein coupled estrogen receptor 1; Hsp90, heat shock protein 90; IGFR, insulin-like growth factor 1 receptor; IP3, inositol trisphosphate; LH, luteinizing hormone; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; mER, membrane-bound estrogen receptor; mTOR, mammalian target of rapamycin; PI3K, phosphoinositol-3-kinase; PKA, protein kinase A; PKC, protein kinase; PLC, phospholipase C; Raf, Rapidly Accelerated Fibrosarcoma Kinase; Ras, Ras GTPase; TFs, transcription factors.

Experimental studies using animal models

Diverse animal species and techniques have been used for the in vivo investigation of uterine fibroid pathophysiology. These animal models include the xenotransplantation of human uterine fibroid tissues ( 250-252 ) or cells ( 253 , 254 ) in mice, the implementation of genetically modified mice ( Tsc2 knockout ( 255 ), GPR10 overexpression ( 256 ), β-catenin overexpression ( 257 )), and the utilization of species that spontaneously develop uterine fibroids, such as the guinea pig ( 258 ), the potbellied pig ( 257 ), and the Eker rat. The latter carries a germline mutation in the tuberous sclerosis complex-2 ( Tsc2 ) tumor suppressor gene and develop uterine fibroids with a frequency of about 65% by 16 months of age ( 259 ). Although the Eker rat model is the most widely used in vivo animal model to study uterine fibroids, this animal model has some limitations. For example, mutations in the Tsc gene have not been linked to the disease in humans. In addition, the developing uterine fibroids show relatively small amounts of collagenous connective tissue stroma ( 260 ), unlike the human uterine fibroids, which present a high amount of abnormally formed cross-linked collagen ( 261 ). Finally, Eker rats develop both benign and malignant smooth muscle tumors ( 260 ). However, studies in the Eker rat animal model provide a great opportunity to reveal links between early-life exposure to EDCs and the origin and development of uterine fibroids. Upon neonatal exposure to EDCs, Eker rats developed increased susceptibility to spontaneous uterine fibroids, multiplicity, and tumor size with age ( 208 , 262-264 ), whereas those without the Tsc2 mutation did not develop any tumors. These studies suggest that developmental exposure to EDCs increases the penetrance of the Tsc2 mutation ( 208 ). In addition, the window of susceptibility to environmental exposures coincided with critical periods of myometrial development ( 208 ). Exposure to DES during postnatal day (PND) 3–5 or 10–12 increased tumor incidence from 63% to 95% and 100%, respectively, in Eker rats carrying germline TSC2 mutation. During this time, estrogen protection of the developing uterus is disrupted ( 265 ) as DES and other xenoestrogens do not bind circulating steroid hormone–binding proteins, such as alpha-feto protein A. A later exposure at PND 17–19 did not result in increased uterine fibroid incidence. Overall, developmental exposure to EDCs during a critical time window of uterus development increases uterine fibroid risk later in life ( Figs 1 & 2).

Molecular mechanism underlying developmental EDC exposure–induced risks of uterine fibroids

During development, various niche factors act on stem cells to alter gene expression, therefore altering the signaling pathway and modulating its biological characteristics for the development of the fetus. The adverse developmental exposure can lead to persistent, life-long effects and result various diseases via pathological reprogramming ( 208 , 209 , 234 , 240 , 266 ).

Early-life exposures to 3 EDCs (ie, DES, genistein, and BPA) have been investigated to detect their effect on estrogen signaling, which plays a role in triggering fibroids formation in an animal model ( 267-269 ). All 3 EDCs act as ER ligands and induce ER-mediated gene transcription. However, only DES and genistein induced nongenomic ER signaling to activate phosphoinositide-3-kinase (PI3K)/AKT in the developing uterus. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) is phosphorylated by activated PI3K/AKT signaling to repress EZH2 activity and reduce the levels of histone 3 lysine 27 trimethyl (H3K27me3). Significantly, decreased H3K27 methylation via developmental exposure correlated with the promoting effect of xenoestrogens on uterine fibroids.

In addition to EZH2, altered DNA methylation patterns due to environmental exposure have been reported in animal studies. Neonatal exposure induced the reprogramming of DNA methylation in animals exposed to DES during PND 1–5 compared with PND 17 (prepubertal), 21, and 30 (postpuberty) ( 270 ). Furthermore, neonatal DES exposure reprogrammed LTF, an estrogen-responsive gene. At PND 21 and 30, the promoter upstream of the estrogen response element was demethylated in animals exposed to DES during PND 1–5. Importantly, this postpubertal DES-induced demethylation was dependent on ovarian hormones, as evidenced by the absence of this demethylation in DES-exposed ovariectomized mice ( 270 ). Another animal study showed that neonatal DES exposure–induced metabolic changes last until adulthood, suggesting a permanent effect on energy metabolism in the uterus ( 271 ). Thus, developmental exposure to EDCs causes uterine diseases via epigenomic reprogramming. However, studies on the mechanism of epigenetic reprogramming by EDCs and its influence on fibroids development are limited. Additional mechanistic studies to elucidate the epigenetic biomarkers/signatures specific to EDCs can contribute to the development of precision medicine.

The reprograming of MMSCs, the cell origin of uterine fibroids, was recently identified following early-life exposure in the Eker rat (PND 10-12) to EDC. MMSCs isolated from prefibroid-stage tissue were analyzed using omics methods and showed altered biological pathways, including estrogen signaling ( 272 ) and inflammatory pathways ( 273 , 274 ). The reprogramming of estrogen pathways is driven by activated mixed-lineage leukemia protein-1 ( 275 ). In addition, DNA hypomethylation is involved in regulating estrogen and estrogen-responsive genes in MMSCs ( 274 , 276 ). In summary, EDC exposure epigenetically targeted MMSCs, imparting a hormonal imprint on key signaling pathways, thus resulting in an increased risk of uterine fibroids in a hormone-dependent manner ( 274 ) ( Figs. 1 , 2 , and 4 ).

Due to some limitations using animal models, the use of 3-dimensional (3D) models has attracted more attention in uterine fibroids research ( 277-279 ), particularly using myometrial stem cells instead of differentiated myometrial cells ( 280 ). The 3D model provides a more biomimetic cell culture environment than 2D substrates, with the advantage of more closely mimicking in vivo tissue architecture. MMSC-material interactions in 3D with topographical cues may provide an effective means to regulate many fibroid-related biological events, including differentiation, epigenetic state, or cell reprogramming, and rapidly advance our understanding of how the environment impacts risk for this disease as well as the tumor process via conversion of MMSCs to tumor-initiating cells.

Notably, so far, very few studies have attempted to disentangle the effects of early-life exposures concomitantly with late-life exposure on the pathogenesis of uterine fibroids. Thus, mechanistic insights into fibroid pathogenesis through the integration of risk exposures, genetic, epigenome, and MMSC biology will better understand the onset of fibroids.

Estrogen and Progesterone

Classically, uterine fibroids were considered estrogen-dependent tumors, based on their association with reproductive age ( 281 , 282 ). The estrogen signaling pathway as a major impactful pathway in uterine fibroids comprises genomic (direct and indirect effects of gene expression) and nongenomic factors, including the Ras-Raf-MEK (MAPK/ERK kinase)-mitogen-activated protein kinase (MAPK) and PI3K-phosphatidylinositol-3,4,5-trisphosphate (PIP3)-Akt-mTOR) pathways (the Ras-Raf-MEK-MAPK and PI3K-PIP3-Akt-mTOR pathways, respectively) ( Figs. 4 and 5 ).

Critical pathways in uterine fibroids pathogenesis. The WNT/β-catenin, TGF-β, growth factor–regulated signaling, ECM, estrogen signaling, YAP/TAZ, Rho/ROCK, and DNA damage repair pathways play essential roles in fibroids formation and development. In addition, the crosstalk and interaction among these pathways may initiate and trigger uterine fibroids pathogenesis. Abbreviations: AKT, protein kinase B; APC, adenomatous polyposis coli; Bad, BCL2 associated agonist of cell death; CK1α, casein kinase 1 alpha; E2, Estrogen; ECM, extracellular matrix; ERE, estrogen-responsive elements; ERK, extracellular-signal-regulated kinase; ERα/β, estrogen receptor alpha/beta; FAK, focal adhesion kinase; GSK-3β, glycogen synthase kinase 3 beta; Hsp90, heat shock protein 90; LRP, lipoprotein receptor-related protein; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; mER, membrane-bound estrogen; MLC, Myosin regulatory light chain 2; MRN, Mre11-Rad50-Nbs1 complex; mTOR, mechanistic target of rapamycin; P, phosphorylated site; PDK1, 3-phosphoinositide-dependent protein kinase 1; PI3K, phosphatidylinositol 3-kinase; RAF, Rapidly Accelerated Fibrosarcoma kinase; RHO, Ras-homologous; RTK, receptor tyrosine kinases; SMAD, mothers against DPP (decapentaplegic); Src, proto-oncogene tyrosine-protein kinase; TF, transcription factor; TGFβ, transforming growth factor beta; TGFβR, transforming growth factor beta receptor; Wnt, Wingless-related integration site; YAP, Yes-associated protein; TAZ, transcriptional coactivator with PDZ-binding domain.

Several aberrations in ERs and signaling pathways are implicated in uterine fibroid pathobiology ( 283 ). Recently, another role for estrogen has been identified, ie, estrogen-induced, progesterone receptor expression and allowing progesterone receptor ligands to act on their target cells ( 284 ). Uterine fibroid cells have been shown to increase the expression of progesterone receptors in response to estradiol ( 285 ). Progesterone and progesterone receptors play a key role in uterine fibroid growth and development ( 286 , 287 ). Increased proliferation of uterine fibroid cells in vitro was observed upon exposure to both estradiol and progesterone ( 288 ). Finally, a uterine fibroid xenograft animal model showed that steroids, including estradiol and progesterone, are required for tumor growth ( 289 ), supported by selective progesterone receptor modulators (SPRMs) ( 290 ).

Extracellular Matrix and Growth Factors

Excessive ECM accumulation and aberrant remodeling are crucial for fibrotic diseases, including uterine fibroids ( Fig. 5 ). Uterine fibroid cells are characterized by abundant disorganized ECM deposition, which contributes to the formation of the bulk structure of the tumor. The large amounts of glycosaminoglycans and highly cross-linked interstitial collagens present in uterine fibroids ( 291 ) underlie the increased stiffness of the ECM. It is proposed that this ECM-rich rigid structure is the cause of the abnormal bleeding and pelvic pain ( 292 ). Moreover, ECM stiffness greatly impacts how cells sense physical forces and translate them into biochemical and biological responses, a molecular process collectively known as mechanotransduction. A clear example of proteins that respond to mechanical signals is β-catenin ( 293 , 294 ), a protein known to be involved in the pathobiology of uterine fibroids ( 294 ). It has been proposed that uterine fibroids can be divided into 4 stages based on the extracellular collagenous matrix content ( 295 , 296 ). Excessive collagen production by the transformed myocyte and its accumulation in the ECM results in decreased microvessel density, followed by myocyte death due to extreme deprivation of nutrients and oxygen ( 297 ). At the same time, changes in the ECM stiffness may activate mechanotransduction pathways that contribute to the myocyte phenotypic transformation. Interestingly, recent studies have linked mechanotransduction, nuclear rupture, and subsequent DNA damage in other diseases ( 298 , 299 ). Unraveling the interactions among different mechanobiology pathways in the uterine fibroid’s context would eventually help to comprehend better the origin and development of these tumors.

ECM accumulation is also affected by growth factors (transforming growth factor [TGF]-β, activin-A, and platelet-derived growth factor ), cytokines (tumor necrosis factor-α [TNF-α]), steroid hormones (estrogen and progesterone) ( 300 ), and microRNAs (particularly the miR-29 family, including miR-200c and miR-93/106b) ( 301-303 ). Interestingly, ECM acts as a reservoir of profibrotic growth factors and enhances their activity by increasing their stability and prolonging signaling duration. Therefore, a better understanding of ECM composition and metabolism in uterine fibroids is critical for developing new therapeutics for uterine fibroids. At present, several classes of drugs, including gonadotropin-releasing hormone (GnRH) agonist (leuprolide acetate), GnRH antagonists, SPRMs (eg, ulipristal acetate), and natural compounds (vitamin D), targeting the ECM have been studied as treatment options for uterine fibroids ( 303 , 304 ). In this sense, a local collagenase injection from Clostridium histolyticum , which specifically cleavage interstitial collagens, has been proposed as an alternative treatment for uterine fibroids. Notably, a phase I clinical trial (NCT02889848) has been completed, and it demonstrated the safety and tolerability of this treatment. Furthermore, direct injection of collagenase from C. histolyticum significantly reduced the stiffness of uterine fibroid tissue ( 305 ), which is fundamental to continued tumor growth throughout the activation of mechanotransduction pathways. Therefore, such mechanotransduction pathways may be disturbed after the reduction of fibroid stiffness, leading to ECM remodeling and finally to reduced fibroid size.

DNA Damage and Repair

Dna damage in the uterus.

Women are exposed to several exogenous (eg, EDCs) and endogenous factors that can impart pathophysiological alterations in internal organs, including the uterus. Endogenous factors include regular menses and hormonal changes that induce DNA damage through oxidative stress. Fluctuations in circulating estrogen and progesterone levels during the menstrual cycle can lead to increased tumor susceptibility in women, including breast cancer. Additionally, DNA damage and repair, and apoptosis occur cyclically in the normal myometrium during the follicular phase. Smooth muscle cells proliferate in the luteal phase, which may be a vulnerable period for DNA damage. These damages need to be properly repaired; otherwise, the hormonal imbalance can lead to diseases. For example, repeated incidents of damage to myometrial cells affect DNA repair activity, which could predispose the uterine environment to chronic inflammation, thereby creating an ideal environment for uterine fibroid development. However, the biological mechanisms involved in uterine fibroid progression remain unknown. This section will discuss studies on DNA lesions in uterine fibroids ( 306-308 ) ( Fig. 5 ).

Defective DNA damage response pathways

Although the mechanistic basis underlying genomic instability in uterine fibroids remains to be established, defects in DNA damage response and repair gene expression programs are heavily involved. Several DNA repair genes in uterine fibroid tumors are downregulated compared with adjacent matched myometrium from the same women, suggesting that impaired DNA repair capacity is linked to the genomic integrity and subsequent initiation/propagation of uterine fibroids. In addition, the expression of DNA repair-related genes RAD51 and BRCA1 , which are involved in double-stranded break (DSB) homologous recombination (HR), were deregulated in uterine fibroid tumors ( 309 , 310 ).

Interestingly, human uterine fibroid stem cells have accumulated DNA damage and reduced DNA repair gene expression and signaling, suggesting that human fibroid stem cells have impaired DNA repair capacity compared with normal myometrium stem cells. This compromised DNA repair system may contribute to promote mutagenesis, as well as the growth and propagation of uterine fibroids ( 311 ). In addition, DNA damage was significantly increased in uterine fibroids relative to MMSCs, as shown by increased mean percentage DNA in the tail of alkaline comet assay. Moreover, uterine fibroid stem cells had decreased expression of total DNA repair-related proteins belonging to DSB repair, specifically HR, and differential phosphorylation in comparison to adjacent MMSCs, indicating altered DNA damage response and increased DNA damage as evidenced by increased phosphorylation of histone H2A.X at serine 139 (ie, γ-H2AX) as a response to DNA DSB formation ( 311 ).

A germline mutation in Tsc2 predisposes to uterine fibroids in Eker rats, which is attributed to “second hits” in the normal allele of this gene. The risk for developing these tumors is significantly increased by early-life exposure to EDCs, suggesting that the early drivers for these tumors modulate increased uterine fibroid penetrance. Analyses of DNA repair capacity using gene and protein expression and DNA repair function in MMSCs derived from adult rats exposed to DES during uterine development were conducted. Adult MMSCs isolated from developmentally exposed rats showed decreased DNA end-joining ability, increased DNA damage, and impaired ability to repair DNA double-strand breaks compared with those from age-matched, vehicle-exposed rats, suggesting that early-life developmental EDC exposure alters the power of MMSCs to repair and reverse DNA damage, thereby providing a driver for the acquisition of mutations that may promote the development of these tumors in adulthood ( 312 ).

Other types of DNA repair, including nucleotide excision repair, which removes bulky DNA adducts caused by polycyclic aromatic hydrocarbons, and base-excision repair of oxidative DNA damage ( 313 ), should be explored in the context of uterine fibroids ( Fig. 5 ).

Wnt/β-Catenin Signaling Pathway

The Wnt/β-catenin signaling pathway is involved in various physiological events, including development, tissue renewal, cell proliferation and differentiation, and several types of tumorigenesis ( 314 , 315 ). This pathway has also been recently investigated in uterine fibroid formation ( 241 , 316 , 317 ) ( Fig. 5 ). However, contrasting results on the β-catenin expression in uterine fibroids have been reported: 1 study detected upregulated expression in uterine fibroids ( 318 ), whereas others detected no difference between uterine fibroids and myometrium ( 319 ). Recently, the mislocalization of β-catenin has been causally linked to uterine fibroids phenotype, wherein fibroids expressed higher levels of nuclear β-catenin than normal myometrium tissues. Moreover, estrogen activated β-catenin nuclear translocation and enhanced β-catenin responsive gene expression in human uterine fibroids cells via the ER ( 320 ). Thus, a paracrine role for the WNT/β-catenin pathway that enables mature myometrium or fibroid cells to send mitogenic signals to neighboring tissue stem cells in response to estrogen and progesterone has been proposed, thus leading to the growth of uterine fibroids ( 241 ).

The use of vitamin D3 has been associated with the inhibition of the Wnt/β-catenin pathway and decreased uterine fibroid cell proliferation ( 321 , 322 ). β-catenin inhibitors, such as ICG-001, cordycepin, and XAV939, and histone deacetylase (HDAC) inhibitors (HDACi), including apicidin and HDACi VIII, exhibited antiproliferative effects on uterine fibroid cells by suppressing the β-catenin signaling pathway. Additionally, HDACi exposure induced cell cycle arrest and apoptosis of uterine fibroid cells, thus representing a promising epigenetic-based therapy for uterine fibroids ( 320 ). Recently, the MED12 somatic mutation has been revealed to modulate oncogenic Wnt4/β-catenin and mTOR signaling pathways in uterine fibroids ( 174 ).

Compounds targeting Wnt/β-catenin signaling and other vital pathways are summarized in Table 2 .

YAP/TAZ Pathway

ECM accumulation and aberrant cell proliferation are essential components in uterine fibroid pathogenesis. An important regulatory mechanism that connects mechanical stimuli to cellular proliferation is the Hippo pathway, including the effector proteins Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) as main mediators. YAP/TAZ has been involved in fibrotic diseases such as lung fibrosis ( 323 ) as well as in hormone-regulated organs such as ovary ( 324 ) with aberrant activation that resulted in tumorigenesis ( 325 ). A recent study has shown that YAP/TAZ nuclear localization in situ and confluent cells was higher in uterine fibroid cells compared with normal myometrium and associated tissue stiffness was higher in uterine fibroids compared with normal myometrium. Moreover, exposing fibroid cells to verteporfin (a YAP inhibitor) reduced cell survival and reduced fibronectin deposition ( 326 ). Furthermore, a recent study showed that the antifibrotic drug nintedanib inhibited YAP and produced antifibrotic effects ( 327 ). The same study showed that in vivo injection of collagenase into uterine fibroids led to a reduction in Hippo/YAP signaling and crucial genes and pathways involved in fibroid growth ( 327 ) ( Table 2 ). More studies are encouraged to further explore the role of the Hippo/YAP/TAZ pathway in fibroid pathogenesis with subsequent identification of novel targeted therapeutic strategies.

Rho/ROCK Signaling Pathway

Studies showed that mechanotransduction activates the Ras homolog family (Rho), which interacts with its downstream target Rho-kinase (ROCK) and activates the ERK/p38 MAPK-signaling cascade, and resulting in increased cell proliferation, decreased apoptosis, and upregulation of genes involved in ECM composition and remodeling ( 303 ). RhoA expression was found to be higher in uterine fibroid compared with myometrial cells ( 328 ). Interestingly, inhibition of integrin-β1 caused a decrease in active RhoA expression in uterine fibroid cells ( 301 ), while Fasudil, a ROCK inhibitor, relaxed the contraction of uterine fibroid cells in 3D collagen gels ( 278 ). It might be interesting to pursue potential antifibrotic effects of these pathway inhibitors in further studies.

Epigenetic Regulation

Tumorigenesis cannot be exclusively explained by genetic changes, as epigenetic processes are also involved ( 329 , 330 ). All epigenetics involved in regulation of gene activities, including DNA methylation, histone modification, non-coding RNA, and heterochromatinization, are disturbed in the pathogenomics of uterine fibroids ( 331 , 332 ).

Numerous data demonstrated aberrant alterations of genome methylation/demethylation in uterine fibroid cells ( 175 , 333 ). In addition, unsupervised clustering of results from DNA methylation analysis can segregate normal myometrium from uterine fibroids and classify uterine fibroids into subtypes according to MED12 mutation or the activation of HMGA2 or HMGA1 . Moreover, HOXA13 encoding the class of transcription factors called homeobox genes was identified to be hypomethylated and upregulated in fibroids compared to myometria. Abnormal HOXA13 expression was considered an essential factor contributing to the homeotic transformation into a more cervical phenotype which was linked to the development of uterine fibroids ( 135 ). MicroRNAs play a significant role in the epigenetic control of uterine fibroid development. Significant alteration in the synthesis profile of regulatory microRNAs of the families let7, miR-21, miR-93, miR-106b, miR-29, and miR-200 has been observed ( 334 , 335 ). More recently, studies on the role of long non-coding RNAs in the pathogenesis of uterine fibroids have been investigated, further demonstrating the critical role of RNA network in uterine fibroids ( 332 , 336-338 ). Epigenetic changes in the uterine fibroid genome can activate critical transduction signaling pathways, such as Wnt/β-catenin and Wnt/MAPK ( 320 , 339 ). More studies focusing on the epigenetic regulation of pathways involved in uterine fibroid pathogenesis can provide potential therapies against this disease.

Inflammation

Inflammation is a protective response from the immune system against foreign agents and involves immune cells and the release of molecular mediators. However, prolonged inflammatory status leaves the body in a constant state of alert and subsequently transforms into chronic inflammation. Chronic inflammation contributes to various conditions, including gynecologic diseases and cancer ( 340 , 341 ).

Tumor-extrinsic chronic systemic inflammation is caused by many factors, including obesity, tobacco smoking, autoimmune diseases, environmental chemical exposure, vitamin D deficiency, and excessive alcohol consumption ( 342 , 343 ). In addition, a normal cell can be transformed into a tumorous cell when repeatedly subjected to DNA damage during prolonged inflammatory status, thus triggering tumor-initiating mutations via impaired DNA repair pathways ( Fig. 2 ). Consequently, these genetic events may induce the proliferation, recruitment, and activation of inflammatory cells and increase the production of reactive oxygen species and cytokines, contributing to tumor-intrinsic inflammation ( 344 ).

Some epidemiological studies have explored the relationship between uterine fibroids and self-reported diagnosis of reproductive tract infection (RTIs) and inflammation ( 233 , 345 , 346 ). History of pelvic inflammatory disease and chlamydia infection, and intrauterine device use have been positive associated with uterine fibroid risk ( 233 ). In contrast, no association between uterine fibroids and self-reported diagnosis of pelvic inflammatory disease in African American and Caucasian women was found. However, a positive correlation with a self-reported history of chlamydia infection in Caucasian women and trichomonas, syphilis, and bacterial vaginosis in African American women has been reported ( 345 ). There is no significant association between self-reported RTIs and uterine fibroids. However, adverse associations of chlamydia infection and pelvic inflammatory disease with multiple fibroids have been reported ( 346 ). More studies using serology and biochemical characterization of past infections are needed to clarify the associations between RTIs and uterine fibroids. Interestingly, multiple associations between the higher occurrence of uterine fibroid inflammatory mediator gene polymorphisms, including interleukin (IL)-1β ( 347 , 348 ), IL-4 ( 349 ), TNF-α ( 349 , 350 ), IL-6 ( 351 ), IL-10 ( 348 ), and IL-12b receptor ( 352 ), have been reported.

A chronically active inflammatory immune system is suggested to be involved in uterine fibroid formation ( 341 , 353-355 ). It is hypothesized that in the uterus of a woman with a chronically inflammatory immune profile (due to chronic low-grade systemic inflammation) suffering a series of insults, including intrauterine infection, injury, and menses, the immune system response is exacerbated, thereby directly or indirectly inducing cell proliferation and fibrosis, which are implicated in the formation and growth of uterine fibroids ( 354 ). Numerous studies using molecular strategies and focusing on inflammatory mediators in the context of uterine fibroids have been conducted. They detected the expression of a significant number of cytokines and chemokines with proinflammatory and profibrotic features in uterine fibroids ( Table 1 ). Future research employing high-throughput methods and bioinformatic analysis should be conducted.

Inflammatory factors involved in uterine fibroids pathophysiology

Abbreviations: CCR5, C-C chemokine receptor type 5; CXCL12, C-X-C Motif Chemokine Ligand 12; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; INF-γ, interferon gamma; MCP-1, monocyte chemoattractant protein-1; MIP-1α/β, macrophage inflammatory protein 1 alpha/beta; NFkB, nuclear factor kappa B; PD-L1, programmed death-ligand 1; SCs, stem cells; TMA, tissue microarray; TNF-α, tumor necrosis factor alpha; TSLP, thymic stromal lymphopoietin; UF, uterine fibroid.

Compounds targeting key pathways involved in uterine fibroids pathogenesis

Abbreviations: Akt, protein kinase B; COMT, Catechol-O-methyltransferase; ECM, extracellular matrix; EGCG, epigallocatechin gallate; GnRH, gonadotropin-releasing hormone; HDAC, histone deacetylase; miR, microRNA; mTOR, mechanistic target of rapamycin; PI3K, phosphoinositide 3-kinase; SPRM, selective progesterone receptor modulator; TGF-β, transforming growth factor beta; PGR, progesterone receptor; UF, uterine fibroids.

The characterization of infiltrating and circulating immune cells in women with uterine fibroids has received increasing attention. More tissue-CD68-positive macrophages inside the uterine fibroids and in the surrounding myometrium have been found than in distant myometrium tissues (at least 1.5 cm from the border of fibroids). However, no differences in the number of CD45-positive leukocytes and MCT-positive mast cells have been observed ( 355 ). A recent study in a Chinese population demonstrated that the numbers of circulating CD4+CD8+ T cells, regulatory T (Treg, CD4+) cells, and T follicular helper (Tfh) cells was notably increased in patients with uterine fibroids relative to the healthy controls, whereas the numbers of natural killer (NK) and delta gamma (γδ) T cells (CD4− CD8−) was reduced ( 356 ). Furthermore, the levels of immune check-point PD-L1 proteins were increased in uterine fibroids compared to adjacent myometrial tissues ( 357 ). Interestingly, uterine fibroids demonstrated decreased PD-L1 expression and cytotoxic T-cell infiltration compared with malignant leiomyosarcomas, indicating that the immune system behavior spectrum varies among different uterine smooth muscle tumors ( 358 ).

The expression of growth factors and cytokines is partly regulated by ovarian steroid hormones ( 359 ), critical in uterine fibroids formation and growth ( 197 ). The relationship between uterine fibroid development and early-life exposure to xenoestrogen in the context of inflammation was recently revealed in an Eker rat animal model ( 360 ). The immune cells and secreted cytokines and chemokines may influence uterine fibroid development and the tumor microenvironment. The myometrial and systemic immune profiles of women with fibroids should be investigated better to understand the role of inflammation linking to epigenome ( 33 ) in uterine fibroid pathogenesis.

Role of Vitamin D Pathway

Vitamin D forms a complex with a specific receptor called the vitamin D receptor (VDR) to mediate its pleiotropic functions via steroid transcriptional mechanisms ( 361 ). VDR modulates the expression of various genes in a tissue-specific manner. Vitamin D exhibits antiproliferative and pro-apoptotic activities and induces cell differentiation in different diseases ( 82 , 362 ), including musculoskeletal, infectious, cardiovascular, metabolic, autoimmune, neurocognitive diseases, and cancers. The role and mechanism of vitamin D action in uterine fibroids have been investigated in the past decade. In 2011, the antifibrotic effect of vitamin D was reported, showing that vitamin D is associated with reduced expression of TGF-β3-induced ECM proteins, including fibronectin and collagen type 1 in uterine fibroid cells, which were otherwise overexpressed ( 363 ). Vitamin D also inhibited the growth and proliferation of uterine fibroid cells by downregulating proliferating cell nuclear antigen (PCNA), cyclin-dependent kinase 1 (CDK1), and B-cell lymphoma 2, and inhibiting the expression and activity of catechol-O-methyltransferase (COMT) ( 364 ). In addition, TGF-β3, a vital factor in the pathogenesis of uterine fibroids, was inhibited by increased concentrations of vitamin D ( 365 ). In the Eker rat uterine fibroid model, the administration of vitamin D decreased the size of uterine fibroids ( 366 ). In 2013, the regulatory role of vitamin D in the expression and activity of matrix metalloproteinases (MMPs), which are involved in ECM deposition, was revealed ( 99 ). Later, active vitamin D was reported to function as a potent anti-estrogen and antiprogesterone agent ( 367 ).

Furthermore, the administration of vitamin D reduced the levels of Wnt/β-catenin, leading to the downregulation of mTOR signaling expression in uterine fibroids with MED12 somatic mutations ( 321 ). The same study reported that vitamin D suppresses the expression of FEN1, an enzyme involved in DNA damage repair, in a concentration-dependent manner ( 321 ). In 2018, low serum vitamin D levels in animals were associated with increased expression of sex steroid receptors and proliferation-related genes, fibrosis, and enhanced inflammation. Vitamin D-deficient diet enhanced DNA damage in murine myometrium ( 368 ). Importantly, vitamin D also exhibits anti-inflammatory functions, and the inflammation-induced pathology of uterine fibroids has been described ( 369 ). Vitamin D suppressed the uterine fibroid phenotype by targeting different DNA repair networks ( 370 ). Recently it was reported that long-lasting and high-dose treatment with vitamin D induced significant lesion volume reduction through reduced cell proliferation via the inhibition of TGF-β3 expression and inducing apoptosis ( 371 ). Italian researchers found that vitamin D in women acted as an antiproliferative compound against small uterine fibroids ( 372 ) by arresting cell growth and inhibiting the Wnt/β-catenin pathway ( 322 ). Vitamin D effectively reduces proliferation and extracellular matrix formation in different molecular subtypes of uterine fibroids ( 371 ). In the first randomized study trial, the supplementation of 50 000 IU of vitamin D for 12 weeks inhibited lesion growth, whereas the volume of uterine fibroids in the placebo group increased ( 373 ).

Overall, the relationship between vitamin D and uterine fibroid metabolism has been characterized. Recently, our research team proposed a preliminary clinical instruction of 25(OH)D measurements and vitamin D supplementation that may be useful for clinicians involved in treating patients with uterine fibroids ( 374 ).

Role of the Microbiome

Foreign microorganisms colonizing our body include bacteria, yeasts, fungi, protozoa, archaea, and viruses; these are collectively referred to as the “microbiome” ( 375 ). The cells comprising the microbiome and the host are considered as a single ecological and biological unit, the so-called human halobiont .

Intestinal estrogen metabolism

Gut microbes shape the complex micro-ecological system of the human body ( 376 , 377 ). Many human intestinal microbes influence the physiological functions of the host and have profound effects on the synthesis and secretion of hormones, trace elements, growth factors, and immune system function. The intestinal flora and the host have a mutually beneficial relationship and are interdependent ( 377 ). The intestinal flora can be modified via hormone interaction both in vitro and in vivo, thus affecting the body’s biological equilibrium ( 378 ). Recently, whether the intestinal flora can control the levels of estrogen and its metabolites has been explored. The enzyme glucuronidase in the intestinal flora improved estrogen reabsorption ( 377 , 379 , 380 ). Several bacteria in the intestinal flora can metabolize estrogen, and they are referred to as the estrobolome . High bacterial enzyme activity of the estrobolome elevates the level of free estrogen in the enterohepatic circulation by promoting an endogenous hormonal environment, leading to an increase in hormone levels which may have a direct and indirect impact on the risk of uterine fibroids ( 381 ).

The abundance of the intestinal flora closely correlates to systemic estrogen. Many bacteria at the family and species levels control estrogen content, particularly Clostridium and Pneumococcus exhibit the most significant effect on estrogen metabolism ( 377 , 382 ). Reduced estrogen levels have been related to decreased intestinal flora diversity, including the phylum Bacteroidetes , and increased abundance of the phylum Firmicutes and species diversity of the phylum Proteobacteria ( 377 , 383 ). In addition, it has been shown that elevated levels of estrogen and its metabolites have related to the abundance of several taxa in the class Clostridia , including the order Clostridiales and the family Ruminococcaceae ( 384 ).

Wang et al have studied the effect of hysterectomy on the intestinal flora diversity, ie, the number of different species present, in patients with uterine fibroids ( 377 ). The top 3 dominant bacteria, Bacteroidetes, Proteobacteria , and Firmicutes , were the same in preoperative and postoperative patients at the phylum level. However, the enrichment of Bacteroidetes in postoperative patients was significantly lower than in preoperative patients, whereas the abundance of Proteobacteria was significantly higher. Although at the class level, Gammaproteobacteria, Bacteroidia , and Clostridia predominated in both groups, the author found a statistically higher abundance of Gammaproteobacteria (Proteobacteria) in patients after the surgery. Specifically, at the order level, the higher average abundance observed was in Enterobacteriales ( 377 ). Wang’s study reported that estrogen levels in the body could alter the intestinal flora; however, the underlying mechanism of this regulation remains unknown ( 377 ). Deeper analysis may help to understand whether gut microbiota could influence the risk of uterine fibroids through effects on endogenous estrogens.

Female reproductive tract sterility and uterine fibroid microbiome

For many years, the female reproductive tract was considered a sterile organ ( 30 , 385 , 386 ). Culture-based technologies were usually utilized to detect bacterial residence; however, they have limited applications as many microorganisms are difficult to culture in vitro. With the launch of the Human Microbiome Project in 2007, modern sequencing technologies using taxonomy-associated marker genes, such as the 16s rRNA gene or whole-genome sequences, have been used to distinguish bacteria at the species level ( 387 ). In addition, body sites that were historically supposed to be sterile are colonized by microorganisms ( 386 , 388 ). Specifically, the Human Microbiome Project reported that the uterine cavity harbors a unique microbiome ( 30 , 386 , 389 ). However, the specific function of the uterine microbiome remains unknown ( 385 , 389 ).

A pilot study evaluated the distribution of bacteria in African American women with uterine fibroids. The authors evaluated the bacterial diversity on the endometrium, adjacent myometrium, and uterine fibroids and compared them with samples from healthy controls. A greater diversity was found in the uterine fibroid patient samples compared with controls. In addition, uterine fibroid patients showed a significantly increased abundance of Bacteroidetes, Firmicutes , and Actinobacteria in the endometrium. At the general level, uterine fibroid tissues were significantly enriched in Clostridium, Allobaculum, Anaerostipes, Odoribacter, Turicibacter, Oscillospira, Ruminococcus, and Coprococcus , which are commonly associated with the gut environment. These results suggest that the systemic distribution of the gut bacteria extends to the uterus of patients with uterine fibroids, following dysbiosis or gut-barrier impairment ( 390 ). Further studies are needed to better understand whether the uterine microbiome play a role in the pathogenesis of uterine fibroids.

Conducting investigations using human tissue is critical for deciphering many normal and pathogenic processes and developing disease diagnosis techniques and future therapies. However, it could be a challenge to state the significance of the findings since uterine fibroid samples are obtained at a specific time point, at which limited information about biological samples is available. For example, whether the uterine fibroids are growing or shrinking at the time of sample collection is a relevant question. In addition, the heterogeneity of uterine fibroids also represent structural properties and collagen content changes ( 391 ), genetic ( 9 ), epigenetic ( 194 , 392 ), and cell type variations. Furthermore, due to the paracrine and mechanical effect of uterine fibroids, the manner of collecting the myometrium is a significant factor. Notably, the biology of myometrium from the uterus with fibroids or without fibroids differs ( 393 , 394 ). For these reasons and more, uterine fibroid studies need to be carefully designed and should take these factors into consideration. When working with samples, it is crucial to consider multiple factors, including race, age, BMI, menstrual cycle phase, driver mutations, to draw concise conclusions.

Integration of Multiple Pathways in Uterine Fibroids

It is important to emphasize that during the initiation and development of uterine fibroids, many biological events coincide, and multiple abnormal pathways interact, contributing to the pathogenesis of uterine fibroids. For instance, estrogen signaling activated the β-catenin pathway via the estrogen/receptor axis, therefore induced β-catenin nuclear translocation and enhanced β-catenin responsive gene expression in human uterine fibroids cells. Vitamin D3 has been associated with inhibiting the Wnt/ β-catenin, proinflammatory pathways, and ECM deposition in uterine fibroid cells ( 395 ) and restored the DNA repair capacity in both uterine fibroid cells and at-risk MMSCs ( 370 , 396 ). Diet-induced vitamin D deficiency triggered inflammation and DNA damage in murine myometrium ( 368 ). Moreover, VDR -knockdown in normal human myometrial cells increased DNA damage and inhibited DNA repair capacity ( 370 ). These studies suggested the interaction of the vitamin D3/receptor pathway with β-catenin and DNA repair pathway. Activator protein 1 (AP1) is a family of transcription factors consisting of FOS and JUN members that form homodimers or heterodimers involved in many biological processes, including differentiation, proliferation, apoptosis, and fibrotic diseases. Recent studies demonstrated that AP1 signaling promotes ECM deposition ( 397 ), and ECM activated β-catenin signaling in uterine fibroids ( 317 ). In addition, uterine fibroids expressed higher Class I HDAC enzyme levels than normal myometrial tissues, associated with activated β-catenin signaling. ( 320 ). Notably, MED12 mutations have been linked to multiple pathways directly implicated in uterine fibroid pathology as described ( 7 , 134 , 137 , 174 , 175 ). Considering that diverse pathways play a role in the pathogenesis of uterine fibroids ( Fig. 5 ), additional studies will be necessary to identify the molecular mechanism underlying the interaction network and signaling in uterine fibroids.

Uterine leiomyosarcoma is a rare, aggressive, malignant tumor, which originates from the smooth muscle layer in the uterus and shares many common clinical grounds with uterine fibroids ( 398 ). Approximately 6 out of every 1 000 000 women are diagnosed with uterine leiomyosarcoma yearly. Unfortunately, its prognosis is poor, with the lowest survival rates among soft-tissue sarcomas. Uterine leiomyosarcoma represents ~1% of all uterine malignancies, and the average age of patients ranges from 40 to 50 years. Uterine leiomyosarcoma mainly metastasizes to the lungs, liver, brain, kidney, and bones ( 399 ).

Characteristics Common Between Uterine Fibroids and Leiomyosarcoma

Notably, uterine leiomyosarcomas and uterine fibroids share several common clinicopathological features that complicate their differential diagnosis. First, both tumors arise from the myometrium as focal masses within the uterine wall. Second, abnormal uterine bleeding, pelvic pain/pressure, and a pelvic mass are the primary presenting signs and symptoms for both uterine leiomyosarcoma and uterine fibroids, making it difficult to differentiate between them ( 400-403 ). Third, uterine leiomyosarcoma and fibroids share morphological and molecular characteristics that cannot be differentiated through current clinical diagnostic tests. Finally, it is said that the Black women are at higher risk for both uterine fibroids and leiomyosarcoma ( 404 , 405 ). Because suspected uterine fibroids are often conservatively managed or with minimally invasive treatments, the misdiagnosis of leiomyosarcoma for a benign uterine fibroid could potentially result in significant treatment delays, increasing patient morbidity and mortality ( 406 ).

Malignant Transformation of Uterine Fibroids to Leiomyosarcomas

It has been debated whether uterine fibroids and uterine leiomyosarcoma are part of a disease continuum. Genetic studies have demonstrated that uterine leiomyosarcomas arise de novo and may be unrelated to benign fibroids. Uterine leiomyosarcoma typically has complex karyotypes and aneuploids, while uterine fibroids have characteristic rearrangements, many of which are shared by other benign neoplasms. Intermediate forms between these 2 patterns had not been described. However, recent microarray data identified a rare subset of uterine fibroids with deletions of chromosome 1 that have transcriptional profiles that cluster with those of uterine leiomyosarcoma, suggesting that some rare leiomyosarcomas may arise from a specific subset of uterine fibroids ( 407 ). Moreover, the observation that up to 4% to 30% of uterine leiomyosarcomas harbor exon 2 mutations in the established fibroids driver gene MED12 suggests that a subset of malignant leiomyosarcomas may derive from benign uterine fibroids ( 119 , 408 , 409 ). The discrepancy in the frequency of uterine fibroids and uterine leiomyosarcoma lies in the fact that only rare histological and karyotypic variants of fibroids may be responsive to malignant progression ( 410 ). Notably, a large number of random chromosomal aberrations in uterine leiomyosarcoma suggests that genomic instability is involved in the pathogenesis of these tumors, and such instability hinders efforts to identify the primary change(s) that may now be discovered through studies of variant uterine fibroids ( 411 ).

Novel therapeutic advances for the aggressive type of uterine cancer leiomyosarcoma are hindered by the overall lack of knowledge about the functional consequences of the complex genomic and pathway alterations found in patients and limited characterization of tumor biology. The employment of new models together with advanced technologies such as single-cell sequencing, mass cytometry, and other high-throughput approaches will ultimately help to characterize the mechanisms of its pathogenesis, resistance to conventional treatments and develop novel options for treating the patients with this aggressive disease.

Despite substantial progress in our understanding of the pathobiology of uterine fibroids, several gaps need to be addressed ( Fig. 6 ).

Future research prospects. Studies elucidating the interplay among genes, epigenome, and epitranscriptome in the context of stem cell biology, microbiome, and the interaction between the endometrium and uterine fibroids can advance the knowledge on the pathogenesis of uterine fibroids and are expected to contribute to developing novel therapeutic approaches for the treatment of patients with uterine fibroids. Abbreviations: ALKBH5, ALKB homolog 5; FTO, fat mass and obesity-associated protein; HMB: heavy menstrual bleeding; IGFBPs, insulin-like growth factor binding protein-3; METTL3,14, methyltransferase like 3 and 14; UFs, uterine fibroids; YTHDF1/YTHDC1, YTH domain-containing protein.

Transcriptome and Epigenome Analysis

The early-life environment dramatically affects the functions of developing organs and increases disease susceptibility across the lifespan. In a rat model, early-life exposure to DES affected several signaling pathways, including estrogen signaling, and reprogrammed histone mark H3K4me3 and DNA methylation patterns in MMSCs derived from the developing myometrium, thus accelerating the acquisition of an adult epigenomic signature. Furthermore, this epigenomic reprogramming persisted long after the initial exposure. These findings demonstrate the importance of the epigenome, that is, early interactions between the gene and environment reprogram the epigenome, and interactions in adulthood accelerate or activate restricted epigenetic reprogramming to increase genome instability and initiate fibroids pathogenesis. Omics studies also demonstrated that uterine fibroids contain disrupted epigenome linked with genetic stability ( 135 , 412 ). Notably, the myometrium of uterine fibroids patients has a distinct transcriptomic pattern compared with non-diseased myometrium ( 394 ), and cells from diseased myometrium responded differently to progesterone ( 413 ). These studies suggest that adjacent myometrium from the uterus with uterine fibroids should not be considered as normal tissue.

To further elucidate the role of interaction among the genes, epigenome, and environment in process of uterine fibroid pathogenesis, the following issues should be addressed. First, the genetic landscapes of normal, at-risk, and uterine fibroids stem cells should be characterized using genome-wide omics methods to better understand the genome, epigenome, and epitranscriptome. Second, the other insults that cause the abnormal reprogramming of MMSCs should be identified. Lastly, the interaction between early hits in early life and late hits in adult life should be explored in the context of uterine fibroid development.

Recently, the rapid development of single-cell multi-omics approaches is transforming our understanding of disease initiation and progression. Therefore, they can be utilized to assess the transcriptome, epigenome, spatial profiling, and proteome of uterine fibroids, contributing to increased knowledge on the cell state, ontogeny, epigenome state, phenotype, and function of uterine fibroids ( Fig. 6 ).

Epitranscriptomics

The epitranscriptome refers to the complete ensemble of chemical modifications affecting the RNA transcripts (coding and non-coding RNAs), and epitranscriptomics is an emerging field in molecular medicine with vast potential. To date, more than 160 different chemical modifications in RNA have been identified in living organisms. N6-methyladenosine (m 6 A) is the most pervasive, abundant, and conserved in eukaryotic mRNAs, occurring in ~25% of transcripts genome-wide, and it is enriched near stop codons, 5′- and 3′-untranslated regions, and within long internal exons ( 414 , 415 ). m 6 A is co-transcriptionally incorporated by so-called writers , including the METTL3-METTL14 core methyltransferase complex and associated proteins, such as RBM15, WTPA, and VIRMA, that confer target mRNA specificity, eliminated by demethylases FTO and ALKBH5 ( erasers ), and recognized by readers , including the YTH protein family ( Fig. 6 ). m 6 A-bound readers ultimately determine the posttranscriptional fate of methylated mRNAs by modulating cellular activities that control RNA stability, processing, and translation. m 6 A is thus a pervasive regulator of gene expression and a key determinant of cell fate and function. Accordingly, the disruption of its homeostasis has been implicated in several pathological conditions, including cancer. Thus far, epitranscriptomic studies on uterine fibroids are mainly unknown. However, several key m 6 A regulators were recently revealed to be dysregulated in uterine fibroids, suggesting that epitranscriptomics play an important role in uterine fibroid pathogenesis ( 416 , 417 ). However, more studies are needed to explore the function of the RNA methylation machinery and m 6 A in uterine fibroid development. Recently, a potent and selective catalytic inhibitor of METTL3 was developed and can reduce acute myeloid leukemia growth and increase differentiation and apoptosis, suggesting that targeting METTL3 as a potential therapeutic strategy against diseases such as acute myeloid leukemia. Therefore, investigations on epitranscriptomic targeting uterine fibroids should be conducted.

Endometrium Receptivity and Heavy Menstrual Bleeding

Uterine fibroids cause female reproductive disorders, including heavy menstrual bleeding and poor receptivity and implantation, leading to infertility and affecting millions of women globally. These disorders indicate endometrial dysfunctions and are related to the presence of adjacent uterine fibroids. Remarkably, the degree of dysfunction is associated with the location and size of the uterine fibroids ( 418 ). However, how fibroids affect endometrial functions remains unclear.

Uterine fibroid-caused expansion in the endometrial surface area generally results in more significant menstrual bleeding and transformations in the shape of uterine cells, thus eventually affecting gene expression and function. Furthermore, recent studies demonstrated that uterine fibroids could actively influence the adjacent endometrium and the entire uterine cavity ( 419 ). Therefore, elucidating the mechanism underlying the effect of uterine fibroids on the endometrium is necessary. In addition, the impact of uterine fibroids on endometrium function via exosome is a promising area to be explored ( 266 , 420 ) ( Fig. 6 ).

The impact of alterations in the endometrial microbiome on uterine fibroid pathogenesis has not been investigated. The paradigm that the uterus is a sterile environment remains highly controversial. The vagina contains trillions of bacterial cells, whereas the uterus and the Fallopian tubes are generally considered sterile. As alterations in the gut microbiota can lead to several pathologies, such as inflammation, autoimmune diseases, and obesity, it is proposed that the uterine microbiota may be altered in patients with uterine fibroids. A diverse microbiota has been detected in fibroids relative to other uterine tissues and those from healthy controls. In addition, uterine fibroids may associate with local and systemic inflammation that may promote the translocation of the gut microbiota into the endometrium. Future studies should explore the composition and identify the role of the microbiome in uterine fibroids. How bioactive metabolites from the microbiome provide the constituents of the fibroids microenvironment and affect the surrounding tissues should also be investigated ( Fig. 6 ).

Leiomyosarcoma

Although the current standard practice has been used to differentiate aggressive leiomyosarcoma from benign uterine fibroids, further studies are needed to explore early diagnosis tools to distinguish these 2 uterine tumors. Currently, several approaches are employed in basic research, which may lead to future clinical practice options.

Promoter-based imaging system

Uterine leiomyosarcoma is most often discovered by chance when a woman has a hysterectomy performed for uterine fibroids. To differentiate uterine leiomyosarcomas from fibroids with imaging, a molecular bio-imaging probe for noninvasive differentiation approach was recently established in a preclinical animal model ( 398 ). The diagnostic strategy was to use the cancer-specific enhanced survivin expression in malignant vs normal/benign cells to test its promoter driving potential of a downstream reporter gene that will detect cancer cells once activated. Because of solid promoter activity, tumor specificity, and capacity for clinical translation, survivin promoter-driven biological signal may represent a practical, new system to facilitate early leiomyosarcomas diagnosis. One study reported that adenovirus (Ad-SUR-LUC) was injected into the animals and paired the imaging reporter gene with a complementary imaging agent in a system that can be used to measure bioluminescence driven by the surviving promoter. This approach could distinguish leiomyosarcoma lesions from normal uterine tissue or benign uterine fibroid lesions with good accuracy. In this regard, this system can impact the management of suspicious uterine masses, a current major challenge in clinical gynecology.

Genetic and transcriptome profiling

In recent years, high-throughput sequencing technologies have provided unprecedented opportunities to depict the development of diseases at multiple molecular levels. The integration and analysis of these multi-omics datasets allow us to yield a better understanding and a clearer picture of the under-studied systems ( 421 , 422 ). Through integrated comparative genomic and transcriptomic analysis, differential genetic targets between uterine leiomyosarcoma and fibroids have been identified ( 423 , 424 ). In leiomyosarcomas, genetic mutation burden exhibited higher copy number variations, single nucleotide variants, small insertions/deletions, and gene fusions compared with uterine fibroids. Comparative genomic hybridization (CGH) array analysis reveals a chromosomal and genomic complexity starting from uterine fibroids, with few chromosomal alterations, to uterine leiomyosarcoma, which harbors many intrachromosomal damages, and chromothripsis as evidence of their genomic complexity ( 116 , 424 , 425 ). In addition, a differential transcriptomic profile was observed for uterine leiomyosarcomas ( 423 ). These novel genetic and transcriptional targets may be potential diagnostic markers to differentiate uterine leiomyosarcoma from fibroids ( 423 , 426 ).

Aberrant specific pathways

The Hedgehog pathway is one of the key regulators involved in many biological events. Malfunction of this pathway is associated with various diseases, including several types of female cancers ( 427 ). An initial study demonstrated that elevated expression of SMO and GLI 1, the key members of the Hedgehog pathway, was observed in leiomyosarcoma relative to normal myometrium and uterine fibroid tumors. In addition, overexpression of Hedgehog proteins was correlated with poor prognosis in leiomyosarcomas patients ( 428 ). A subsequent study demonstrated that the expression profile of Hedgehog signaling pathway markers and the response to Hedgehog pharmacological inhibition differed between leiomyosarcoma cells and fibroids cells ( 429 ). The expression of crucial Hedgehog members SMO and GLIs 1, 2, and 3 was upregulated in leiomyosarcoma cells, increasing the nuclear levels of GLI proteins. Treatment with LDE225 (SMO inhibitor) and Gant61 (GLI inhibitor) resulted in a significant reduction in GLI protein levels in leiomyosarcoma concomitantly with a decrease in leiomyosarcoma cell proliferation, migration, and invasion ( 429 ).

Additionally, the expression of DNMT members (1, 3a, and 3b) was upregulated in leiomyosarcoma compared to normal uterine smooth muscle cells. Treatment of leiomyosarcoma cells with DNMT inhibitor (5-Aza-dC) decreased the expression of SMO and GLI1 as well as nuclear translocation of GL1 and 2 concomitantly with a decrease in leiomyosarcoma cell proliferation, migration, and increase in leiomyosarcoma cell apoptosis ( 429 ). These studies showed that the Hedgehog pathway and DNA methylation network and their interaction might play an essential role in uterine leiomyosarcoma development.

Targeted Therapeutics

Targeted therapy exclusively focuses on uterine fibroid cells to shrink tumor lesions with minimal insult to surrounding tissues, not interfering with systemic hormones or fertility. Targeted therapies have been proposed via the local injection of collagenase from Clostridium histolyticum and gene therapy to deliver designed viral vectors. Collagenase can dissolve disorganized extracellular collagen fibers in uterine fibroids, and proof-of-principle studies have significantly reduced uterine fibroid size ( 430 , 431 ). Moreover, a phase I clinical trial with 15 women demonstrated the safety and tolerability of collagenase derived from C. histolyticum (NCT02889848). Localized targeted strategy via modified adenovirus vectors ( 432 , 433 ) resulted in reduced tumor size and showed the absence of adenovirus in surrounding tissues, uterine fibroid-targeting specificity, and good safety profile. Adenovirus expressing dominantly negative ERs has also been used, and inhibition of fibroid growth in nude mice was observed ( 434 ). Magnetic nanoparticles can enhance the effectiveness of gene therapy against both differentiated human fibroid cells and tumor-initiating stem cells ( 435 ). Using localized nonsurgical adenovirus-based alternative for the treatment of uterine fibroids, the combination of viral-based gene delivery and nanotechnology led to more efficient targeting of fibroid tumors, the lower viral dose required, and consequently, an overall safer profile ( 435 ). Novel targeted therapies against uterine fibroids with better efficacy profile are needed, especially for African American women.

In summary, considerable progress has been made in the past decade to study the interplay of steroid hormones, risk factors, stem cells, genetics, and epigenetics that contribute to the developmental origin and pathogenesis of uterine fibroids. Deeper mechanistic insights into uterine fibroids’ etiology and complexity will lead to long-term, fertility-friendly, and effective drugs for preventing patients with this common tumor.

Abbreviations

25-hydroxyvitamin D

protein kinase B

body mass index

diethylstilbestrol

double-stranded break

extracellular matrix

endocrine-disrupting chemical

estrogen receptor

enhancer of zeste homolog 2

fumarate hydratase

gonadotropin-releasing hormone

histone deacetylase

histone deacetylase inhibitor

high mobility group A

insulin-like growth factor 1

interleukin

mitogen-activated protein kinase

RNA polymerase II transcriptional mediator complex subunit 12

myometrial stem cells

mammalian target of rapamycin

phosphoinositide-3-kinase

reproductive tract infection

selective progesterone receptor modulator

tumor-associated fibroblast

transcriptional coactivator with PDZ-binding domain

transforming growth factor β

tumor necrosis factor-α

vitamin D receptor

Yes-associated protein

We would like to thank Dr. Darlene Dixon for critically reviewing our manuscript and Ms. Jinda Sekhon for editing our manuscript. Figures were created using BioRender.

Financial Support: This work was supported in part by National Institutes of Health (grant numbers: RO1 ES028615, RO1 HD094378, U54 MD007602, RO1 087417, RO1 HD094380, and HD106285).

Author Contributions: Q.Y. and A.A. conceived the manuscript. M.V.B., T.B., and Q.Y. contributed to the figures. M.V.B., M.A., and Q.Y. contributed to the tables. All authors wrote sections of the manuscript.

Disclosures: Dr. Ayman Al-Hendy is a consultant for Abb-vie, Myovant, and OBS-EVA. No conflicts are declared for the remaining authors.

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Al-Hendy A , Myers ER , Stewart E . Uterine fibroids: burden and unmet medical need . Semin Reprod Med. 2017 ; 35 ( 6 ): 473 - 480 .

Google Scholar

Wise LA , Laughlin-Tommaso SK . Epidemiology of uterine fibroids: from menarche to menopause . Clin Obstet Gynecol. 2016 ; 59 ( 1 ): 2 - 24 .

Baird DD , Dunson DB , Hill MC , Cousins D , Schectman JM . High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence . Am J Obstet Gynecol. 2003 ; 188 ( 1 ): 100 - 107 .

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 ( 4 ): e0215646 .

Stewart EA , Laughlin-Tommaso SK , Catherino WH , Lalitkumar S , Gupta D , Vollenhoven B . Uterine fibroids . Nat Rev Dis Primers. 2016 ; 2 : 16043 .

Hodge JC , Quade BJ , Rubin MA , Stewart EA , Dal Cin P , Morton CC . Molecular and cytogenetic characterization of plexiform leiomyomata provide further evidence for genetic heterogeneity underlying uterine fibroids . Am J Pathol. 2008 ; 172 ( 5 ): 1403 - 1410 .

Mäkinen N , Mehine M , Tolvanen J , et al.  MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas . Science. 2011 ; 334 ( 6053 ): 252 - 255 .

McGuire MM , Yatsenko A , Hoffner L , Jones M , Surti U , Rajkovic A . Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas . Plos One. 2012 ; 7 ( 3 ): e33251 .

Yatsenko SA , Mittal P , Wood-Trageser MA , et al.  Highly heterogeneous genomic landscape of uterine leiomyomas by whole exome sequencing and genome-wide arrays . Fertil Steril. 2017 ; 107 ( 2 ): 457 - 466.e9 .

Heinonen HR , Pasanen A , Heikinheimo O , et al.  Multiple clinical characteristics separate MED12-mutation-positive and -negative uterine leiomyomas . Sci Rep. 2017 ; 7 ( 1 ): 1015 .

Jamaluddin MFB , Nahar P , Tanwar PS . Proteomic characterization of the extracellular matrix of human uterine fibroids . Endocrinology. 2018 ; 159 ( 7 ): 2656 - 2669 .

Jamaluddin MFB , Ko YA , Kumar M , et al.  Proteomic profiling of human uterine fibroids reveals upregulation of the extracellular matrix protein periostin . Endocrinology. 2018 ; 159 ( 2 ): 1106 - 1118 .

Heinonen HR , Mehine M , Mäkinen N , et al.  Global metabolomic profiling of uterine leiomyomas . Br J Cancer. 2017 ; 117 ( 12 ): 1855 - 1864 .

Holdsworth-Carson SJ , Zhao D , Cann L , Bittinger S , Nowell CJ , Rogers PA . Differences in the cellular composition of small versus large uterine fibroids . Reproduction. 2016 ; 152 ( 5 ): 467 - 480 .

Tinelli A , Malvasi A , Hurst BS , et al.  Surgical management of neurovascular bundle in uterine fibroid pseudocapsule . JSLS. 2012 ; 16 ( 1 ): 119 - 129 .

Tinelli A , Mynbaev OA , Sparic R , et al.  Angiogenesis and vascularization of uterine leiomyoma: clinical value of pseudocapsule containing peptides and neurotransmitters . Curr Protein Pept Sci. 2017 ; 18 ( 2 ): 129 - 139 .

Tinelli A , Kosmas I , Mynbaev OA , et al.  Submucous fibroids, fertility, and possible correlation to pseudocapsule thickness in reproductive surgery . Biomed Res Int. 2018 ; 2018 : 2804830 .

Tinelli A , Favilli A , Lasmar RB , et al.  The importance of pseudocapsule preservation during hysteroscopic myomectomy . Eur J Obstet Gynecol Reprod Biol. 2019 ; 243 : 179 - 184 .

Stewart EA . Uterine fibroids . Lancet. 2001 ; 357 ( 9252 ): 293 - 298 .

Walker CL , Stewart EA . Uterine fibroids: the elephant in the room . Science. 2005 ; 308 ( 5728 ): 1589 - 1592 .

Cardozo ER , Clark AD , Banks NK , Henne MB , Stegmann BJ , Segars JH . The estimated annual cost of uterine leiomyomata in the United States . Am J Obstet Gynecol. 2012 ; 206 ( 3 ): 211.e1 - 211.e9 .

Lee M , Chung YJ , Kim HK , et al.  Estimated prevalence and incidence of uterine leiomyoma, and its treatment trend in South Korean women for 12 years: a national population-based study . J Womens Health (Larchmt). 2021 ; 30 ( 7 ): 1038 - 1046 .

Ciebiera M , Włodarczyk M , Słabuszewska-Jóźwiak A , Nowicka G , Jakiel G . Influence of vitamin D and transforming growth factor β3 serum concentrations, obesity, and family history on the risk for uterine fibroids . Fertil Steril. 2016 ; 106 ( 7 ): 1787 - 1792 .

Faerstein E , Szklo M , Rosenshein N . Risk factors for uterine leiomyoma: a practice-based case-control study. I. African-American heritage, reproductive history, body size, and smoking . Am J Epidemiol. 2001 ; 153 ( 1 ): 1 - 10 .

Wise LA , Palmer JR , Spiegelman D , et al.  Influence of body size and body fat distribution on risk of uterine leiomyomata in U.S. black women . Epidemiology. 2005 ; 16 ( 3 ): 346 - 354 .

Ciebiera M , Wlodarczyk M , Ciebiera M , Zareba K , Lukaszuk K , Jakiel G . Vitamin D and uterine fibroids-review of the literature and novel concepts . Int J Mol Sci . 2018 ; 19 ( 7 ). doi: 10.3390/ijms19072051 .

Sabry M , Halder SK , Allah AS , Roshdy E , Rajaratnam V , Al-Hendy A . Serum vitamin D3 level inversely correlates with uterine fibroid volume in different ethnic groups: a cross-sectional observational study . Int J Womens Health. 2013 ; 5 : 93 - 100 .

Mohammadi R , Tabrizi R , Hessami K , et al.  Correlation of low serum vitamin-D with uterine leiomyoma: a systematic review and meta-analysis . Reprod Biol Endocrinol. 2020 ; 18 ( 1 ): 85 .

Ciebiera M , Szymańska-Majchrzak J , Sentkowska A , et al.  Alpha-tocopherol serum levels are increased in caucasian women with uterine fibroids: a pilot study . Biomed Res Int. 2018 ; 2018 : 6793726 .

Baker JM , Chase DM , Herbst-Kralovetz MM . Uterine microbiota: residents, tourists, or invaders? Front Immunol. 2018 ; 9 : 208 .

Lee G , Kim S , Bastiaensen M , et al.  Exposure to organophosphate esters, phthalates, and alternative plasticizers in association with uterine fibroids . Environ Res. 2020 ; 189 : 109874 .

Bariani MV , Rangaswamy R , Siblini H , Yang Q , Al-Hendy A , Zota AR . The role of endocrine-disrupting chemicals in uterine fibroid pathogenesis . Curr Opin Endocrinol Diabetes Obes. 2020 ; 27 ( 6 ): 380 - 387 .

Yang Q , Ali M , El Andaloussi A , Al-Hendy A . The emerging spectrum of early life exposure-related inflammation and epigenetic therapy . Cancer Stud Mol Med. 2018 ; 4 ( 1 ): 13 - 23 .

Wong JY , Chang PY , Gold EB , Johnson WO , Lee JS . Environmental tobacco smoke and risk of late-diagnosis incident fibroids in the Study of Women’s Health across the Nation (SWAN) . Fertil Steril. 2016 ; 106 ( 5 ): 1157 - 1164 .

Takala H , Yang Q , El Razek AMA , Ali M , Al-Hendy A . Alcohol consumption and risk of uterine fibroids . Curr Mol Med. 2020 ; 20 ( 4 ): 247 - 258 .

Baird DD , Patchel SA , Saldana TM , et al.  Uterine fibroid incidence and growth in an ultrasound-based, prospective study of young African Americans . Am J Obstet Gynecol. 2020 ; 223 ( 3 ): 402.e1 - 402.e18 .

Marsh EE , Al-Hendy A , Kappus D , Galitsky A , Stewart EA , Kerolous M . Burden, prevalence, and treatment of uterine fibroids: a survey of U.S. Women . J Womens Health (Larchmt). 2018 ; 27 ( 11 ): 1359 - 1367 .

Jager KJ , Tripepi G , Chesnaye NC , Dekker FW , Zoccali C , Stel VS . Where to look for the most frequent biases? Nephrology (Carlton). 2020 ; 25 ( 6 ): 435 - 441 .

Marshall LM , Spiegelman D , Barbieri RL , et al.  Variation in the incidence of uterine leiomyoma among premenopausal women by age and race . Obstet Gynecol. 1997 ; 90 ( 6 ): 967 - 973 .

Wise LA , Palmer JR , Stewart EA , Rosenberg L . Age-specific incidence rates for self-reported uterine leiomyomata in the Black Women’s Health Study . Obstet Gynecol. 2005 ; 105 ( 3 ): 563 - 568 .

Wright KN , Laufer MR . Leiomyomas in adolescents . Fertil Steril. 2011 ; 95 ( 7 ): 2434.e15 - 2434.e17 .

Moroni RM , Vieira CS , Ferriani RA , Reis RM , Nogueira AA , Brito LG . Presentation and treatment of uterine leiomyoma in adolescence: a systematic review . BMC Womens Health. 2015 ; 15 : 4 .

Yang CH , Lee JN , Hsu SC , Kuo CH , Tsai EM . Effect of hormone replacement therapy on uterine fibroids in postmenopausal women–a 3-year study . Maturitas. 2002 ; 43 ( 1 ): 35 - 39 .

Stewart EA , Cookson CL , Gandolfo RA , Schulze-Rath R . Epidemiology of uterine fibroids: a systematic review . BJOG. 2017 ; 124 ( 10 ): 1501 - 1512 .

Eltoukhi HM , Modi MN , Weston M , Armstrong AY , Stewart EA . The health disparities of uterine fibroid tumors for African American women: a public health issue . Am J Obstet Gynecol. 2014 ; 210 ( 3 ): 194 - 199 .

Stewart EA , Nicholson WK , Bradley L , Borah BJ . The burden of uterine fibroids for African-American women: results of a national survey . J Womens Health (Larchmt). 2013 ; 22 ( 10 ): 807 - 816 .

Al-Hendy A , Salama SA . Catechol-O-methyltransferase polymorphism is associated with increased uterine leiomyoma risk in different ethnic groups . J Soc Gynecol Investig. 2006 ; 13 ( 2 ): 136 - 144 .

Baird DD , Hill MC , Schectman JM , Hollis BW . Vitamin D and the risk of uterine fibroids . Epidemiology. 2013 ; 24 ( 3 ): 447 - 453 .

Brakta S , Diamond JS , Al-Hendy A , Diamond MP , Halder SK . Role of vitamin D in uterine fibroid biology . Fertil Steril. 2015 ; 104 ( 3 ): 698 - 706 .

Geronimus AT , Hicken M , Keene D , Bound J . “Weathering” and age patterns of allostatic load scores among blacks and whites in the United States . Am J Public Health. 2006 ; 96 ( 5 ): 826 - 833 .

Van Dyke ME , Baumhofer NK , Slopen N , et al.  Pervasive discrimination and allostatic load in African American and white adults . Psychosom Med. 2020 ; 82 ( 3 ): 316 - 323 .

Williams DR , Mohammed SA . Discrimination and racial disparities in health: evidence and needed research . J Behav Med. 2009 ; 32 ( 1 ): 20 - 47 .

Wise LA , Palmer JR , Cozier YC , Hunt MO , Stewart EA , Rosenberg L . Perceived racial discrimination and risk of uterine leiomyomata . Epidemiology. 2007 ; 18 ( 6 ): 747 - 757 .

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 ( 4 ): 294 - 298 .

Thompson VL . Perceived experiences of racism as stressful life events . Community Ment Health J. 1996 ; 32 ( 3 ): 223 - 233 .

Paradies Y , Ben J , Denson N , et al.  Racism as a determinant of health: a systematic review and meta-analysis . Plos One. 2015 ; 10 ( 9 ): e0138511 .

Dhama K , Latheef SK , Dadar M , et al.  Biomarkers in stress related diseases/disorders: diagnostic, prognostic, and therapeutic values . Front Mol Biosci. 2019 ; 6 : 91 .

Matyakhina L , Freedman RJ , Bourdeau I , et al.  Hereditary leiomyomatosis associated with bilateral, massive, macronodular adrenocortical disease and atypical Cushing syndrome: a clinical and molecular genetic investigation . J Clin Endocrinol Metab. 2005 ; 90 ( 6 ): 3773 - 3779 .

Herrera AY , Nielsen SE , Mather M . Stress-induced increases in progesterone and cortisol in naturally cycling women . Neurobiol Stress. 2016 ; 3 : 96 - 104 .

Puder JJ , Freda PU , Goland RS , Ferin M , Wardlaw SL . Stimulatory effects of stress on gonadotropin secretion in estrogen-treated women . J Clin Endocrinol Metab. 2000 ; 85 ( 6 ): 2184 - 2188 .

Simons RL , Lei MK , Beach SRH , et al.  Discrimination, segregation, and chronic inflammation: Testing the weathering explanation for the poor health of Black Americans . Dev Psychol. 2018 ; 54 ( 10 ): 1993 - 2006 .

Romieu I , Dossus L , Barquera S , et al. ; IARC working group on Energy Balance and Obesity . Energy balance and obesity: what are the main drivers? Cancer Causes Control. 2017 ; 28 ( 3 ): 247 - 258 .

Afzal S , Brøndum-Jacobsen P , Bojesen SE , Nordestgaard BG . Vitamin D concentration, obesity, and risk of diabetes: a Mendelian randomisation study . Lancet Diabetes Endocrinol. 2014 ; 2 ( 4 ): 298 - 306 .

Sun K , Xie Y , Zhao N , Li Z . A case-control study of the relationship between visceral fat and development of uterine fibroids . Exp Ther Med. 2019 ; 18 ( 1 ): 404 - 410 .

Ellulu MS , Patimah I , Khaza’ai H , Rahmat A , Abed Y . Obesity and inflammation: the linking mechanism and the complications . Arch Med Sci. 2017 ; 13 ( 4 ): 851 - 863 .

Shozu M , Murakami K , Inoue M . Aromatase and leiomyoma of the uterus . Semin Reprod Med. 2004 ; 22 ( 1 ): 51 - 60 .

Bulun SE , Imir G , Utsunomiya H , et al.  Aromatase in endometriosis and uterine leiomyomata . J Steroid Biochem Mol Biol. 2005 ; 95 ( 1-5 ): 57 - 62 .

Bulun SE , Lin Z , Imir G , et al.  Regulation of aromatase expression in estrogen-responsive breast and uterine disease: from bench to treatment . Pharmacol Rev. 2005 ; 57 ( 3 ): 359 - 383 .

Hautanen A . Synthesis and regulation of sex hormone-binding globulin in obesity . Int J Obes Relat Metab Disord. 2000 ; 24 Suppl 2 : S64 - S70 .

Baird DD , Dunson DB , Hill MC , Cousins D , Schectman JM . Association of physical activity with development of uterine leiomyoma . Am J Epidemiol. 2007 ; 165 ( 2 ): 157 - 163 .

Shikora SA , Niloff JM , Bistrian BR , Forse RA , Blackburn GL . Relationship between obesity and uterine leiomyomata . Nutrition. 1991 ; 7 ( 4 ): 251 - 255 .

Yang Y , He Y , Zeng Q , Li S . Association of body size and body fat distribution with uterine fibroids among Chinese women . J Womens Health (Larchmt). 2014 ; 23 ( 7 ): 619 - 626 .

Parazzini F , Negri E , La Vecchia C , Chatenoud L , Ricci E , Guarnerio P . Reproductive factors and risk of uterine fibroids . Epidemiology. 1996 ; 7 ( 4 ): 440 - 442 .

Sommer EM , Balkwill A , Reeves G , Green J , Beral DV , Coffey K ; Million Women Study Collaborators . Effects of obesity and hormone therapy on surgically-confirmed fibroids in postmenopausal women . Eur J Epidemiol. 2015 ; 30 ( 6 ): 493 - 499 .

Okolo S . Incidence, aetiology and epidemiology of uterine fibroids . Best Pract Res Clin Obstet Gynaecol. 2008 ; 22 ( 4 ): 571 - 588 .

Baird DD , Dunson DB . Why is parity protective for uterine fibroids? Epidemiology. 2003 ; 14 ( 2 ): 247 - 250 .

Laughlin SK , Herring AH , Savitz DA , et al.  Pregnancy-related fibroid reduction . Fertil Steril. 2010 ; 94 ( 6 ): 2421 - 2423 .

Boynton-Jarrett R , Rich-Edwards J , Malspeis S , Missmer SA , Wright R . A prospective study of hypertension and risk of uterine leiomyomata . Am J Epidemiol. 2005 ; 161 ( 7 ): 628 - 638 .

Radin RG , Rosenberg L , Palmer JR , Cozier YC , Kumanyika SK , Wise LA . Hypertension and risk of uterine leiomyomata in US black women . Hum Reprod. 2012 ; 27 ( 5 ): 1504 - 1509 .

Takeda T , Sakata M , Isobe A , et al.  Relationship between metabolic syndrome and uterine leiomyomas: a case-control study . Gynecol Obstet Invest. 2008 ; 66 ( 1 ): 14 - 17 .

Holick MF . Vitamin D deficiency . N Engl J Med. 2007 ; 357 ( 3 ): 266 - 281 .

Bikle D . Vitamin D: production, metabolism, and mechanisms of action . In: Feingold KR , Anawalt B , Boyce A , et al. , eds. Endotext . MDText.com, Inc; 2000 .

Google Preview

Nair R , Maseeh A . Vitamin D: The “sunshine” vitamin . J Pharmacol Pharmacother. 2012 ; 3 ( 2 ): 118 - 126 .

Norman AW . From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health . Am J Clin Nutr . 2008 ; 88 ( 2 ): 491S - 499S .

Wacker M , Holick MF . Sunlight and Vitamin D: A global perspective for health . Dermatoendocrinol. 2013 ; 5 ( 1 ): 51 - 108 .

Prentice A , Schoenmakers I , Jones KS , Jarjou LM , Goldberg GR . Vitamin D deficiency and its health consequences in Africa . Clin Rev Bone Miner Metab. 2009 ; 7 : 94 - 106 .

Zhao G , Ford ES , Tsai J , Li C , Croft JB . Factors associated with vitamin D deficiency and inadequacy among women of childbearing age in the United States . ISRN Obstet Gynecol. 2012 ; 2012 : 691486 .

Clemens TL , Adams JS , Henderson SL , Holick MF . Increased skin pigment reduces the capacity of skin to synthesise vitamin D3 . Lancet. 1982 ; 1 ( 8263 ): 74 - 76 .

Pilz S , Zittermann A , Trummer C , et al.  Vitamin D testing and treatment: a narrative review of current evidence . Endocr Connect. 2019 ; 8 ( 2 ): R27 - R43 .

Holick MF . Vitamin D status: measurement, interpretation, and clinical application . Ann Epidemiol. 2009 ; 19 ( 2 ): 73 - 78 .

Holick MF , Binkley NC , Bischoff-Ferrari HA , et al. ; Endocrine Society . Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline . J Clin Endocrinol Metab. 2011 ; 96 ( 7 ): 1911 - 1930 .

Rosen CJ , Abrams SA , Aloia JF , et al.  IOM committee members respond to Endocrine Society vitamin D guideline . J Clin Endocrinol Metab. 2012 ; 97 ( 4 ): 1146 - 1152 .

Kennel KA , Drake MT , Hurley DL . Vitamin D deficiency in adults: when to test and how to treat . Mayo Clin Proc. 2010 ; 85 ( 8 ): 752 - 7; quiz 757 .

Jukic AMZ , Upson K , Harmon QE , Baird DD . Increasing serum 25-hydroxyvitamin D is associated with reduced odds of long menstrual cycles in a cross-sectional study of African American women . Fertil Steril. 2016 ; 106 ( 1 ): 172 - 179.e2 .

Nandi A , Sinha N , Ong E , Sonmez H , Poretsky L . Is there a role for vitamin D in human reproduction? Horm Mol Biol Clin Investig. 2016 ; 25 ( 1 ): 15 - 28 .

Triunfo S , Lanzone A . Potential impact of maternal vitamin D status on obstetric well-being . J Endocrinol Invest. 2016 ; 39 ( 1 ): 37 - 44 .

Bläuer M , Rovio PH , Ylikomi T , Heinonen PK . Vitamin D inhibits myometrial and leiomyoma cell proliferation in vitro . Fertil Steril. 2009 ; 91 ( 5 ): 1919 - 1925 .

Halder SK , Osteen KG , Al-Hendy A . Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and -9 in human uterine fibroid cells . Hum Reprod. 2013 ; 28 ( 9 ): 2407 - 2416 .

Halder SK , Osteen KG , Al-Hendy A . 1,25-dihydroxyvitamin d3 reduces extracellular matrix-associated protein expression in human uterine fibroid cells . Biol Reprod. 2013 ; 89 ( 6 ): 150 .

Paffoni A , Somigliana E , Vigano’ P , et al.  Vitamin D status in women with uterine leiomyomas . J Clin Endocrinol Metab. 2013 ; 98 ( 8 ): E1374 - E1378 .

Chiaffarino F , Parazzini F , La Vecchia C , Chatenoud L , Di Cintio E , Marsico S . Diet and uterine myomas . Obstet Gynecol. 1999 ; 94 ( 3 ): 395 - 398 .

Parker WH . Etiology, symptomatology, and diagnosis of uterine myomas . Fertil Steril. 2007 ; 87 ( 4 ): 725 - 736 .

Wise LA , Radin RG , Palmer JR , Kumanyika SK , Boggs DA , Rosenberg L . Intake of fruit, vegetables, and carotenoids in relation to risk of uterine leiomyomata . Am J Clin Nutr. 2011 ; 94 ( 6 ): 1620 - 1631 .

Wise LA , Radin RG , Kumanyika SK , Ruiz-Narváez EA , Palmer JR , Rosenberg L . Prospective study of dietary fat and risk of uterine leiomyomata . Am J Clin Nutr. 2014 ; 99 ( 5 ): 1105 - 1116 .

Harris SS . Vitamin D and African Americans . J Nutr. 2006 ; 136 ( 4 ): 1126 - 1129 .

Chwalisz K , Taylor H . Current and emerging medical treatments for uterine fibroids . Semin Reprod Med. 2017 ; 35 ( 6 ): 510 - 522 .

Marshall LM , Spiegelman D , Goldman MB , et al.  A prospective study of reproductive factors and oral contraceptive use in relation to the risk of uterine leiomyomata . Fertil Steril. 1998 ; 70 ( 3 ): 432 - 439 .

Marshall LM , Spiegelman D , Manson JE , et al.  Risk of uterine leiomyomata among premenopausal women in relation to body size and cigarette smoking . Epidemiology. 1998 ; 9 ( 5 ): 511 - 517 .

Chiaffarino F , Parazzini F , La Vecchia C , Marsico S , Surace M , Ricci E . Use of oral contraceptives and uterine fibroids: results from a case-control study . Br J Obstet Gynaecol. 1999 ; 106 ( 8 ): 857 - 860 .

Islam MS , Segars JH , Castellucci M , Ciarmela P . Dietary phytochemicals for possible preventive and therapeutic option of uterine fibroids: Signaling pathways as target . Pharmacol Rep. 2017 ; 69 ( 1 ): 57 - 70 .

Islam MS , Akhtar MM , Segars JH , Castellucci M , Ciarmela P . Molecular targets of dietary phytochemicals for possible prevention and therapy of uterine fibroids: Focus on fibrosis . Crit Rev Food Sci Nutr. 2017 ; 57 ( 17 ): 3583 - 3600 .

Ali M , Al-Hendy A . Uterine fibroid therapy: the pharmacokinetic considerations . Expert Opin Drug Metab Toxicol. 2018 ; 14 ( 9 ): 887 - 889 .

Gao M , Wang H . Frequent milk and soybean consumption are high risks for uterine leiomyoma: A prospective cohort study . Medicine (Baltimore). 2018 ; 97 ( 41 ): e12009 .

Orta OR , Terry KL , Missmer SA , Harris HR . Dairy and related nutrient intake and risk of uterine leiomyoma: a prospective cohort study . Hum Reprod. 2020 ; 35 ( 2 ): 453 - 463 .

Croce S , Ribeiro A , Brulard C , et al.  Uterine smooth muscle tumor analysis by comparative genomic hybridization: a useful diagnostic tool in challenging lesions . Mod Pathol. 2015 ; 28 ( 7 ): 1001 - 1010 .

Mehine M , Mäkinen N , Heinonen HR , Aaltonen LA , Vahteristo P . Genomics of uterine leiomyomas: insights from high-throughput sequencing . Fertil Steril. 2014 ; 102 ( 3 ): 621 - 629 .

Mäkinen N , Heinonen HR , Moore S , Tomlinson IP , van der Spuy ZM , Aaltonen LA . MED12 exon 2 mutations are common in uterine leiomyomas from South African patients . Oncotarget. 2011 ; 2 ( 12 ): 966 - 969 .

Kämpjärvi K , Mäkinen N , Kilpivaara O , et al.  Somatic MED12 mutations in uterine leiomyosarcoma and colorectal cancer . Br J Cancer. 2012 ; 107 ( 10 ): 1761 - 1765 .

Je EM , Kim MR , Min KO , Yoo NJ , Lee SH . Mutational analysis of MED12 exon 2 in uterine leiomyoma and other common tumors . Int J Cancer. 2012 ; 131 ( 6 ): E1044 - E1047 .

Markowski DN , Bartnitzke S , Löning T , Drieschner N , Helmke BM , Bullerdiek J . MED12 mutations in uterine fibroids–their relationship to cytogenetic subgroups . Int J Cancer. 2012 ; 131 ( 7 ): 1528 - 1536 .

Markowski DN , Huhle S , Nimzyk R , Stenman G , Löning T , Bullerdiek J . MED12 mutations occurring in benign and malignant mammalian smooth muscle tumors . Genes Chromosomes Cancer. 2013 ; 52 ( 3 ): 297 - 304 .

Sadeghi S , Khorrami M , Amin-Beidokhti M , et al.  The study of MED12 gene mutations in uterine leiomyomas from Iranian patients . Tumour Biol. 2016 ; 37 ( 2 ): 1567 - 1571 .

Shahbazi S , Fatahi N , Amini-Moghaddam S . Somatic mutational analysis of MED12 exon 2 in uterine leiomyomas of Iranian women . Am J Cancer Res. 2015 ; 5 ( 8 ): 2441 - 2446 .

Halder SK , Laknaur A , Miller J , Layman LC , Diamond M , Al-Hendy A . Novel MED12 gene somatic mutations in women from the Southern United States with symptomatic uterine fibroids . Mol Genet Genomics. 2015 ; 290 ( 2 ): 505 - 511 .

Wang H , Ye J , Qian H , Zhou R , Jiang J , Ye L . High-resolution melting analysis of MED12 mutations in uterine leiomyomas in Chinese patients . Genet Test Mol Biomarkers. 2015 ; 19 ( 3 ): 162 - 166 .

Wu B , Słabicki M , Sellner L , et al.  MED12 mutations and NOTCH signalling in chronic lymphocytic leukaemia . Br J Haematol. 2017 ; 179 ( 3 ): 421 - 429 .

Park MJ , Shen H , Kim NH , et al.  Mediator kinase disruption in MED12-mutant uterine fibroids from Hispanic women of south Texas . J Clin Endocrinol Metab. 2018 ; 103 ( 11 ): 4283 - 4292 .

Kämpjärvi K , Park MJ , Mehine M , et al.  Mutations in Exon 1 highlight the role of MED12 in uterine leiomyomas . Hum Mutat. 2014 ; 35 ( 9 ): 1136 - 1141 .

Hodge JC , Pearce KE , Clayton AC , Taran FA , Stewart EA . Uterine cellular leiomyomata with chromosome 1p deletions represent a distinct entity . Am J Obstet Gynecol. 2014 ; 210 ( 6 ): 572.e1 - 572.e7 .

Nezhad MH , Drieschner N , Helms S , et al.  6p21 rearrangements in uterine leiomyomas targeting HMGA1 . Cancer Genet Cytogenet. 2010 ; 203 ( 2 ): 247 - 252 .

Vanharanta S , Pollard PJ , Lehtonen HJ , et al.  Distinct expression profile in fumarate-hydratase-deficient uterine fibroids . Hum Mol Genet. 2006 ; 15 ( 1 ): 97 - 103 .

Vanharanta S , Wortham NC , Laiho P , et al.  7q deletion mapping and expression profiling in uterine fibroids . Oncogene. 2005 ; 24 ( 43 ): 6545 - 6554 .

Mehine M , Kaasinen E , Heinonen HR , et al.  Integrated data analysis reveals uterine leiomyoma subtypes with distinct driver pathways and biomarkers . Proc Natl Acad Sci U S A. 2016 ; 113 ( 5 ): 1315 - 1320 .

George JW , Fan H , Johnson B , et al.  Integrated epigenome, exome, and transcriptome analyses reveal molecular subtypes and homeotic transformation in uterine fibroids . Cell Rep. 2019 ; 29 ( 12 ): 4069 - 4085.e6 .

He C , Nelson W , Li H , et al.  Frequency of MED12 mutation in relation to tumor and patient’s clinical characteristics: a meta-analysis . Reprod Sci . Published online February 10, 2021 . doi: 10.1007/s43032-021-00473-x

Clark AD , Oldenbroek M , Boyer TG . Mediator kinase module and human tumorigenesis . Crit Rev Biochem Mol Biol. 2015 ; 50 ( 5 ): 393 - 426 .

Lim WK , Ong CK , Tan J , et al.  Exome sequencing identifies highly recurrent MED12 somatic mutations in breast fibroadenoma . Nat Genet. 2014 ; 46 ( 8 ): 877 - 880 .

Yoshida M , Sekine S , Ogawa R , et al.  Frequent MED12 mutations in phyllodes tumours of the breast . Br J Cancer. 2015 ; 112 ( 10 ): 1703 - 1708 .

Piscuoglio S , Murray M , Fusco N , et al.  MED12 somatic mutations in fibroadenomas and phyllodes tumours of the breast . Histopathology. 2015 ; 67 ( 5 ): 719 - 729 .

Nagasawa S , Maeda I , Fukuda T , et al.  MED12 exon 2 mutations in phyllodes tumors of the breast . Cancer Med. 2015 ; 4 ( 7 ): 1117 - 1121 .

Mishima C , Kagara N , Tanei T , et al.  Mutational analysis of MED12 in fibroadenomas and phyllodes tumors of the breast by means of targeted next-generation sequencing . Breast Cancer Res Treat. 2015 ; 152 ( 2 ): 305 - 312 .

Tan J , Ong CK , Lim WK , et al.  Genomic landscapes of breast fibroepithelial tumors . Nat Genet. 2015 ; 47 ( 11 ): 1341 - 1345 .

Kämpjärvi K , Järvinen TM , Heikkinen T , et al.  Somatic MED12 mutations are associated with poor prognosis markers in chronic lymphocytic leukemia . Oncotarget. 2015 ; 6 ( 3 ): 1884 - 1888 .

Mittal P , Shin YH , Yatsenko SA , Castro CA , Surti U , Rajkovic A . Med12 gain-of-function mutation causes leiomyomas and genomic instability . J Clin Invest. 2015 ; 125 ( 8 ): 3280 - 3284 .

Croce S , Chibon F . MED12 and uterine smooth muscle oncogenesis: state of the art and perspectives . Eur J Cancer. 2015 ; 51 ( 12 ): 1603 - 1610 .

Heinonen HR , Sarvilinna NS , Sjöberg J , et al.  MED12 mutation frequency in unselected sporadic uterine leiomyomas . Fertil Steril. 2014 ; 102 ( 4 ): 1137 - 1142 .

Markowski DN , Helmke BM , Bartnitzke S , Löning T , Bullerdiek J . Uterine fibroids: do we deal with more than one disease? Int J Gynecol Pathol. 2014 ; 33 ( 6 ): 568 - 572 .

Matsubara A , Sekine S , Yoshida M , et al.  Prevalence of MED12 mutations in uterine and extrauterine smooth muscle tumours . Histopathology. 2013 ; 62 ( 4 ): 657 - 661 .

Mäkinen N , Vahteristo P , Kämpjärvi K , Arola J , Bützow R , Aaltonen LA . MED12 exon 2 mutations in histopathological uterine leiomyoma variants . Eur J Hum Genet. 2013 ; 21 ( 11 ): 1300 - 1303 .

Pérot G , Croce S , Ribeiro A , et al.  MED12 alterations in both human benign and malignant uterine soft tissue tumors . Plos One. 2012 ; 7 ( 6 ): e40015 .

Zhang Q , Ubago J , Li L , et al.  Molecular analyses of 6 different types of uterine smooth muscle tumors: emphasis in atypical leiomyoma . Cancer. 2014 ; 120 ( 20 ): 3165 - 3177 .

Äyräväinen A , Pasanen A , Ahvenainen T , et al.  Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy . Hum Reprod. 2020 ; 35 ( 10 ): 2237 - 2244 .

Nadine Markowski D , Tadayyon M , Bartnitzke S , Belge G , Maria Helmke B , Bullerdiek J . Cell cultures in uterine leiomyomas: rapid disappearance of cells carrying MED12 mutations . Genes Chromosomes Cancer. 2014 ; 53 ( 4 ): 317 - 323 .

Bloch J , Holzmann C , Koczan D , Helmke BM , Bullerdiek J . Factors affecting the loss of MED12-mutated leiomyoma cells during in vitro growth . Oncotarget. 2017 ; 8 ( 21 ): 34762 - 34772 .

Holdsworth-Carson SJ , Zaitseva M , Vollenhoven BJ , Rogers PA . Clonality of smooth muscle and fibroblast cell populations isolated from human fibroid and myometrial tissues . Mol Hum Reprod. 2014 ; 20 ( 3 ): 250 - 259 .

Salo T , Sutinen M , Hoque Apu E , et al.  A novel human leiomyoma tissue derived matrix for cell culture studies . BMC Cancer. 2015 ; 15 : 981 .

Wu X , Serna VA , Thomas J , Qiang W , Blumenfeld ML , Kurita T . Subtype-specific tumor-associated fibroblasts contribute to the pathogenesis of uterine leiomyoma . Cancer Res. 2017 ; 77 ( 24 ): 6891 - 6901 .

Serna VA , Wu X , Qiang W , Thomas J , Blumenfeld ML , Kurita T . Cellular kinetics of MED12-mutant uterine leiomyoma growth and regression in vivo . Endocr Relat Cancer. 2018 ; 25 ( 7 ): 747 - 759 .

Barbieri CE , Baca SC , Lawrence MS , et al.  Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer . Nat Genet. 2012 ; 44 ( 6 ): 685 - 689 .

Arai E , Sakamoto H , Ichikawa H , et al.  Multilayer-omics analysis of renal cell carcinoma, including the whole exome, methylome and transcriptome . Int J Cancer. 2014 ; 135 ( 6 ): 1330 - 1342 .

Kämpjärvi K , Kim NH , Keskitalo S , et al.  Somatic MED12 mutations in prostate cancer and uterine leiomyomas promote tumorigenesis through distinct mechanisms . Prostate. 2016 ; 76 ( 1 ): 22 - 31 .

Knuesel MT , Meyer KD , Donner AJ , Espinosa JM , Taatjes DJ . The human CDK8 subcomplex is a histone kinase that requires Med12 for activity and can function independently of mediator . Mol Cell Biol. 2009 ; 29 ( 3 ): 650 - 661 .

Knuesel MT , Meyer KD , Bernecky C , Taatjes DJ . The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function . Genes Dev. 2009 ; 23 ( 4 ): 439 - 451 .

Turunen M , Spaeth JM , Keskitalo S , et al.  Uterine leiomyoma-linked MED12 mutations disrupt mediator-associated CDK activity . Cell Rep. 2014 ; 7 ( 3 ): 654 - 660 .

Park MJ , Shen H , Spaeth JM , et al.  Oncogenic exon 2 mutations in Mediator subunit MED12 disrupt allosteric activation of cyclin C-CDK8/19 . J Biol Chem. 2018 ; 293 ( 13 ): 4870 - 4882 .

Li YC , Chao TC , Kim HJ , et al.  Structure and noncanonical Cdk8 activation mechanism within an argonaute-containing mediator kinase module . Sci Adv . 2021 ; 7 ( 3 ). doi: 10.1126/sciadv.abd4484

Spaeth JM , Kim NH , Boyer TG . Mediator and human disease . Semin Cell Dev Biol. 2011 ; 22 ( 7 ): 776 - 787 .

Fant CB , Taatjes DJ . Regulatory functions of the Mediator kinases CDK8 and CDK19 . Transcription. 2019 ; 10 ( 2 ): 76 - 90 .

Aranda-Orgilles B , Saldaña-Meyer R , Wang E , et al.  MED12 regulates HSC-specific enhancers independently of mediator kinase activity to control hematopoiesis . Cell Stem Cell. 2016 ; 19 ( 6 ): 784 - 799 .

Papadopoulou T , Kaymak A , Sayols S , Richly H . Dual role of Med12 in PRC1-dependent gene repression and ncRNA-mediated transcriptional activation . Cell Cycle. 2016 ; 15 ( 11 ): 1479 - 1493 .

Huang S , Hölzel M , Knijnenburg T , et al.  MED12 controls the response to multiple cancer drugs through regulation of TGF-β receptor signaling . Cell. 2012 ; 151 ( 5 ): 937 - 950 .

Ding N , Zhou H , Esteve PO , et al.  Mediator links epigenetic silencing of neuronal gene expression with x-linked mental retardation . Mol Cell. 2008 ; 31 ( 3 ): 347 - 359 .

El Andaloussi A , Al-Hendy A , Ismail N , Boyer TG , Halder SK . Introduction of somatic mutation in MED12 induces Wnt4/β-catenin and disrupts autophagy in human uterine myometrial cell . Reprod Sci. 2020 ; 27 ( 3 ): 823 - 832 .

Liu S , Yin P , Kujawa SA , Coon JS 5th , Okeigwe I , Bulun SE . Progesterone receptor integrates the effects of mutated MED12 and altered DNA methylation to stimulate RANKL expression and stem cell proliferation in uterine leiomyoma . Oncogene. 2019 ; 38 ( 15 ): 2722 - 2735 .

Asano R , Asai-Sato M , Matsukuma S , et al.  Expression of erythropoietin messenger ribonucleic acid in wild-type MED12 uterine leiomyomas under estrogenic influence: new insights into related growth disparities . Fertil Steril. 2019 ; 111 ( 1 ): 178 - 185 .

Lynch CJ , Bernad R , Martínez-Val A , et al.  Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases . Nat Cell Biol. 2020 ; 22 ( 10 ): 1223 - 1238 .

Martinez-Val A , Lynch CJ , Calvo I , et al.  Dissection of two routes to naïve pluripotency using different kinase inhibitors . Nat Commun. 2021 ; 12 ( 1 ): 1863 .

Adler AS , McCleland ML , Truong T , et al.  CDK8 maintains tumor dedifferentiation and embryonic stem cell pluripotency . Cancer Res. 2012 ; 72 ( 8 ): 2129 - 2139 .

Fukasawa K , Kadota T , Horie T , et al.  CDK8 maintains stemness and tumorigenicity of glioma stem cells by regulating the c-MYC pathway . Oncogene. 2021 ; 40 ( 15 ): 2803 - 2815 .

Técher H , Koundrioukoff S , Nicolas A , Debatisse M . The impact of replication stress on replication dynamics and DNA damage in vertebrate cells . Nat Rev Genet. 2017 ; 18 ( 9 ): 535 - 550 .

Bullerdiek J , Rommel B . Factors targeting MED12 to drive tumorigenesis? F1000Res. 2018 ; 7 : 359 .

Helmink BA , Khan MAW , Hermann A , Gopalakrishnan V , Wargo JA . The microbiome, cancer, and cancer therapy . Nat Med. 2019 ; 25 ( 3 ): 377 - 388 .

Łaniewski P , Ilhan ZE , Herbst-Kralovetz MM . The microbiome and gynaecological cancer development, prevention and therapy . Nat Rev Urol. 2020 ; 17 ( 4 ): 232 - 250 .

Gallagher CS , Morton CC . Genetic association studies in uterine fibroids: risk alleles presage the path to personalized therapies . Semin Reprod Med. 2016 ; 34 ( 4 ): 235 - 241 .

Quade BJ , Weremowicz S , Neskey DM , et al.  Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15 . Cancer Res. 2003 ; 63 ( 6 ): 1351 - 1358 .

Gross KL , Morton CC . Genetics and the development of fibroids . Clin Obstet Gynecol. 2001 ; 44 ( 2 ): 335 - 349 .

Gross KL , Neskey DM , Manchanda N , et al.  HMGA2 expression in uterine leiomyomata and myometrium: quantitative analysis and tissue culture studies . Genes Chromosomes Cancer. 2003 ; 38 ( 1 ): 68 - 79 .

Stewart L , Glenn GM , Stratton P , et al.  Association of germline mutations in the fumarate hydratase gene and uterine fibroids in women with hereditary leiomyomatosis and renal cell cancer . Arch Dermatol. 2008 ; 144 ( 12 ): 1584 - 1592 .

Badeloe S , Bladergroen RS , Jonkman MF , et al.  Hereditary multiple cutaneous leiomyoma resulting from novel mutations in the fumarate hydratase gene . J Dermatol Sci. 2008 ; 51 ( 2 ): 139 - 143 .

Wheeler KC , Warr DJ , Warsetsky SI , Barmat LI . Novel fumarate hydratase mutation in a family with atypical uterine leiomyomas and hereditary leiomyomatosis and renal cell cancer . Fertil Steril. 2016 ; 105 ( 1 ): 144 - 148 .

Popp B , Erber R , Kraus C , et al.  Targeted sequencing of FH-deficient uterine leiomyomas reveals biallelic inactivating somatic fumarase variants and allows characterization of missense variants . Mod Pathol. 2020 ; 33 ( 11 ): 2341 - 2353 .

Berta DG , Kuisma H , Välimäki N , et al.  Deficient H2A.Z deposition is associated with genesis of uterine leiomyoma . Nature. 2021 ; 596 ( 7872 ): 398 - 403 .

Leistico JR , Saini P , Futtner CR , et al.  Epigenomic tensor predicts disease subtypes and reveals constrained tumor evolution . Cell Rep. 2021 ; 34 ( 13 ): 108927 .

Linder D , Gartler SM . Glucose-6-phosphate dehydrogenase mosaicism: utilization as a cell marker in the study of leiomyomas . Science. 1965 ; 150 ( 3692 ): 67 - 69 .

Bulun SE . Uterine fibroids . N Engl J Med. 2013 ; 369 ( 14 ): 1344 - 1355 .

Ono M , Maruyama T , Masuda H , et al.  Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells . Proc Natl Acad Sci U S A. 2007 ; 104 ( 47 ): 18700 - 18705 .

Chang HL , Senaratne TN , Zhang L , et al.  Uterine leiomyomas exhibit fewer stem/progenitor cell characteristics when compared with corresponding normal myometrium . Reprod Sci. 2010 ; 17 ( 2 ): 158 - 167 .

Mas A , Cervelló I , Gil-Sanchis C , et al.  Identification and characterization of the human leiomyoma side population as putative tumor-initiating cells . Fertil Steril. 2012 ; 98 ( 3 ): 741 - 751.e6 .

Mas A , Nair S , Laknaur A , Simón C , Diamond MP , Al-Hendy A . Stro-1/CD44 as putative human myometrial and fibroid stem cell markers . Fertil Steril. 2015 ; 104 ( 1 ): 225 - 34.e3 .

Patterson AL , George JW , Chatterjee A , et al.  Putative human myometrial and fibroid stem-like cells have mesenchymal stem cell and endometrial stromal cell properties . Hum Reprod. 2020 ; 35 ( 1 ): 44 - 57 .

Ono M , Qiang W , Serna VA , et al.  Role of stem cells in human uterine leiomyoma growth . Plos One. 2012 ; 7 ( 5 ): e36935 .

Elkafas H , Qiwei Y , Al-Hendy A . Origin of uterine fibroids: conversion of myometrial stem cells to tumor-initiating cells . Semin Reprod Med. 2017 ; 35 ( 6 ): 481 - 486 .

Afify SM , Seno M . Conversion of stem cells to cancer stem cells: undercurrent of cancer initiation . Cancers (Basel). 2019 ; 11 ( 3 ). doi: 10.3390/cancers11030345

Mas A , Stone L , O’Connor PM , et al.  Developmental exposure to endocrine disruptors expands murine myometrial stem cell compartment as a prerequisite to leiomyoma tumorigenesis . Stem Cells. 2017 ; 35 ( 3 ): 666 - 678 .

Hu WY , Shi GB , Hu DP , Nelles JL , Prins GS . Actions of estrogens and endocrine disrupting chemicals on human prostate stem/progenitor cells and prostate cancer risk . Mol Cell Endocrinol. 2012 ; 354 ( 1-2 ): 63 - 73 .

Cook JD , Davis BJ , Cai SL , Barrett JC , Conti CJ , Walker CL . Interaction between genetic susceptibility and early-life environmental exposure determines tumor-suppressor-gene penetrance . Proc Natl Acad Sci U S A. 2005 ; 102 ( 24 ): 8644 - 8649 .

Treviño LS , Dong J , Kaushal A , et al.  Epigenome environment interactions accelerate epigenomic aging and unlock metabolically restricted epigenetic reprogramming in adulthood . Nat Commun. 2020 ; 11 ( 1 ): 2316 .

Zhang J , Liu J , Ren L , et al.  PM2.5 induces male reproductive toxicity via mitochondrial dysfunction, DNA damage and RIPK1 mediated apoptotic signaling pathway . Sci Total Environ. 2018 ; 634 : 1435 - 1444 .

Hendryx M , Luo J , Chojenta C , Byles JE . Air pollution exposures from multiple point sources and risk of incident chronic obstructive pulmonary disease (COPD) and asthma . Environ Res. 2019 ; 179 ( Pt A ): 108783 .

Herbert C , Kumar RK . Ambient air pollution and asthma . Eur Respir J . 2017 ; 49 ( 5 ). doi: 10.1183/13993003.00230-2017

Shukla A , Bunkar N , Kumar R , et al.  Air pollution associated epigenetic modifications: Transgenerational inheritance and underlying molecular mechanisms . Sci Total Environ. 2019 ; 656 : 760 - 777 .

Fuchs LFP , Veras MM , Saldiva PHN , et al.  Ambient levels of concentrated PM2.5 affects cell kinetics in adrenal glands: an experimental study in mice . Gynecol Endocrinol. 2017 ; 33 ( 6 ): 490 - 495 .

VoPham T , Bertrand KA , Tamimi RM , Laden F , Hart JE . Ambient PM2.5 air pollution exposure and hepatocellular carcinoma incidence in the United States . Cancer Causes Control. 2018 ; 29 ( 6 ): 563 - 572 .

Mahalingaiah S , Hart JE , Laden F , et al.  Air pollution and risk of uterine leiomyomata . Epidemiology. 2014 ; 25 ( 5 ): 682 - 688 .

Lin CY , Wang CM , Chen ML , Hwang BF . The effects of exposure to air pollution on the development of uterine fibroids . Int J Hyg Environ Health. 2019 ; 222 ( 3 ): 549 - 555 .

Chiaffarino F , Cipriani S , Ricci E , et al.  Alcohol consumption and risk of uterine myoma: a systematic review and meta analysis . Plos One. 2017 ; 12 ( 11 ): e0188355 .

Wise LA , Palmer JR , Harlow BL , et al.  Risk of uterine leiomyomata in relation to tobacco, alcohol and caffeine consumption in the Black Women’s Health Study . Hum Reprod. 2004 ; 19 ( 8 ): 1746 - 1754 .

Templeman C , Marshall SF , Clarke CA , et al.  Risk factors for surgically removed fibroids in a large cohort of teachers . Fertil Steril. 2009 ; 92 ( 4 ): 1436 - 1446 .

Nagata C , Nakamura K , Oba S , Hayashi M , Takeda N , Yasuda K . Association of intakes of fat, dietary fibre, soya isoflavones and alcohol with uterine fibroids in Japanese women . Br J Nutr. 2009 ; 101 ( 10 ): 1427 - 1431 .

Reichman ME , Judd JT , Longcope C , et al.  Effects of alcohol consumption on plasma and urinary hormone concentrations in premenopausal women . J Natl Cancer Inst. 1993 ; 85 ( 9 ): 722 - 727 .

Hankinson SE , Willett WC , Manson JE , et al.  Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women . J Natl Cancer Inst. 1995 ; 87 ( 17 ): 1297 - 1302 .

Katsouyanni K , Boyle P , Trichopoulos D . Diet and urine estrogens among postmenopausal women . Oncology. 1991 ; 48 ( 6 ): 490 - 494 .

Garaycoechea JI , Crossan GP , Langevin F , et al.  Alcohol and endogenous aldehydes damage chromosomes and mutate stem cells . Nature. 2018 ; 553 ( 7687 ): 171 - 177 .

Sadikot RT , Bedi B , Li J , Yeligar SM . Alcohol-induced mitochondrial DNA damage promotes injurious crosstalk between alveolar epithelial cells and alveolar macrophages . Alcohol. 2019 ; 80 : 65 - 72 .

Kruman II , Henderson GI , Bergeson SE . DNA damage and neurotoxicity of chronic alcohol abuse . Exp Biol Med (Maywood). 2012 ; 237 ( 7 ): 740 - 747 .

Zhao M , Howard EW , Guo Z , Parris AB , Yang X . p53 pathway determines the cellular response to alcohol-induced DNA damage in MCF-7 breast cancer cells . Plos One. 2017 ; 12 ( 4 ): e0175121 .

Chiaffarino F , Ricci E , Cipriani S , Chiantera V , Parazzini F . Cigarette smoking and risk of uterine myoma: systematic review and meta-analysis . Eur J Obstet Gynecol Reprod Biol. 2016 ; 197 : 63 - 71 .

Ross RK , Pike MC , Vessey MP , Bull D , Yeates D , Casagrande JT . Risk factors for uterine fibroids: reduced risk associated with oral contraceptives . Br Med J (Clin Res Ed). 1986 ; 293 ( 6543 ): 359 - 362 .

Lumbiganon P , Rugpao S , Phandhu-fung S , Laopaiboon M , Vudhikamraksa N , Werawatakul Y . Protective effect of depot-medroxyprogesterone acetate on surgically treated uterine leiomyomas: a multicentre case–control study . Br J Obstet Gynaecol. 1996 ; 103 ( 9 ): 909 - 914 .

D’Aloisio AA , Baird DD , DeRoo LA , Sandler DP . Association of intrauterine and early-life exposures with diagnosis of uterine leiomyomata by 35 years of age in the Sister Study . Environ Health Perspect. 2010 ; 118 ( 3 ): 375 - 381 .

Faerstein E , Szklo M , Rosenshein NB . Risk factors for uterine leiomyoma: a practice-based case-control study. II. Atherogenic risk factors and potential sources of uterine irritation . Am J Epidemiol. 2001 ; 153 ( 1 ): 11 - 19 .

Wang Q , Trevino LS , Wong RL , et al.  Reprogramming of the epigenome by MLL1 links early-life environmental exposures to prostate cancer risk . Mol Endocrinol. 2016 ; 30 ( 8 ): 856 - 871 .

Walker CL , Ho SM . Developmental reprogramming of cancer susceptibility . Nat Rev Cancer. 2012 ; 12 ( 7 ): 479 - 486 .

McCampbell AS , Walker CL , Broaddus RR , Cook JD , Davies PJ . Developmental reprogramming of IGF signaling and susceptibility to endometrial hyperplasia in the rat . Lab Invest. 2008 ; 88 ( 6 ): 615 - 626 .

Gore AC , Walker DM , Zama AM , Armenti AE , Uzumcu M . Early life exposure to endocrine-disrupting chemicals causes lifelong molecular reprogramming of the hypothalamus and premature reproductive aging . Mol Endocrinol. 2011 ; 25 ( 12 ): 2157 - 2168 .

Sirohi D , Al Ramadhani R , Knibbs LD . Environmental exposures to endocrine disrupting chemicals (EDCs) and their role in endometriosis: a systematic literature review . Rev Environ Health. 2021 ; 36 ( 1 ): 101 - 115 .

Liu Q . Effects of environmental endocrine-disrupting chemicals on female reproductive health . Adv Exp Med Biol. 2021 ; 1300 : 205 - 229 .

Prusinski L , Al-Hendy A , Yang Q . Developmental exposure to endocrine disrupting chemicals alters the epigenome: identification of reprogrammed targets . Gynecol Obstet Res. 2016 ; 3 ( 1 ): 1 - 6 .

Ono M , Yin P , Navarro A , et al.  Paracrine activation of WNT/β-catenin pathway in uterine leiomyoma stem cells promotes tumor growth . Proc Natl Acad Sci U S A. 2013 ; 110 ( 42 ): 17053 - 17058 .

Hall JM , Greco CW . Perturbation of nuclear hormone receptors by endocrine disrupting chemicals: mechanisms and pathological consequences of exposure . Cells . 2019 ; 9 ( 1 ). doi: 10.3390/cells9010013

Toporova L , Balaguer P . Nuclear receptors are the major targets of endocrine disrupting chemicals . Mol Cell Endocrinol. 2020 ; 502 : 110665 .

Moore AB , Castro L , Yu L , et al.  Stimulatory and inhibitory effects of genistein on human uterine leiomyoma cell proliferation are influenced by the concentration . Hum Reprod. 2007 ; 22 ( 10 ): 2623 - 2631 .

Baird DD , Newbold R . Prenatal diethylstilbestrol (DES) exposure is associated with uterine leiomyoma development . Reprod Toxicol. 2005 ; 20 ( 1 ): 81 - 84 .

Mahalingaiah S , Hart JE , Wise LA , Terry KL , Boynton-Jarrett R , Missmer SA . Prenatal diethylstilbestrol exposure and risk of uterine leiomyomata in the Nurses’ Health Study II . Am J Epidemiol. 2014 ; 179 ( 2 ): 186 - 191 .

Zota AR , Geller RJ , Calafat AM , Marfori CQ , Baccarelli AA , Moawad GN . Phthalates exposure and uterine fibroid burden among women undergoing surgical treatment for fibroids: a preliminary study . Fertil Steril. 2019 ; 111 ( 1 ): 112 - 121 .

Zota AR , Geller RJ , VanNoy BN , et al.  Phthalate exposures and MicroRNA expression in uterine fibroids: The FORGE Study . Epigenet Insights. 2020 ; 13 : 2516865720904057 .

Lee J , Jeong Y , Mok S , et al.  Associations of exposure to phthalates and environmental phenols with gynecological disorders . Reprod Toxicol. 2020 ; 95 : 19 - 28 .

Hassan MH , Eyzaguirre E , Arafa HM , Hamada FM , Salama SA , Al-Hendy A . Memy I: a novel murine model for uterine leiomyoma using adenovirus-enhanced human fibroid explants in severe combined immune deficiency mice . Am J Obstet Gynecol. 2008 ; 199 ( 2 ): 156.e1 - 156.e8 .

Ishikawa H , Ishi K , Serna VA , Kakazu R , Bulun SE , Kurita T . Progesterone is essential for maintenance and growth of uterine leiomyoma . Endocrinology. 2010 ; 151 ( 6 ): 2433 - 2442 .

Croy A , Fritsch M , Schmidt N , et al.  Application of a patient derived xenograft model for predicative study of uterine fibroid disease . Plos One . 2015 ; 10 ( 11 ). doi: 10.1371/journal.pone.0142429

Suo G , Sadarangani A , Lamarca B , Cowan B , Wang JY . Murine xenograft model for human uterine fibroids: an in vivo imaging approach . Reprod Sci. 2009 ; 16 ( 9 ): 827 - 842 .

Prizant H , Sen A , Light A , et al.  Uterine-specific loss of Tsc2 leads to myometrial tumors in both the uterus and lungs . Mol Endocrinol. 2013 ; 27 ( 9 ): 1403 - 1414 .

Varghese BV , Koohestani F , McWilliams M , et al.  Loss of the repressor REST in uterine fibroids promotes aberrant G protein-coupled receptor 10 expression and activates mammalian target of rapamycin pathway . Proc Natl Acad Sci U S A. 2013 ; 110 ( 6 ): 2187 - 2192 .

Tanwar PS , Lee HJ , Zhang L , et al.  Constitutive activation of Beta-catenin in uterine stroma and smooth muscle leads to the development of mesenchymal tumors in mice . Biol Reprod. 2009 ; 81 ( 3 ): 545 - 552 .

Field KJ , Griffith JW , Lang CM . Spontaneous reproductive tract leiomyomas in aged guinea-pigs . J Comp Pathol. 1989 ; 101 ( 3 ): 287 - 294 .

Walker CL , Hunter D , Everitt JI . Uterine leiomyoma in the Eker rat: a unique model for important diseases of women . Genes Chromosomes Cancer. 2003 ; 38 ( 4 ): 349 - 356 .

Everitt JI , Wolf DC , Howe SR , Goldsworthy TL , Walker C . Rodent model of reproductive tract leiomyomata. Clinical and pathological features . Am J Pathol. 1995 ; 146 ( 6 ): 1556 - 1567 .

Leppert PC , Baginski T , Prupas C , Catherino WH , Pletcher S , Segars JH . Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium . Fertil Steril. 2004 ; 82 Suppl 3 : 1182 - 1187 .

Brody JR , Cunha GR . Histologic, morphometric, and immunocytochemical analysis of myometrial development in rats and mice: II. Effects of DES on development . Am J Anat. 1989 ; 186 ( 1 ): 21 - 42 .

Newbold RR , Jefferson WN , Grissom SF , Padilla-Banks E , Snyder RJ , Lobenhofer EK . Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life . Mol Carcinog. 2007 ; 46 ( 9 ): 783 - 796 .

Cook JD , Davis BJ , Goewey JA , Berry TD , Walker CL . Identification of a sensitive period for developmental programming that increases risk for uterine leiomyoma in Eker rats . Reprod Sci. 2007 ; 14 ( 2 ): 121 - 136 .

Branham WS , Sheehan DM . Ovarian and adrenal contributions to postnatal growth and differentiation of the rat uterus . Biol Reprod. 1995 ; 53 ( 4 ): 863 - 872 .

Yang Q , Diamond MP , Al-Hendy A . Early life adverse environmental exposures increase the risk of uterine fibroid development: role of epigenetic regulation . Front Pharmacol. 2016 ; 7 : 40 .

Greathouse KL , Bredfeldt T , Everitt JI , et al.  Environmental estrogens differentially engage the histone methyltransferase EZH2 to increase risk of uterine tumorigenesis . Mol Cancer Res. 2012 ; 10 ( 4 ): 546 - 557 .

Treviño LS , Wang Q , Walker CL . Phosphorylation of epigenetic “readers, writers and erasers”: Implications for developmental reprogramming and the epigenetic basis for health and disease . Prog Biophys Mol Biol. 2015 ; 118 ( 1-2 ): 8 - 13 .

Wong RL , Wang Q , Treviño LS , et al.  Identification of secretaglobin Scgb2a1 as a target for developmental reprogramming by BPA in the rat prostate . Epigenetics. 2015 ; 10 ( 2 ): 127 - 134 .

Li S , Washburn KA , Moore R , et al.  Developmental exposure to diethylstilbestrol elicits demethylation of estrogen-responsive lactoferrin gene in mouse uterus . Cancer Res. 1997 ; 57 ( 19 ): 4356 - 4359 .

Yin Y , Lin C , Veith GM , Chen H , Dhandha M , Ma L . Neonatal diethylstilbestrol exposure alters the metabolic profile of uterine epithelial cells . Dis Model Mech. 2012 ; 5 ( 6 ): 870 - 880 .

Yang Q , Trevino LS , Mas A , et al.  Early life developmental exposure to endocrine disrupting chemicals increases the risk of adult onset of uterine fibroids by permanently reprograming the epigenome of myometrial stem cells towards a pro-fibroid landscape . Fertil Steril . 2016 ; 106(3): suppl e2 .

Elkafas H , Badary OA , Elmorsy E , Kamel R , Al-Hendy A , Yang Q . Targeting activated pro-inflammatory pathway in primed myometrial stem cells with vitamin D3 and Paricalcitol . Fertil Steril . 2019 ; 112 ( 3 ): e100 - e101 .

Yang Q , Treviño L , Mas A , Diamond M , Walker C , Al-Hendy A . Identification of novel epigenetic reprogrammed genes in myometrial stem cells developmentally exposed to endocrine disrupting chemicals . Reprod Sci . 2017;24 suppl 1:103A.

Mohamed Ali HE , Ismail N , Al-Hendy A , Yang Q. Inhibition of MLL1 and HDAC activity reverses reprogrammed inflammatory components induced by developmental exposure to an endocrine disruptor (diethylstibesterol) in myometrial stem cells . Reprod Sci . 2020 ; 27 suppl 1 : 229A . doi:10.1007/s43032-020-00176-9

Yang Q , Al-Hendy A . Integrated multi-omics analyses of high-risk myometrial progenitor/stem cells: implication for uterine fibroid pathogenesis . Reprod Sci. 2021;28 suppl 1:37A.

Levy G , Malik M , Britten J , Gilden M , Segars J , Catherino WH . Liarozole inhibits transforming growth factor-β3–mediated extracellular matrix formation in human three-dimensional leiomyoma cultures . Fertil Steril. 2014 ; 102 ( 1 ): 272 - 281.e2 .

Malik M , Britten J , Segars J , Catherino WH . Leiomyoma cells in 3-dimensional cultures demonstrate an attenuated response to fasudil, a rho-kinase inhibitor, when compared to 2-dimensional cultures . Reprod Sci. 2014 ; 21 ( 9 ): 1126 - 1138 .

Xie J , Xu X , Yin P , et al.  Application of ex-vivo spheroid model system for the analysis of senescence and senolytic phenotypes in uterine leiomyoma . Lab Invest. 2018 ; 98 ( 12 ): 1575 - 1587 .

Thompson WE , Al-Hendy A , Yang Q , et al.  OR20-04 modeling uterine disorders utilizing adult uterine stem cells . J Endocr Soc . 2020 ; 4 ( Supplement_1 ). doi: 10.1210/jendso/bvaa046.668

Ishikawa H , Reierstad S , Demura M , et al.  High aromatase expression in uterine leiomyoma tissues of African-American women . J Clin Endocrinol Metab. 2009 ; 94 ( 5 ): 1752 - 1756 .

Nierth-Simpson EN , Martin MM , Chiang TC , et al.  Human uterine smooth muscle and leiomyoma cells differ in their rapid 17beta-estradiol signaling: implications for proliferation . Endocrinology. 2009 ; 150 ( 5 ): 2436 - 2445 .

Borahay MA , Asoglu MR , Mas A , Adam S , Kilic GS , Al-Hendy A . Estrogen receptors and signaling in fibroids: role in pathobiology and therapeutic implications . Reprod Sci. 2017 ; 24 ( 9 ): 1235 - 1244 .

Bulun SE , Moravek MB , Yin P , et al.  Uterine leiomyoma stem cells: linking progesterone to growth . Semin Reprod Med. 2015 ; 33 ( 5 ): 357 - 365 .

Hodges LC , Houston KD , Hunter DS , et al.  Transdominant suppression of estrogen receptor signaling by progesterone receptor ligands in uterine leiomyoma cells . Mol Cell Endocrinol. 2002 ; 196 ( 1-2 ): 11 - 20 .

Cermik D , Arici A , Taylor HS . Coordinated regulation of HOX gene expression in myometrium and uterine leiomyoma . Fertil Steril. 2002 ; 78 ( 5 ): 979 - 984 .

Kawaguchi K , Fujii S , Konishi I , et al.  Immunohistochemical analysis of oestrogen receptors, progesterone receptors and Ki-67 in leiomyoma and myometrium during the menstrual cycle and pregnancy . Virchows Arch A Pathol Anat Histopathol. 1991 ; 419 ( 4 ): 309 - 315 .

Matsuo H , Kurachi O , Shimomura Y , Samoto T , Maruo T . Molecular bases for the actions of ovarian sex steroids in the regulation of proliferation and apoptosis of human uterine leiomyoma . Oncology. 1999 ; 57 Suppl 2 : 49 - 58 .

Ali M , Al-Hendy A . Selective progesterone receptor modulators for fertility preservation in women with symptomatic uterine fibroids . Biol Reprod. 2017 ; 97 ( 3 ): 337 - 352 .

Rogers R , Norian J , Malik M , et al.  Mechanical homeostasis is altered in uterine leiomyoma . Am J Obstet Gynecol. 2008 ; 198 ( 4 ): 474.e1 - 474.11 .

Martino F , Perestrelo AR , Vinarský V , Pagliari S , Forte G . Cellular mechanotransduction: from tension to function . Front Physiol. 2018 ; 9 : 824 .

Ko YA , Jamaluddin MFB , Adebayo M , et al.  Extracellular matrix (ECM) activates β-catenin signaling in uterine fibroids . Reproduction. 2018 ; 155 ( 1 ): 61 - 71 .

Flake GP , Moore AB , Sutton D , et al.  The natural history of uterine leiomyomas: light and electron microscopic studies of fibroid phases, interstitial ischemia, inanosis, and reclamation . Obstet Gynecol Int. 2013 ; 2013 : 528376 .

Flake GP , Moore AB , Sutton D , et al.  The life cycle of the uterine fibroid myocyte . Curr Obstet Gynecol Rep. 2018 ; 7 ( 2 ): 97 - 105 .

Cho S , Vashisth M , Abbas A , et al.  Mechanosensing by the lamina protects against nuclear rupture, DNA damage, and cell-cycle arrest . Dev Cell. 2019 ; 49 ( 6 ): 920 - 935.e5 .

Gilbert HTJ , Mallikarjun V , Dobre O , et al.  Nuclear decoupling is part of a rapid protein-level cellular response to high-intensity mechanical loading . Nat Commun. 2019 ; 10 ( 1 ): 4149 .

Leavy M , Trottmann M , Liedl B , et al.  Effects of elevated β-estradiol levels on the functional morphology of the testis—new insights . Sci Rep. 2017 ; 7 : 39931 .

Malik M , Segars J , Catherino WH . Integrin β1 regulates leiomyoma cytoskeletal integrity and growth . Matrix Biol. 2012 ; 31 ( 7-8 ): 389 - 397 .

Stewart EA , Friedman AJ , Peck K , Nowak RA . Relative overexpression of collagen type I and collagen type III messenger ribonucleic acids by uterine leiomyomas during the proliferative phase of the menstrual cycle . J Clin Endocrinol Metab. 1994 ; 79 ( 3 ): 900 - 906 .

Islam MS , Ciavattini A , Petraglia F , Castellucci M , Ciarmela P . Extracellular matrix in uterine leiomyoma pathogenesis: a potential target for future therapeutics . Hum Reprod Update. 2018 ; 24 ( 1 ): 59 - 85 .

Ciebiera M , Ali M , Zgliczynska M , Skrzypczak M , Al-Hendy A . Vitamins and uterine fibroids: current data on pathophysiology and possible clinical relevance . Int J Mol Sci . 2020 ; 21 ( 15 ). doi: 10.3390/ijms21155528

Jayes FL , Liu B , Moutos FT , Kuchibhatla M , Guilak F , Leppert PC . Loss of stiffness in collagen-rich uterine fibroids after digestion with purified collagenase Clostridium histolyticum . Am J Obstet Gynecol. 2016 ; 215 ( 5 ): 596.e1 - 596.e8 .

Suzuki A , Kariya M , Matsumura N , et al.  Expression of p53 and p21(WAF-1), apoptosis, and proliferation of smooth muscle cells in normal myometrium during the menstrual cycle: implication of DNA damage and repair for leiomyoma development . Med Mol Morphol. 2012 ; 45 ( 4 ): 214 - 221 .

Karowicz-Bilinska A , Plodzidym M , Krol J , Lewinska A , Bartosz G . Changes of markers of oxidative stress during menstrual cycle . Redox Rep. 2008 ; 13 ( 5 ): 237 - 240 .

Atashgaran V , Wrin J , Barry SC , Dasari P , Ingman WV . Dissecting the biology of menstrual cycle-associated breast cancer risk . Front Oncol. 2016 ; 6 : 267 .

Yang Q , Laknaur A , Elam L , et al.  Identification of polycomb group protein EZH2-mediated DNA mismatch repair gene MSH2 in human uterine fibroids . Reprod Sci. 2016 ; 23 ( 10 ): 1314 - 1325 .

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 . Biol Reprod. 2016 ; 94 ( 3 ): 69 .

Prusinski Fernung LE , Al-Hendy A , Yang Q . A preliminary study: human fibroid Stro-1+/CD44+ stem cells isolated from uterine fibroids demonstrate decreased DNA repair and genomic integrity compared to adjacent myometrial Stro-1+/CD44+ Cells . Reprod Sci. 2019 ; 26 ( 5 ): 619 - 638 .

Prusinski Fernung LE , Yang Q , Sakamuro D , Kumari A , Mas A , Al-Hendy A . Endocrine disruptor exposure during development increases incidence of uterine fibroids by altering DNA repair in myometrial stem cells . Biol Reprod. 2018 ; 99 ( 4 ): 735 - 748 .

Chatterjee N , Walker GC . Mechanisms of DNA damage, repair, and mutagenesis . Environ Mol Mutagen. 2017 ; 58 ( 5 ): 235 - 263 .

Thakur R , Mishra DP . Pharmacological modulation of beta-catenin and its applications in cancer therapy . J Cell Mol Med. 2013 ; 17 ( 4 ): 449 - 456 .

Zhan T , Rindtorff N , Boutros M . Wnt signaling in cancer . Oncogene. 2017 ; 36 ( 11 ): 1461 - 1473 .

Al-Hendy A , Laknaur A , Diamond MP , Ismail N , Boyer TG , Halder SK . Silencing Med12 gene reduces proliferation of human leiomyoma cells mediated via Wnt/β-catenin signaling pathway . Endocrinology. 2017 ; 158 ( 3 ): 592 - 603 .

Zaitseva M , Holdsworth-Carson SJ , Waldrip L , et al.  Aberrant expression and regulation of NR2F2 and CTNNB1 in uterine fibroids . Reproduction. 2013 ; 146 ( 2 ): 91 - 102 .

Tai CT , Lin WC , Chang WC , Chiu TH , Chen GT . Classical cadherin and catenin expression in normal myometrial tissues and uterine leiomyomas . Mol Reprod Dev. 2003 ; 64 ( 2 ): 172 - 178 .

Ulin M , Ali M , Chaudhry ZT , Al-Hendy A , Yang Q . Uterine fibroids in menopause and perimenopause . Menopause. 2020 ; 27 ( 2 ): 238 - 242 .

Al-Hendy A , Diamond MP , Boyer TG , Halder SK . Vitamin D3 inhibits Wnt/β-catenin and mTOR signaling pathways in human uterine fibroid cells . J Clin Endocrinol Metab. 2016 ; 101 ( 4 ): 1542 - 1551 .

Corachán A , Ferrero H , Aguilar A , et al.  Inhibition of tumor cell proliferation in human uterine leiomyomas by vitamin D via Wnt/β-catenin pathway . Fertil Steril. 2019 ; 111 ( 2 ): 397 - 407 .

Dieffenbach PB , Haeger CM , Coronata AMF , et al.  Arterial stiffness induces remodeling phenotypes in pulmonary artery smooth muscle cells via YAP/TAZ-mediated repression of cyclooxygenase-2 . Am J Physiol Lung Cell Mol Physiol. 2017 ; 313 ( 3 ): L628 - L647 .

Mulder CL , Eijkenboom LL , Beerendonk CCM , Braat DDM , Peek R . Enhancing the safety of ovarian cortex autotransplantation: cancer cells are purged completely from human ovarian tissue fragments by pharmacological inhibition of YAP/TAZ oncoproteins . Hum Reprod. 2019 ; 34 ( 3 ): 506 - 518 .

Park JH , Shin JE , Park HW . The role of Hippo pathway in cancer stem cell biology . Mol Cells. 2018 ; 41 ( 2 ): 83 - 92 .

Purdy MP , Ducharme M , Haak AJ , et al.  YAP/TAZ are activated by mechanical and hormonal stimuli in myometrium and exhibit increased baseline activation in uterine fibroids . Reprod Sci. 2020 ; 27 ( 4 ): 1074 - 1085 .

Islam MS , Afrin S , Singh B , et al.  Extracellular matrix and Hippo signaling as therapeutic targets of antifibrotic compounds for uterine fibroids . Clin Transl Med. 2021 ; 11 ( 7 ): e475 .

Norian JM , Owen CM , Taboas J , et al.  Characterization of tissue biomechanics and mechanical signaling in uterine leiomyoma . Matrix Biol. 2012 ; 31 ( 1 ): 57 - 65 .

Berdasco M , Esteller M . Clinical epigenetics: seizing opportunities for translation . Nat Rev Genet. 2019 ; 20 ( 2 ): 109 - 127 .

Eckschlager T , Plch J , Stiborova M , Hrabeta J . Histone deacetylase inhibitors as anticancer drugs . Int J Mol Sci . 2017 ; 18 ( 7 ). doi: 10.3390/ijms18071414

Yang Q , Mas A , Diamond MP , Al-Hendy A . The mechanism and function of epigenetics in uterine leiomyoma development . Reprod Sci. 2016 ; 23 ( 2 ): 163 - 175 .

Yang Q , Al-Hendy A . Non-coding RNAs: an important regulatory mechanism in pathogenesis of uterine fibroids . Fertil Steril. 2018 ; 109 ( 5 ): 802 - 803 .

Navarro A , Yin P , Ono M , et al.  5-Hydroxymethylcytosine promotes proliferation of human uterine leiomyoma: a biological link to a new epigenetic modification in benign tumors . J Clin Endocrinol Metab. 2014 ; 99 ( 11 ): E2437 - E2445 .

Ciebiera M , Wlodarczyk M , Zgliczynski S , Lozinski T , Walczak K , Czekierdowski A . The role of miRNA and related pathways in pathophysiology of uterine fibroids-from bench to bedside . Int J Mol Sci . 2020 ; 21 ( 8 ). doi: 10.3390/ijms21083016

Wang T , Zhang X , Obijuru L , et al.  A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas . Genes Chromosomes Cancer. 2007 ; 46 ( 4 ): 336 - 347 .

Falahati Z , Mohseni-Dargah M , Mirfakhraie R . Emerging roles of long non-coding RNAs in uterine leiomyoma pathogenesis: a review . Reprod Sci . 2021 . doi: 10.1007/s43032-021-00571-w

Zhou W , Wang G , Li B , Qu J , Zhang Y . LncRNA APTR promotes uterine leiomyoma cell proliferation by targeting erα to activate the Wnt/β-catenin pathway . Front Oncol. 2021 ; 11 : 536346 .

Chuang TD , Rehan A , Khorram O . Functional role of the long noncoding RNA X-inactive specific transcript in leiomyoma pathogenesis . Fertil Steril. 2021 ; 115 ( 1 ): 238 - 247 .

Borahay MA , Al-Hendy A , Kilic GS , Boehning D . Signaling pathways in leiomyoma: understanding pathobiology and implications for therapy . Mol Med. 2015 ; 21 : 242 - 256 .

Weiss G , Goldsmith LT , Taylor RN , Bellet D , Taylor HS . Inflammation in reproductive disorders . Reprod Sci. 2009 ; 16 ( 2 ): 216 - 229 .

AlAshqar A , Reschke L , Kirschen GW , Borahay MA . Role of inflammation in benign gynecologic disorders: from pathogenesis to novel therapies† . Biol Reprod. 2021 ; 105 ( 1 ): 7 - 31 .

Sassi F , Tamone C , D’Amelio P . Vitamin D: nutrient, hormone, and immunomodulator . Nutrients . 2018 ; 10 ( 11 ). doi: 10.3390/nu10111656

Singh N , Baby D , Rajguru JP , Patil PB , Thakkannavar SS , Pujari VB . Inflammation and cancer . Ann Afr Med. 2019 ; 18 ( 3 ): 121 - 126 .

Coussens LM , Werb Z . Inflammation and cancer . Nature. 2002 ; 420 ( 6917 ): 860 - 867 .

Laughlin SK , Schroeder JC , Baird DD . New directions in the epidemiology of uterine fibroids . Semin Reprod Med. 2010 ; 28 ( 3 ): 204 - 217 .

Moore KR , Cole SR , Dittmer DP , Schoenbach VJ , Smith JS , Baird DD . Self-reported reproductive tract infections and ultrasound diagnosed uterine fibroids in African-American Women . J Womens Health (Larchmt). 2015 ; 24 ( 6 ): 489 - 495 .

Pietrowski D , Thewes R , Sator M , Denschlag D , Keck C , Tempfer C . Uterine leiomyoma is associated with a polymorphism in the interleukin 1-beta gene . Am J Reprod Immunol. 2009 ; 62 ( 2 ): 112 - 117 .

Prokofiev V , Konenkov V , Koroleva E , Shevchenko A , Dergacheva T , Novikov A . The structure of the cytokine gene network in uterine fibroids . Presented at: 2020 Cognitive Sciences, Genomics and Bioinformatics (CSGB) ; 2020 . doi: 10.1109/CSGB51356.2020.9214588

Sosna O , Kolesár L , Slavčev A , et al.  Th1/Th2 cytokine gene polymorphisms in patients with uterine fibroid . Folia Biol (Praha). 2010 ; 56 ( 5 ): 206 - 210 .

Hsieh YY , Chang CC , Tsai FJ , Lin CC , Yeh LS , Tsai CH . Tumor necrosis factor-alpha-308 promoter and p53 codon 72 gene polymorphisms in women with leiomyomas . Fertil Steril. 2004 ; 82 Suppl 3 : 1177 - 1181 .

Litovkin KV , Domenyuk VP , Bubnov VV , Zaporozhan VN . Interleukin-6 -174G/C polymorphism in breast cancer and uterine leiomyoma patients: a population-based case control study . Exp Oncol. 2007 ; 29 ( 4 ): 295 - 298 .

Hsieh YY , Chang CC , Tsai CH , Lin CC , Tsai FJ . Interleukin (IL)-12 receptor beta1 codon 378 G homozygote and allele, but not IL-1 (beta-511 promoter, 3953 exon 5, receptor antagonist), IL-2 114, IL-4-590 intron 3, IL-8 3’-UTR 2767, and IL-18 105, are associated with higher susceptibility to leiomyoma . Fertil Steril. 2007 ; 87 ( 4 ): 886 - 895 .

Chegini N . Proinflammatory and profibrotic mediators: principal effectors of leiomyoma development as a fibrotic disorder . Semin Reprod Med. 2010 ; 28 ( 3 ): 180 - 203 .

Wegienka G . Are uterine leiomyoma a consequence of a chronically inflammatory immune system? Med Hypotheses. 2012 ; 79 ( 2 ): 226 - 231 .

Protic O , Toti P , Islam MS , et al.  Possible involvement of inflammatory/reparative processes in the development of uterine fibroids . Cell Tissue Res. 2016 ; 364 ( 2 ): 415 - 427 .

Liu ZQ , Lu MY , Sun RL , Yin ZN , Liu B , Wu YZ . Characteristics of peripheral immune function in reproductive females with uterine leiomyoma . J Oncol. 2019 ; 2019 : 5935640 .

Elkafas H , Bariani MV , Ali M , et al.  Pro-inflammatory and immunosuppressive environment contributes to the development and progression of uterine fibroids . Fertil Steril . 2020 ; 114 ( 3 ). doi: 10.1016/j.fertnstert.2020.08.264

Shanes ED , Friedman LA , Mills AM . PD-L1 expression and tumor-infiltrating lymphocytes in uterine smooth muscle tumors: implications for immunotherapy . Am J Surg Pathol. 2019 ; 43 ( 6 ): 792 - 801 .

Bouman A , Heineman MJ , Faas MM . Sex hormones and the immune response in humans . Hum Reprod Update. 2005 ; 11 ( 4 ): 411 - 423 .

Yang Q , Trevino LS , El Andaloussi A , Ismail N , Walker C , Al-Hendy A. Developmental Reprogramming of Pro-Inflammatory Pathway Mediates Adult Onset of Uterine Fibroids. Fertil Steril . 2018 ; 110 : 4 suppl e377-378 .

Pike JW , Christakos S . Biology and mechanisms of action of the vitamin D hormone . Endocrinol Metab Clin North Am. 2017 ; 46(4) : 815 - 843 .

Young MRI , Xiong Y . Influence of vitamin D on cancer risk and treatment: Why the variability? Trends Cancer Res. 2018 ; 13 : 43 - 53 .

Halder SK , Goodwin JS , Al-Hendy A . 1,25-Dihydroxyvitamin D3 reduces TGF-beta3-induced fibrosis-related gene expression in human uterine leiomyoma cells . J Clin Endocrinol Metab. 2011 ; 96 ( 4 ): E754 - E762 .

Sharan C , Halder SK , Thota C , Jaleel T , Nair S , Al-Hendy A . Vitamin D inhibits proliferation of human uterine leiomyoma cells via catechol-O-methyltransferase . Fertil Steril. 2011 ; 95 ( 1 ): 247 - 253 .

Ciebiera M , Wlodarczyk M , Wrzosek M , et al.  Role of transforming growth factor beta in uterine fibroid biology . Int J Mol Sci . 2017 ; 18 ( 11 ). doi: 10.3390/ijms18112435

Halder SK , Sharan C , Al-Hendy A . 1,25-dihydroxyvitamin D3 treatment shrinks uterine leiomyoma tumors in the Eker rat model . Biol Reprod. 2012 ; 86 ( 4 ): 116 .

Al-Hendy A , Diamond MP , El-Sohemy A , Halder SK . 1,25-dihydroxyvitamin D3 regulates expression of sex steroid receptors in human uterine fibroid cells . J Clin Endocrinol Metab. 2015 ; 100 ( 4 ): E572 - E582 .

Elhusseini H , Elkafas H , Abdelaziz M , et al.  Diet-induced vitamin D deficiency triggers inflammation and DNA damage profile in murine myometrium . Int J Womens Health. 2018 ; 10 : 503 - 514 .

Ciebiera M , Wlodarczyk M , Zgliczynska M , et al.  The role of tumor necrosis factor alpha in the biology of uterine fibroids and the related symptoms . Int J Mol Sci . 2018 ; 19 ( 12 ). doi: 10.3390/ijms19123869

Ali M , Shahin SM , Sabri NA , Al-Hendy A , Yang Q . Hypovitaminosis D exacerbates the DNA damage load in human uterine fibroids, which is ameliorated by vitamin D3 treatment . Acta Pharmacol Sin. 2019 ; 40 ( 7 ): 957 - 970 .

Corachán A , Ferrero H , Escrig J , et al.  Long-term vitamin D treatment decreases human uterine leiomyoma size in a xenograft animal model . Fertil Steril. 2020 ; 113 ( 1 ): 205 - 216.e4 .

Ciavattini A , Delli Carpini G , Serri M , et al.  Hypovitaminosis D and “small burden” uterine fibroids: Opportunity for a vitamin D supplementation . Medicine (Baltimore). 2016 ; 95 ( 52 ): e5698 .

Arjeh S , Darsareh F , Asl ZA , Azizi Kutenaei M . Effect of oral consumption of vitamin D on uterine fibroids: a randomized clinical trial . Complement Ther Clin Pract. 2020 ; 39 : 101159 .

Ciebiera M , Ali M , Prince L , Zgliczyński S , Jakiel G , Al-Hendy A . The significance of measuring vitamin D serum levels in women with uterine fibroids . Reprod Sci. 2021 ; 28 ( 8 ): 2098 - 2109 .

Marchesi JR , Ravel J . The vocabulary of microbiome research: a proposal . Microbiome. 2015 ; 3 : 31 .

Lv LX , Fang DQ , Shi D , et al.  Alterations and correlations of the gut microbiome, metabolism and immunity in patients with primary biliary cirrhosis . Environ Microbiol. 2016 ; 18 ( 7 ): 2272 - 2286 .

Wang W , Li Y , Wu Q , Pan X , He X , Ma X . High-throughput sequencing study of the effect of transabdominal hysterectomy on intestinal flora in patients with uterine fibroids . BMC Microbiol. 2020 ; 20 ( 1 ): 98 .

Qin J , Li R , Raes J , et al. ; MetaHIT Consortium . A human gut microbial gene catalogue established by metagenomic sequencing . Nature. 2010 ; 464 ( 7285 ): 59 - 65 .

Claesson MJ , Cusack S , O’Sullivan O , et al.  Composition, variability, and temporal stability of the intestinal microbiota of the elderly . Proc Natl Acad Sci U S A. 2011 ; 108 Suppl 1 : 4586 - 4591 .

Plottel CS , Blaser MJ . Microbiome and malignancy . Cell Host Microbe. 2011 ; 10 ( 4 ): 324 - 335 .

Rajagopala SV , Vashee S , Oldfield LM , et al.  The human microbiome and cancer . Cancer Prev Res (Phila). 2017 ; 10 ( 4 ): 226 - 234 .

Flores R , Shi J , Fuhrman B , et al.  Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study . J Transl Med. 2012 ; 10 : 253 .

Breban M . Gut microbiota and inflammatory joint diseases . Joint Bone Spine. 2016 ; 83 ( 6 ): 645 - 649 .

Fuhrman BJ , Feigelson HS , Flores R , et al.  Associations of the fecal microbiome with urinary estrogens and estrogen metabolites in postmenopausal women . J Clin Endocrinol Metab. 2014 ; 99 ( 12 ): 4632 - 4640 .

Verstraelen H , Vilchez-Vargas R , Desimpel F , et al.  Characterisation of the human uterine microbiome in nonpregnant women through deep sequencing of the V1-2 region of the 16S rRNA gene . Peerj. 2016 ; 4 : e1602 .

Moreno I , Franasiak JM . Endometrial microbiota-new player in town . Fertil Steril. 2017 ; 108 ( 1 ): 32 - 39 .

Morgan XC , Segata N , Huttenhower C . Biodiversity and functional genomics in the human microbiome . Trends Genet. 2013 ; 29 ( 1 ): 51 - 58 .

Green KA , Zarek SM , Catherino WH . Gynecologic health and disease in relation to the microbiome of the female reproductive tract . Fertil Steril. 2015 ; 104 ( 6 ): 1351 - 1357 .

Pelzer E , Gomez-Arango LF , Barrett HL , Nitert MD . Review: maternal health and the placental microbiome . Placenta. 2017 ; 54 : 30 - 37 .

Abdeljabar El Andaloussi JG , Anukrit S , Al-Hendy A , Ismail N . Impact of uterine microbiota on the prevalence of uterine fibroids in women of colors . Reprod Sci . 2019 ; 26, Supplement 1 : 202A .

Nikitovic D , Jayes FL , Liu B , et al.  Evidence of biomechanical and collagen heterogeneity in uterine fibroids . Plos One . 2019 ; 14 ( 4 ). doi: 10.1371/journal.pone.0215646

Omar M , Laknaur A , Al-Hendy A , Yang Q . Myometrial progesterone hyper-responsiveness associated with increased risk of human uterine fibroids . BMC Womens Health. 2019 ; 19 ( 1 ): 92 .

Paul EN , Burns GW , Carpenter TJ , Grey JA , Fazleabas AT , Teixeira JM . Transcriptome analyses of myometrium from fibroid patients reveals phenotypic differences compared to non-diseased myometrium . Int J Mol Sci . 2021 ; 22 ( 7 ). doi: 10.3390/ijms22073618

Ali M , Shahin SM , Sabri NA , Al-Hendy A , Yang Q . 1,25 Dihydroxyvitamin D3 enhances the antifibroid effects of ulipristal acetate in human uterine fibroids . Reprod Sci. 2019 ; 26 ( 6 ): 812 - 828 .

Elkafas H , Ali M , Elmorsy E , et al.  Vitamin D3 ameliorates DNA damage caused by developmental exposure to endocrine disruptors in the uterine myometrial stem cells of eker rats . Cells . 2020 ; 9 ( 6 ). doi: 10.3390/cells9061459

Pilgrim J , Arismendi J , DeAngelis A , et al.  Characterization of the role of activator protein 1 signaling pathway on extracellular matrix deposition in uterine leiomyoma . F&S Sci . 2020 ; 1 ( 1 ): 78 - 89 .

Shalaby S , Khater M , Laknaur A , Arbab A , Al-Hendy A . molecular bio-imaging probe for noninvasive differentiation between human leiomyoma versus leiomyosarcoma . Reprod Sci. 2020 ; 27 ( 2 ): 644 - 654 .

Bharambe BM , Deshpande KA , Surase SG , Ajmera AP . Malignant transformation of leiomyoma of uterus to leiomyosarcoma with metastasis to ovary . J Obstet Gynaecol India. 2014 ; 64 ( 1 ): 68 - 69 .

Giuntoli RL 2nd , Metzinger DS , DiMarco CS , et al.  Retrospective review of 208 patients with leiomyosarcoma of the uterus: prognostic indicators, surgical management, and adjuvant therapy . Gynecol Oncol. 2003 ; 89 ( 3 ): 460 - 469 .

Dinh TA , Oliva EA , Fuller AF Jr , Lee H , Goodman A . The treatment of uterine leiomyosarcoma. Results from a 10-year experience (1990-1999) at the Massachusetts General Hospital . Gynecol Oncol. 2004 ; 92 ( 2 ): 648 - 652 .

Tsikouras P , Liberis V , Galazios G , et al.  Uterine sarcoma: a report of 57 cases over a 16-year period analysis . Eur J Gynaecol Oncol. 2008 ; 29 ( 2 ): 129 - 134 .

Kho KA , Lin K , Hechanova M , Richardson DL . Risk of occult uterine sarcoma in women undergoing hysterectomy for benign indications . Obstet Gynecol. 2016 ; 127 ( 3 ): 468 - 473 .

Hosh M , Antar S , Nazzal A , Warda M , Gibreel A , Refky B . Uterine sarcoma: analysis of 13 089 cases based on surveillance, epidemiology, and end results database . Int J Gynecol Cancer. 2016 ; 26 ( 6 ): 1098 - 1104 .

Brooks SE , Zhan M , Cote T , Baquet CR . Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999 . Gynecol Oncol. 2004 ; 93 ( 1 ): 204 - 208 .

Sun S , Bonaffini PA , Nougaret S , et al.  How to differentiate uterine leiomyosarcoma from leiomyoma with imaging . Diagn Interv Imaging. 2019 ; 100 ( 10 ): 619 - 634 .

Al Ansari AA , Al Hail FA , Abboud E . Malignant transformation of uterine leiomyoma . Qatar Med J. 2012 ; 2012 ( 2 ): 71 - 74 .

Bertsch E , Qiang W , Zhang Q , et al.  MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma . Mod Pathol. 2014 ; 27 ( 8 ): 1144 - 1153 .

Ravegnini G , Mariño-Enriquez A , Slater J , et al.  MED12 mutations in leiomyosarcoma and extrauterine leiomyoma . Mod Pathol. 2013 ; 26 ( 5 ): 743 - 749 .

Christacos NC , Quade BJ , Dal Cin P , Morton CC . Uterine leiomyomata with deletions of Ip represent a distinct cytogenetic subgroup associated with unusual histologic features . Genes Chromosomes Cancer. 2006 ; 45 ( 3 ): 304 - 312 .

Hodge JC , Morton CC . Genetic heterogeneity among uterine leiomyomata: insights into malignant progression . Hum Mol Genet. 2007 ; 16 Spec No 1 : R7 - 13 .

Moyo MB , Parker JB , Chakravarti D . Altered chromatin landscape and enhancer engagement underlie transcriptional dysregulation in MED12 mutant uterine leiomyomas . Nat Commun. 2020 ; 11 ( 1 ): 1019 .

Omar MK , Yang Q , Laknaur A , Al-Hendy A . Myometrial progesterone hyper-responsivness is associated with increased risk for the development of human uterine fibroids . Fertil Steril . 2016 ; 106 ( 3 ). doi: 10.1016/j.fertnstert.2016.07.280

Huang H , Weng H , Chen J . The Biogenesis and Precise Control of RNA m6A Methylation . Trends Genet. 2020 ; 36 ( 1 ): 44 - 52 .

Nachtergaele S , He C . Chemical modifications in the life of an mRNA transcript . Annu Rev Genet. 2018 ; 52 : 349 - 372 .

Yang Q , Bariani M , He C , Boyer T , Al-Hendy A . Aberrant expression of N6-Methyladenosine regulators in uterine fibroids from the Eker rat model (Abstract P-314) . American Society for Reproductive Medicine, Baltimore, MD ; 2021 .

Yang Q , Shanmugasundaram K , He C , Al-Hendy A , Boyer T . Pathological reprogramming of epitranscriptomics via METTL3 in uterine fibroids (Abstract W-046) . Society for Reproductive Investigation’s 68th Annual Scientific Meeting ; 2021 , Boston, MA .

Zhang X , Yang Q . A Pyroptosis-Related Gene Panel in Prognosis Prediction and Immune Microenvironment of Human Endometrial Cancer . Front Cell Dev Biol. 2021 ; 9 : 705828 .

Rackow BW , Taylor HS . Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity . Fertil Steril. 2010 ; 93 ( 6 ): 2027 - 2034 .

Yang Q , Diamond MP , Al-Hendy A . The emerging role of extracellular vesicle-derived miRNAs: implication in cancer progression and stem cell related diseases . J Clin Epigenet . 2016 ; 2 ( 1 ): 13 .

Li Z , Gao X , Peng X , et al.  Multi-omics characterization of molecular features of gastric cancer correlated with response to neoadjuvant chemotherapy . Sci Adv . 2020 ; 6 ( 9 ): eaay4211 .

Mars RAT , Yang Y , Ward T , et al.  Longitudinal multi-omics reveals subset-specific mechanisms underlying irritable bowel syndrome . Cell. 2020 ; 183 ( 4 ): 1137 - 1140 .

Mas A , Alonso R , Garrido-Gómez T , et al.  The differential diagnoses of uterine leiomyomas and leiomyosarcomas using DNA and RNA sequencing . Am J Obstet Gynecol. 2019 ; 221 ( 4 ): 320.e1 - 320.e23 .

Croce S , Ducoulombier A , Ribeiro A , et al.  Genome profiling is an efficient tool to avoid the STUMP classification of uterine smooth muscle lesions: a comprehensive array-genomic hybridization analysis of 77 tumors . Mod Pathol. 2018 ; 31 ( 5 ): 816 - 828 .

Croce S , Chibon F . Molecular prognostication of uterine smooth muscle neoplasms: from CGH array to CINSARC signature and beyond . Genes Chromosomes Cancer . 2021 ; 60 ( 3 ): 129 - 137 .

Mas A , Simón C . Molecular differential diagnosis of uterine leiomyomas and leiomyosarcomas . Biol Reprod. 2019 ; 101 ( 6 ): 1115 - 1123 .

Garcia N , Ulin M , Al-Hendy A , Yang Q . The role of hedgehog pathway in female cancers . J Cancer Sci Clin Ther. 2020 ; 4 ( 4 ): 487 - 498 .

Garcia N , Bozzini N , Baiocchi G , et al.  May Sonic Hedgehog proteins be markers for malignancy in uterine smooth muscle tumors? Hum Pathol. 2016 ; 50 : 43 - 50 .

Garcia N , Al-Hendy A , Baracat EC , Carvalho KC , Yang Q . Targeting hedgehog pathway and DNA methyltransferases in uterine leiomyosarcoma cells . Cells . 2020 ; 10 ( 1 ). doi: 10.3390/cells10010053

Brunengraber LN , Jayes FL , Leppert PC . Injectable Clostridium histolyticum collagenase as a potential treatment for uterine fibroids . Reprod Sci. 2014 ; 21 ( 12 ): 1452 - 1459 .

Nair S , Curiel DT , Rajaratnam V , Thota C , Al-Hendy A . Targeting adenoviral vectors for enhanced gene therapy of uterine leiomyomas . Hum Reprod. 2013 ; 28 ( 9 ): 2398 - 2406 .

Abdelaziz M , Sherif L , ElKhiary M , et al.  Targeted adenoviral vector demonstrates enhanced efficacy for in vivo gene therapy of uterine leiomyoma . Reprod Sci. 2016 ; 23 ( 4 ): 464 - 474 .

Al-Hendy A , Lee EJ , Wang HQ , Copland JA . Gene therapy of uterine leiomyomas: adenovirus-mediated expression of dominant negative estrogen receptor inhibits tumor growth in nude mice . Am J Obstet Gynecol. 2004 ; 191 ( 5 ): 1621 - 1631 .

Shalaby SM , Khater MK , Perucho AM , et al.  Magnetic nanoparticles as a new approach to improve the efficacy of gene therapy against differentiated human uterine fibroid cells and tumor-initiating stem cells . Fertil Steril. 2016 ; 105 ( 6 ): 1638 - 1648.e8 .

Senturk LM , Sozen I , Gutierrez L , Arici A . Interleukin 8 production and interleukin 8 receptor expression in human myometrium and leiomyoma . Am J Obstet Gynecol. 2001 ; 184 ( 4 ): 559 - 566 .

Orciani M , Caffarini M , Biagini A , et al.  Chronic inflammation may enhance leiomyoma development by the involvement of progenitor cells . Stem Cells Int. 2018 ; 2018 : 1716246 .

Santulli P , Even M , Chouzenoux S , et al.  Profibrotic interleukin-33 is correlated with uterine leiomyoma tumour burden . Hum Reprod. 2013 ; 28 ( 8 ): 2126 - 2133 .

Chegini N , Tang XM , Ma C . Regulation of transforming growth factor-beta1 expression by granulocyte macrophage-colony-stimulating factor in leiomyoma and myometrial smooth muscle cells . J Clin Endocrinol Metab. 1999 ; 84 ( 11 ): 4138 - 4143 .

Kurachi O , Matsuo H , Samoto T , Maruo T . Tumor necrosis factor-alpha expression in human uterine leiomyoma and its down-regulation by progesterone . J Clin Endocrinol Metab. 2001 ; 86 ( 5 ): 2275 - 2280 .

Ciebiera M , Włodarczyk M , Wrzosek M , et al.  TNF-α serum levels are elevated in women with clinically symptomatic uterine fibroids . Int J Immunopathol Pharmacol. 2018 ; 32 : 2058738418779461 .

Moridi I , Mamillapalli R , Kodaman PH , Habata S , Dang T , Taylor HS . CXCL12 attracts bone marrow-derived cells to uterine leiomyomas . Reprod Sci. 2020 ; 27 ( 9 ): 1724 - 1730 .

Sozen I , Olive DL , Arici A . Expression and hormonal regulation of monocyte chemotactic protein-1 in myometrium and leiomyomata . Fertil Steril. 1998 ; 69 ( 6 ): 1095 - 1102 .

Syssoev KA , Kulagina NV , Chukhlovin AB , Morozova EB , Totolian AA . Expression of mRNA for chemokines and chemokine receptors in tissues of the myometrium and uterine leiomyoma . Bull Exp Biol Med. 2008 ; 145 ( 1 ): 84 - 89 .

Ali M , Chaudhry ZT , Al-Hendy A . Successes and failures of uterine leiomyoma drug discovery . Expert Opin Drug Discov. 2018 ; 13 ( 2 ): 169 - 177 .

Mohammed NH , Al-Taie A , Albasry Z . Evaluation of goserelin effectiveness based on assessment of inflammatory cytokines and symptoms in uterine leiomyoma . Int J Clin Pharm. 2020 ; 42 ( 3 ): 931 - 937 .

Alfini P , Bianco V , Felice R , Magro B . [Treatment of uterine fibroma with goserelin] . Ann Ostet Ginecol Med Perinat. 1991 ; 112 ( 6 ): 359 - 367 .

Eizenberg DH . Goserelin reduction of uterine fibroids prior to vaginal hysterectomy . Aust N Z J Obstet Gynaecol. 1995 ; 35 ( 1 ): 109 - 110 .

Ahmed RS , Liu G , Renzetti A , et al.  Biological and mechanistic characterization of novel prodrugs of green tea polyphenol epigallocatechin gallate analogs in human leiomyoma cell lines . J Cell Biochem. 2016 ; 117 ( 10 ): 2357 - 2369 .

Roshdy E , Rajaratnam V , Maitra S , Sabry M , Allah AS , Al-Hendy A . Treatment of symptomatic uterine fibroids with green tea extract: a pilot randomized controlled clinical study . Int J Womens Health. 2013 ; 5 : 477 - 486 .

Shime H , Kariya M , Orii A , et al.  Tranilast inhibits the proliferation of uterine leiomyoma cells in vitro through G1 arrest associated with the induction of p21(waf1) and p53 . J Clin Endocrinol Metab. 2002 ; 87 ( 12 ): 5610 - 5617 .

Chuang TD , Rehan A , Khorram O . Tranilast induces MiR-200c expression through blockade of RelA/p65 activity in leiomyoma smooth muscle cells . Fertil Steril. 2020 ; 113 ( 6 ): 1308 - 1318 .

Chuang TD , Khorram O . Tranilast inhibits genes functionally involved in cell proliferation, fibrosis, and epigenetic regulation and epigenetically induces miR-29c expression in leiomyoma cells . Reprod Sci. 2017 ; 24 ( 9 ): 1253 - 1263 .

Tsuiji K , Takeda T , Li B , et al.  Inhibitory effect of curcumin on uterine leiomyoma cell proliferation . Gynecol Endocrinol. 2011 ; 27 ( 7 ): 512 - 517 .

Malik M , Mendoza M , Payson M , Catherino WH . Curcumin, a nutritional supplement with antineoplastic activity, enhances leiomyoma cell apoptosis and decreases fibronectin expression . Fertil Steril. 2009 ; 91 ( 5 Suppl ): 2177 - 2184 .

Salama SA , Diaz-Arrastia CR , Kilic GS , Kamel MW . 2-Methoxyestradiol causes functional repression of transforming growth factor β3 signaling by ameliorating Smad and non-Smad signaling pathways in immortalized uterine fibroid cells . Fertil Steril. 2012 ; 98 ( 1 ): 178 - 184 .

Han M , Kim JY , Park JE , Kim JM , Lee KS . Effects of letrozole on proliferation and apoptosis in cultured leiomyoma cells treated with prostaglandin E(2) . Eur J Obstet Gynecol Reprod Biol. 2008 ; 138 ( 1 ): 83 - 88 .

Malik M , Webb J , Catherino WH . Retinoic acid treatment of human leiomyoma cells transformed the cell phenotype to one strongly resembling myometrial cells . Clin Endocrinol (Oxf). 2008 ; 69 ( 3 ): 462 - 470 .

Ciebiera M , Ali M , Prince L , et al.  The evolving role of natural compounds in the medical treatment of uterine fibroids . J Clin Med . 2020 ; 9 ( 5 ): 1479 . doi: 10.3390/jcm9051479

Chen HY , Lin PH , Shih YH , et al.  Natural antioxidant resveratrol suppresses uterine fibroid cell growth and extracellular matrix formation in vitro and in vivo . Antioxidants (Basel) . 2019 ; 8 ( 4 ). doi: 10.3390/antiox8040099

Email alerts

Citing articles via.

• About the Endocrine Society
• Recommend to Your Librarian
• Advertising and Corporate Services
• Journals Career Network

Affiliations

• Online ISSN 1945-7189
• Print ISSN 0163-769X
• Copyright © 2024 Endocrine Society
• About Oxford Academic
• Publish journals with us
• University press partners
• What we publish
• New features  
• Open access
• Institutional account management
• Rights and permissions
• Get help with access
• Accessibility
• Advertising
• Media enquiries
• Oxford University Press
• Oxford Languages
• University of Oxford

Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide

• Copyright © 2024 Oxford University Press
• Cookie settings
• Cookie policy
• Privacy policy
• Legal notice

This Feature Is Available To Subscribers Only

Sign In or Create an Account

This PDF is available to Subscribers Only

For full access to this pdf, sign in to an existing account, or purchase an annual subscription.

An official website of the United States government

Official websites use .gov A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

• Publications
• Account settings
• Advanced Search
• Journal List

Currently Available Treatment Modalities for Uterine Fibroids

Jelena micić, maja macura, mladen andjić, katarina ivanović, jelena dotlić, dušan d micić, vladimir arsenijević, jelena stojnić, sandra babić, una šljivančanin, danka mostić stanišić, milan dokić.

• Author information
• Article notes
• Copyright and License information

Correspondence: [email protected]

Received 2024 Mar 30; Revised 2024 May 4; Accepted 2024 May 21; Collection date 2024 Jun.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/ ).

Uterine fibroids (leiomyomas and myomas) are the most common benign gynecological condition in patients presenting with abnormal uterine bleeding, pelvic masses causing pressure or pain, infertility and obstetric complications. Almost a third of women with fibroids need treatment due to symptoms. Objectives: In this review we present all currently available treatment modalities for uterine fibroids. Methods: An extensive search for the available data regarding surgical, medical and other treatment options for uterine fibroids was conducted. Review: Nowadays, treatment for fibroids is intended to control symptoms while preserving future fertility. The choice of treatment depends on the patient’s age and fertility and the number, size and location of the fibroids. Current management strategies mainly involve surgical interventions (hysterectomy and myomectomy hysteroscopy, laparoscopy or laparotomy). Other surgical and non-surgical minimally invasive techniques include interventions performed under radiologic or ultrasound guidance (uterine artery embolization and occlusion, myolysis, magnetic resonance-guided focused ultrasound surgery, radiofrequency ablation of fibroids and endometrial ablation). Medical treatment options for fibroids are still restricted and available medications (progestogens, combined oral contraceptives andgonadotropin-releasing hormone agonists and antagonists) are generally used for short-term treatment of fibroid-induced bleeding. Recently, it was shown that SPRMs could be administered intermittently long-term with good results on bleeding and fibroid size reduction. Novel medical treatments are still under investigation but with promising results. Conclusions: Treatment of fibroids must be individualized based on the presence and severity of symptoms and the patient’s desire for definitive treatment or fertility preservation.

Keywords: myoma, management, medicaments, surgery, minimally invasive procedures

1. Introduction

Uterine smooth-muscle tumors (leiomyomas or myomas), with a prevalence rate of up to 70%, are the most common benign uterine tumors in women during their reproductive years [ 1 ]. Fibroids are diagnosed in women of all ages but are most commonly found in women aged 35–50 years. They are monoclonal tumors of uterine smooth muscle. Some of the known factors that influence the development of uterine fibroids are genetics and race; reproductive and hormonal disturbances and obesity and vitamin D deficiency [ 2 ]. Although they are benign and can be asymptomatic, around 30% of fibroids cause profuse menstrual bleeding, irregular uterine bleeding, dysmenorrhea, pelvic discomfort and even pain due to pressure on adjacent organs and structures as well as obstetric complications such as infertility, recurrent abortions or preterm labor [ 3 ]. The currently adopted classification of fibroids was proposed by FIGO (The International Federation of Gynecology and Obstetrics), and it describes eight types of fibroids and a hybrid class in which two types of fibroids may be present in the same patient ( Table 1 ) [ 4 ].

FIGO classification.

A wide range of therapeutic options is currently available for uterine fibroids (medicamentous and surgical), but their treatment remains an ongoing dilemma for many practitioners. Women generally attempt to avoid surgical treatment because of the potential risks associated with it [ 5 ]. Medical and minimally invasive procedures are currently preferred by both patients and gynecologists for fertility preservation. However, surgical intervention sometimes has to be the primary treatment choice [ 6 , 7 ].

Therefore, bearing in mind the significant prevalence and diverse etiology of uterine fibroids, in this review, we present different medicamentous, classic surgical and minimally invasive procedures performed under radiologic or ultrasound guidance to provide more insight into different more contemporary treatment options for uterine fibroids.

An extensive search of the available data regarding surgical, medical and other treatment options for uterine fibroids was conducted. The search included Scopus, MED-LINE and PubMed, encompassing studies from the previous 23 years, from 2000 until the end of 2023. The keywords and MeSH ID (if available) that were used, alone or in combinations, were as follows: ‘uterine fibroid’ (MeSH ID: D007889), ‘myoma’ (MeSH ID: D009214), ‘uterine fibroid/myoma treatment/management’, ‘uterine fibroid/myoma surgery’, ‘uterine fibroid/myoma medications’, ‘uterine fibroid/myoma minimally invasive procedures/interventions/therapies’ and ‘uterine fibroid/myoma interventional radiology procedures’. Titles and abstracts of studies retrieved using the search strategy, and those from additional sources, were screened independently by two authors to identify those that met our objective. The full texts of these potentially suitable articles were downloaded and assessed for eligibility by two other team members. Any disagreements between them were resolved through discussion with a third collaborator.

Peer-reviewed publications written in English were included in this review. Two authors independently extracted data from articles using a standard form to ensure consistency. The results of the research have been divided into different sections and subsections to illustrate what has been reported regarding the investigated topic.

This work has some limitations. First, only English-language papers were included. Second, the included studies may vary in terms of the quality, study design and outcomes assessed. Therefore, given the heterogeneous nature of the review, only a narrative synthesis was possible.

3. Results and Discussion

Treatment options for uterine fibroids include medicamentous, interventional radiology and surgical options. Generally, it is suggested that the treatment of fibroids begins with medicamentous and minimally invasive treatments before surgery [ 5 , 8 ].

Medicamentous Treatment of Uterine Fibroids

The medicamentous management of fibroids is typically reserved for patients with heavy menstrual bleeding and/or pelvic pain who wish to preserve their fertility. For such patients, the optimal treatment opportunity involves the control and stabilization of hormone levels in fibroid cells with different medications. In addition, medicamentous treatment can serve as a presurgical adjuvant to decrease fibroid mass [ 9 , 10 ]. Medicamentous therapy yields effective results, and symptoms usually improve after one year of treatment. On the other hand, medicamentous therapy for fibroids does not have long-term effects. Therefore, the medicamentous management of fibroids is currently limited, as no pharmacological agents can be used in continuity long-term due to potential side effects [ 11 ]. Estrogen has been well-recognized for some time as the main hormone involved in the development and growth of uterine fibroids. Previous studies have suggested that progesterone and its corresponding receptors also play a significant role in fibroid evolution. Progesterone has both proliferative and antiproliferative effects that are still being investigated. Therefore, these two hormones and their receptors are the central target for medicamentous fibroid therapy [ 10 ].

Combined Oral Contraceptives (COCs)

In the past, it was believed that estrogens and progestogens from COCs could stimulate the fibroid’s growth. However, investigations showed that they can be beneficial for women with abnormal uterine bleeding with and without fibroids. COCs act by downregulating sex/hormone production, triggering suppressive effects on endometrial proliferation [ 12 ]. The main advantages of COCs are their accessibility, oral administration and low cost. Conversely, numerous studies have shown that COCs do not diminish uterine fibroid volume or uterine size. Moreover, they have minimal effects on other fibroid-related symptoms, making their use for fibroid treatment limited [ 13 ].

Levonorgestrel-Releasing Intrauterine System

The levonorgestrel-releasing intrauterine system is a contraceptive method that is also ideal for the treatment of heavy menstrual bleeding in patients who have contraindications for COCs. In addition, it has long-term effects and can be used for up to five years. Levonorgestrel is released into the endometrium where it suppresses proliferation, leading to atrophy and amenorrhea. It also has reduced systemic adverse effects compared to COCs [ 14 ].

On the other hand, its use in women who have myoma-induced heavy menstrual bleeding is limited. While the rate of intrauterine system expulsion is generally low (0–3%), in women with fibroids, the expulsion rate is up to 20%. Therefore, use is not recommended for women who have submucosal fibroids [ 15 ].

Selective Estrogen Receptor Modulators (Raloxifene)

The efficacy of Raloxifene for the treatment of uterine smooth-muscle tumors or their symptoms has still been insufficiently researched. In previous research, after Raloxifene with a gonadotropin-releasing hormone (GnRH) analogue was administered for six cycles of 28 days in premenopausal women, a significant reduction in the size of fibroids was registered. However, no difference was detected in fibroid-related symptoms. Furthermore, a possible risk of venous thrombosis with high doses of Raloxifene remains a concern [ 16 ].

Aromatase Inhibitors and Androgenic Steroids (Danazol and Gestrinone)

Danazol and Gestrinone are aromatase inhibitors and androgenic steroids that are sometimes effective in diminishing fibroid-associated symptoms. Unlike Danazol, Gestrinone can even reduce the size of fibroid mass in perimenopausal women [ 17 ]. Danazol inhibits ovarian estrogen production via pituitary gonadotropin secretion inhibition. It has been proven in various studies to reduce the symptoms associated with fibroids, but it has not been proven to exert effects on the fibroid size. Androgenic side effects such as weight gain, muscle cramps, hot flashes, mood changes, depression, acne and hirsutism are commonly reported during the use of androgenic steroids [ 18 ].

Nonsteroidal Anti-Inflammatory Drugs and Antifibrinolytic Agents (Tranexamic Acid)

Although these agents are less effective than other medications, nonsteroidal anti-inflammatory drugs can, to some extent, reduce symptoms of pelvic pain and heavy menstrual bleeding associated with uterine fibroids. Tranexamic acid, an antifibrinolytic agent, is very effective in the management of fibroid-induced heavy menstrual bleeding [ 19 , 20 ].

Progestogens

High-dose oral progestogens lead to endometrium decidualization and are frequently used for the short-term management of heavy menstrual bleeding [ 14 ]. Some investigations have also confirmed the positive effects of progestogens on reductions in fibroid size and volume. However, high-dose progestogens, either as a monotherapy or in combination with gonadotropin-releasing hormone (GnRH) agonists, cannot be used for long-term treatment because, after some time, this therapy itself might cause spotting and even increased bleeding due to changes in endometrial vasculature [ 21 ].

Selective Progesterone Receptor Modulators (SPRM)

Biochemically, SPRMS are ligands that have selective progesterone agonist, antagonist or dual activity on progesterone receptors [ 22 , 23 ]. Their effects are better within fibroids in which the expression of progesterone receptors is increased. They include several medications, of which the most commonly used are mifepristone, ulipristal acetate (for short-term therapy) and vilaprisan [ 24 , 25 ]. SPRMs cause apoptosis in tumor cells, followed by the downregulation of the proliferation of cells involved in collagen synthesis, with subsequent reductions in the extracellular matrix [ 26 ]. Thus, SPRMs have been shown to diminish uterine fibroid volume by 17–57% and to reduce uterine mass by 9–53% [ 24 , 27 ]. Moreover, with this therapy, the recurrence of fibroids is reduced for up to six months even after the cessation of the use of SPRMs [ 28 , 29 ]. In women with heavy menstrual bleeding and fibroids, the precise mechanisms of SPRM action involve effects on uterine blood flow, endometrial vessels and ovulation, as well as direct progesterone receptor-mediated effects on uterine fibroid cells, including proapoptotic and antiproliferative effects [ 30 ]. In addition, SPRMs do not affect bone mineral density, placing them in a highly favorable category of medical options for fibroid treatment [ 22 , 25 ].

Gonadotropin-Releasing Hormone (GnRH) Agonists and Antagonists

GnRH agonists, when administered, rapidly stimulate the pituitary gonadotrophs to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Via a feedback loop, they subsequently downregulate receptors and inhibit the pituitary–gonadal axis. Gonadotropin secretion is amplified by the flare-up effect of GnRH, but sustained GnRH secretions cause the downregulation of GnRH receptors, which in turn causes decreases in LH and FSH [ 31 ].

GnRH antagonists suppress the secretion of FSH and LH by blocking pituitary GnRH receptors. GnRH antagonists prevent the agonists’ first stimulatory phase, which causes them to reduce pituitary gonadotropins through GnRH receptor competition. Because of their quick action and the avoidance of a gonadotropin flare effect, symptoms are promptly relieved [ 32 ].

Therapy with either GnRH agonists or antagonists puts patients in a pseudo-menopausal state and reduces the size of fibroids and associated symptoms. The suppression of the gonadal axis results in the hypoestrogenic effect, which improves menstrual bleeding and reduces uterine fibroid size in about 3 to 4 weeks after the initiation of treatment [ 13 , 31 ].

Therapy with GnRH agonists is recommended in cases involving large uterine fibroids (>10 cm). Data from the literature indicate that GnRH antagonists can be administered for a longer time to provide persistent gonadal suppression. Both GnRH agonists and antagonists are particularly used as adjuvant therapy before laparoscopic myomectomy to reduce the operative time and blood loss during surgery. Menopausal symptoms such as hot flashes, mood swings and vaginal dryness are the most common side effects that may limit their use. The most severe side effect is decreased bone mineral density [ 13 , 32 , 33 ].

Nonpeptide Oral Gonadotropin-Releasing Hormone Antagonists

Nonpeptide is a short-acting orally active GnRH antagonist. It reversibly blocks receptor signaling, which suppresses LH and FSH in a dose-dependent manner and consequently leads to the suppression of ovarian sex steroids [ 34 ]. Unlike GnRH agonists, which cause hormonal suppression by desensitizing GnRH-R, the effects of nonpeptide have a faster onset and cessation. In that manner, therapy with oral GnRH antagonists overcomes the difficulties and costs associated with injectable GnRH antagonists [ 12 ]. Nonpeptide has been found to be effective in relation to fibroid-induced bleeding, the reduction in other symptoms and quality-of-life improvements. Nonpeptide is effective and safe for short-term use. The main drawbacks are dose-dependent bone mineral density reduction, low-density lipoprotein serum level increase and hypoestrogenic adverse effects, such as hot flashes [ 35 ].

Recent research has demonstrated that uterine fibroids may be treated using antihyperlipidemic medication statins [ 36 ]. Statins cause apoptosis and suppress the growth of fibroid cells via calcium-dependent pathways. Additionally, low doses of statins can prevent extracellular matrix protein production in myomas [ 37 , 38 ].

Interventional Radiology Procedures

Minimally invasive treatments for uterine smooth-muscle tumors are designed with the aim to preserve the fertility of women. They can also be a promising alternative therapeutic option for women who are poor surgical candidates. Such treatments include uterine artery embolization (UAE), magnetic resonance-guided focused ultrasound (MRgFUS) and radiofrequency ablation (RFA). All of these procedures are correlated with satisfactory clinical outcomes [ 39 ]. However, in patients with adenomyosis, endometriosis and/or ovarian cysts, their success is debatable. Submucosal fibroids (type 0 and type 1) and pedunculated subserosal fibroids are not candidates for any of these techniques because the risk of necrosis with expulsion is high [ 40 ]. Notably, no well-designed comparative studies have examined pregnancy outcomes and successes between different techniques. Additionally, the necrosis width effect (coagulative or ischemic) on the uterus walls and surrounding tissue and the consequent effect of the degenerated fibroids on implantation, placentation and contractility are still unknown [ 6 , 22 ].

Uterine Artery Embolization

Uterine artery embolization (UAE) is an interventional radiologic technique with an excellent clinical success rate that results in similar quality of life compared to the surgical management of fibroids, wherein an occlusive agent is used to block the uterine arteries or individual branches that feed a fibroid [ 41 , 42 ]. As the uterus receives accessory blood flow, normal uterine tissue heals from the ischemic shock. In contrast, fibroids are unambiguously damaged, which results in ischemic damage with necrosis and finally an irreparable reduction in fibroid size [ 43 , 44 ].

The most relevant issues associated with the technique are the impact of UAE on reproductive function (loss of ovarian function, radiation exposure and the possibility of subsequent hysterectomy in case of complications) as well as complications of pregnancy after UAE (attachment anomalies of the placenta, fetoplacental insufficiency leading to fetal growth restrictions and premature birth) [ 45 ]. Despite the low invasiveness of such treatment, the average hospital stay after UAE is 4 to 6 days. UAE complications include pain, vaginal discharge and post-embolization syndrome, which consists of mild fever, fatigue, nausea, vomiting, myalgia and leukocytosis. Despite the presence of a significant number of registered reports of healthy pregnancies without complications after the UAE, currently, UAE is not considered a method of choice for symptomatic fibroids for women planning pregnancy [ 46 ].

Uterine Artery Occlusion (Via Laparoscopy or a Vaginally Placed Clamp)

Uterine artery occlusion is a technique in which a clamp is placed on the uterine artery either via laparoscopy or vaginally [ 47 ]. This technique has some advantages over the embolization of uterine arteries, as it enables a direct laparoscopic assessment of the pelvis and abdomen and does not require the introduction of foreign material [ 48 ]. The data in the literature suggest that, after occlusion, menstrual blood loss decreases by 50% and the size of prominent fibroids decreases by 36% six months after treatment. Additionally, compared to uterine artery embolization, postoperative pain and painkiller usage have been found to increase [ 49 ]. However, when compared with UAE, some of the disadvantages include lower mean uterine volume reductions (33% vs. 51%) and the higher recurrence of symptoms (48% vs. 17%) [ 50 ].

Magnetic Resonance-Guided Focused Ultrasound

MRI-guided focused ultrasound surgery is a noninvasive method that uses ultrasound thermal ablation to provoke coagulation necrosis affecting the fibroids individually [ 51 ]. Magnetic resonance imaging provides a higher resolution for the visualization of anatomic structures and enables real-time thermal monitoring to improve tissue destruction. MRI with gadolinium is used to detect the width and boundaries of tissue devascularization [ 52 ]. The major advantage over UAE is the ability to target fibroids individually, while with UAE, ischemic necrosis appears throughout the entire uterus [ 53 ]. Moreover, the beneficial effect of the procedure is that there is no risk of ovarian failure, whereby ovarian tissue stays intact. Additionally, the elimination of all tumor cells is not necessary. It is sufficient to coagulate separate points inside the fibroid to provoke fibroid reduction and improve symptoms [ 54 ].

Limiting factors for this treatment are the size, vascularity and accessibility of fibroids, in conjunction with the fact that the procedure can be lengthy and costly. In addition, the fibroid cannot be treated via this method if the bladder, colon or nerves obstruct the ultrasound waves’ passage [ 51 ]. Furthermore, duration of the procedure for safety concerns should not extend more than three hours, which limits early treatment completion and success [ 53 ]. Finally, drawbacks of the technique include prolonged and heavy menstruation after treatment and occasional pain in the lumbar areas because of the heating of the sciatic nerve roots. Nevertheless, about 80% of women exhibit improvements in their symptoms, while not more than a quarter of women need another round of the procedure after 4 years [ 52 , 54 ].

Radiofrequency Ablation

Radiofrequency ablation causes coagulative necrosis by applying monopolar energy. When a fibroid or other tissue is exposed to high-frequency alternating current (in the radiofrequency range of 3 kHz to 300 GHz), tissue ions oscillate, producing heat that leads to protein denaturation and cell death [ 55 ]. Radiofrequency can be applied via laparoscopic, hysteroscopic or transvaginal routes. It is generally safe and effective, with few severe complications (bleeding, uterine perforation and intestinal perforation). The major risk factor for complications is large size of the fibroid. Therefore, some experts have suggested performing the procedure on less than three fibroids on one occasion and only on fibroids under 110 cc in volume and 5 cm in diameter, classified as FIGO 0–4 type, leaving a safe distance to the serous layer of at least 1 cm [ 56 , 57 ].

Myolysis or myoma coagulation involves the thermal, radiofrequency, laser or cryoablation ablation of fibroid tissue through hysteroscopic or laparoscopic routes. Myolysis can significantly reduce menstrual blood loss and fibroid size [ 58 ]. It is a safe and effective therapeutic option associated with shorter hospitalization and reduced intraoperative blood loss in comparison to laparoscopic myomectomy. Nevertheless, data regarding the subsequent outcome of pregnancies after myolysis are scarce. Therefore, hysteroscopic laser myolysis is indicated only for FIGO type 1 or 2 fibroids in women who are not planning future pregnancies [ 29 ].

Endometrial Ablation

Endometrial ablation, either alone or with hysteroscopic myomectomy, uses hot, cold or mechanical means to ablate the endometrium and reduce menstrual bleeding in the management of fibroids. Previous studies have indicated that more than 90% of women who had hysteroscopic myoma resection in combination with endometrial ablation did not need surgery after a 9-year follow-up, illustrating the long-term efficacy of endometrial ablation in the treatment of fibroid-induced bleeding. However, since this procedure does not affect intramural and subserosal fibroids, pressure symptoms associated with larger fibroids cannot be addressed. Subsequent pregnancies after endometrial ablation may involve the risk of ectopic pregnancy, prematurity or abnormal placentation [ 59 , 60 , 61 ].

Surgical treatment of uterine fibroids

Myomectomy is a surgical treatment in which the fibroids are removed and the uterus is then reconstructed. Therefore, myomectomy remains the standard treatment for women who are planning future pregnancies.

Myomectomy improves symptoms in up to 80% of cases but is associated with about a 27% risk of recurrence if one fibroid is removed and a risk level greater than 50% in the case of multiple fibroids. The literature suggests that myomectomy can decrease the rate of miscarriage in patients with myomas that destroy the cavity of the uterus and increase postoperative pregnancy rates to more than 50% [ 1 ].

Myomectomies generally have a low rate of complications (1–5%). The most common complication is blood loss during surgery, while the most severe is thromboembolism [ 62 ]. Nowadays, various medications and procedures can decrease blood loss during myomectomy, such as the intra-fibroid infiltration of vasopressin, intravaginal misoprostol or dinoprostone, the use of pro-fibrin/thrombin agents or the use of a bandage/tourniquet around the cervix or infundibulo–pelvic ligaments to compress the uterine blood vessels and reduce the blood supply to the uterus during surgery [ 63 , 64 ]. The single technique which is generally used entails the application of the tourniquet around the cervix to occlude both uterine arteries, while the triple technique involves the occlusion of the ovarian vessels as well. To prevent ischemic injuries, the vessel occlusion should be performed medial to the ovaries and Fallopian tubes. The tourniquet can be a suture, clamp or Foley catheter. Finally, a uterine artery ligation can also be performed [ 65 ]. Another significant postoperative complication is the occurrence of scars that lead to the disruption of normal uterine tissue. This is most important during pregnancy due to the increased risk of ruptures caused by stretching and contractions during the delivery [ 66 ].

Surgery can be performed via hysteroscopy, laparoscopy, laparotomy or through a vaginal route for nascent myomas. The choice of the surgical treatment depends on the localization, size, type and number of fibroids, the experience of the surgeon and the anesthetic risks [ 8 , 67 ].

Hysteroscopic Myomectomy

Hysteroscopic myomectomy is indicated for submucosal fibroids. According to FIGO, for leiomyomas classification types 0, 1 and 2, a standard procedure is the wire loop resection under direct visual guidance [ 68 ]. Fibroids should be located at least 5 mm away from the uterine serosa to prevent uterine perforation. Fibroids less than 4 cm in diameter can be easily resected, while in the case of larger fibroids, hysteroscopy becomes difficult to perform which increases potential complications such as excessive bleeding, uterine wall perforation, etc. [ 6 ]. Therefore, all submucosal leiomyomas larger than 3 cm should be treated before surgery with gonadotrophin-releasing hormone agonists (GnRHa) or selective progesterone receptor modulators (SPRM) to decrease the leiomyoma size and make resection possible. On the other hand, in the case of fibroids larger than 4 cm in diameter, a two-step resection with 2- to 3-month intervals should be performed [ 69 , 70 ].

Hysteroscopic myomectomy has a low rate of complications (below 1%). The perioperative risks include excessive liquid absorption, injury of the bladder and bowel and excessive bleeding and uterine perforation, mostly occurring during cervical dilatation [ 71 ]. The substances used for uterine distension can also have different risks. If a hypotonic solution is used together with monopolar energy, it may lead to hyponatremia, which can result in neurological complications. When combined with bipolar energy isotonic solution, as in the case of excessive fluid absorption, hypotonic solution may cause a circulatory overload and lead to pulmonary oedema [ 72 ]. For that reason, fluid inflow and outflow should be carefully monitored. Major postoperative complications include the formation of intrauterine adhesions. To prevent adhesions, applying anti-adhesion gel or intrauterine devices with oxidized regenerated cellulose and silicon immediately after surgical intervention is suggested [ 73 , 74 , 75 ].

Hysteroscopic myomectomy can be performed with several techniques according to myoma type and size. For the pedunculated fibroids, the base can be cut and the fibroid extracted with forceps, while for the intramural fibroids, the usual approach is the slicing technique. During myomectomy, the pseudocapsule and the surrounding healthy myometrium should be preserved to enable uterine regeneration. Therefore, the myomectomy is completed when the fasciculate fibers of the myometrium are visualized. In the case of large fibroids type 1–3, a two-step procedure can be done. During the first step, a portion of the fibroma protruding into the uterine cavity is resected. This causes the residual intramural part of the fibroid to descend into the uterine cavity making it accessible for excision during the second-step hysteroscopy [ 4 , 22 ].

Hysteroscopic myomectomy recently showed notable improvements that continue to spread with new devices and techniques. Outstanding results of this quick, cost-effective procedure have been noted in relation to irregular bleeding and fertility improvement. According to the literature, the hysteroscopic surgical resection of submucosal fibroids increases pregnancy rates up to 75% (usually around 50%). However, the success of the procedure must always be individualized based on patient risk factors, including the number, type, size and location of fibroids, as well as the purpose of the procedure [ 68 , 69 , 70 ].

Laparoscopic Myomectomy

Laparoscopic myomectomy is the minimally invasive treatment approach of choice for the fertility-sparing management of the most symptomatic intramural and subserosal smooth-muscle tumors (FIGO type 3 and 7); this approach decreases the level of postoperative pain, contributes to lower rates of postoperative fever, lowers blood loss and reduces the necessity of blood transfusions. It also contributes to shorter hospitalization time and a rapid recovery time, with a quicker return to normal daily living activities compared to open surgical methods. Laparoscopic myomectomy is a safe and efficient surgical procedure, for which complication rates are lower than 10% [ 76 ].

There are no standardized guidelines about the criteria for a laparoscopic approach to myomectomy, and such guidelines have been quite variable, based on the number, size and position of fibroids. The evaluation of fibroids via ultrasound (and, if it is needed, via magnetic resonance imaging) is of significance for correct pre- and intraoperative surgical planning to ensure complete excision during the procedure, due to the inability to directly palpate the fibroids during laparoscopy [ 77 ]. Some authors suggest that the laparoscopic approach should be avoided in cases involving more than four fibroids in different sites of the uterus requiring numerous incisions, in cases of large fibroids (larger than 10–12 cm) or if fibroids are located in an intraligamental location [ 67 ]. Others have recommended that for the laparoscopic approach, a uterus has to be smaller than the size of 16 gestational weeks, with less than five fibroids, whereby no fibroid should be greater than 15 cm [ 78 ]. A diameter of the člargers myome of 12 cm or more significantly increases the occurrence of surgical complications. College National des Gynecologues—Obstetriciens Francais has stated that if a leiomyoma’s diameter is less than 8 cm and only three of them are present, a laparoscopic surgery could be performed [ 79 ]. In the case of multiple myomas, laparoscopic myomectomy can be performed in several stages. Large fibroids can be safely and effectively treated combining uterine artery embolization as a first step and laparoscopic myomectomy (performed either on the same day or couple of days later) as the second therapeutic step [ 67 , 78 ].

The newest laparoscopic innovation is laparo-endoscopic single-site surgery or single-port laparoscopy. However, it requires more operative time, and the data about its benefits in comparison with standard laparoscopic surgery are currently limited [ 80 ].

Several complications have been registered in relation to laparoscopic myomectomy. Previous studies have suggested that an increased risk of complications is present in case of multiple fibroids, large fibroids and in fibroids with an intraligamental location [ 81 ]. Additionally, the risk of conversion to hysterectomy is increased in cases when fibroids involve the cervix, broad ligaments and uterine cornua. Complications of laparoscopic myomectomies include longer operative times, especially for larger fibroids that require morcellation [ 45 , 82 ]. Although morcellation (cutting large masses of tissue into smaller pieces) can be performed manually, a device called a power morcellator is commonly used. However, using a power morcellator increases the risk of the dissemination of the removed tissue into the abdominal cavity which can, although rarely, lead to the occurrence of pelvic adenomyosis and parasitic leiomyomas. To prevent this complication, morcellation in the endo-bag has been suggested along with extensive peritoneal lavage [ 22 , 83 ]. However, the most concerning complication involves pregnancy-related uterine rupture. Although it is rare, uterine rupture can be lethal, and although it is most frequent during pregnancy, its occurrence and risk are unpredictable. Therefore, when laparoscopic myomectomy is considered in reproductive-aged patients, this hazard should not be overlooked [ 84 ].

Laparoscopically Assisted Myomectomy

Laparoscopically assisted myomectomy offers an updated approach between laparoscopic and open abdominal surgery [ 85 ]. After the laparoscopic entrance into the abdomen and the inspection of the abdominal-pelvic cavity, a suprapubic mini-incision (typically at the level of a standard Pfannenstiel incision) is made. A self-retaining retractor is placed for an adequate exposure through the mini-laparotomy site. In that manner, the position of the uterus can be brought up to the level of the anterior abdominal wall or through the abdominal incision, allowing a myomectomy across a traditional open technique [ 86 ]. This approach should be considered for large fibroids in which major uterus reconstruction or multilayer closure is predicted. Laparoscopically assisted myomectomy is especially useful in cases with deep intramural smooth-muscle tumors where the surgeon is able to utilize palpation for advanced intraoperative surgical planning. Lastly, it enables improved visualization and exposure in situations with difficult hemostasis. In general, postoperative care and considerations for laparoscopically assisted myomectomy procedures mirror those of laparoscopic myomectomy [ 49 , 80 ].

In addition, myomectomy of multiple or large intramural fibroids as well as fibroids of the hybrid type can also be performed through a mixed laparoscopic and hysteroscopic approach [ 1 ].

Robotically Assisted Myomectomy

Robotically assisted myomectomy is a relatively new minimally invasive approach. The abdominal approach involves a central 8 or 12 mm camera port (usually 8–10 cm above the target anatomy) along with two to three ancillary 8 mm ports for the assistant robotic arms and an optional assistant side port. The steps and technical considerations for myomectomy and specimen extraction are otherwise the same as those for the conventional laparoscopic approach [ 87 , 88 ].

Though in this approach tactile feedback is lost, robotically assisted surgery provides several advantages over conventional laparoscopic myomectomy. It allows for a three-dimensional stereoscopic view, greater dexterity with seven degrees of freedom in each of the jointed instruments and the mitigation of hand tremors, which can facilitate fibroid dissection and multilayer suturing. As such, the robotically assisted approach is safe and effective and therefore should be considered in more technically challenging cases, such as those with particularly large bulky fibroids, tumors involving the cervix and lower uterine segment or extending into the pelvic sidewall or extensive pelvic adhesive disease [ 89 , 90 ].

Overall, robotically assisted myomectomy confers similar patient care benefits in comparison to laparoscopic myomectomy. The common disadvantage of robotic surgery is the financial cost, including higher hospital/professional charges and hospital reimbursement rates [ 87 , 89 ].

Open Myomectomy

Open myomectomy is suitable for the removal of larger fibroids. This technique enables excellent operative field exposure, which is helpful to carefully palpate and inspect the whole uterus for fibroids. It is substantially easier to repair uterine defects and control blood loss during an open myomectomy. An open myomectomy allows the removal of fibroids from the uterus, with the size corresponding to 36 weeks of gestation, with acceptable operative time [ 91 ]. This surgery involves myometrial incision, myoma enucleation, hemostasis, re-approximation of the myoma bed and suturing and reconstructing the uterine wall.

On the other hand, the open approach is associated with more postoperative pain, a higher rate of postoperative fever, a longer hospitalization and a longer recovery time; however, it is safer and more efficient in the context of larger and deeper lesions, with more adhesions. Suturing the uterus with an open approach is safer for women who want to give birth after surgery because it bears a smaller risk of uterine rupture [ 62 , 92 ].

Finally, open myomectomy can be performed using a mini-laparotomy, which is a very safe and effective minimally invasive open surgical technique that can enable the same-day discharge of patients [ 93 ].

Hysterectomy

A hysterectomy is the last treatment option for symptomatic fibroids. A hysterectomy is a definitive surgical treatment option that eliminates the risk of future recurrence. Approximately one-third of all hysterectomies worldwide are performed due to uterine fibroids. However, it is an advisable option only for women who have finished their reproduction and are content with losing their uterus [ 94 , 95 ].

Hysterectomies can also be performed using vaginal or abdominal (classic open, laparoscopic or robotic) approaches [ 96 ]. Vaginal and minimally invasive hysterectomies are recommended whenever possible, as they are associated with faster and better recovery, leading to shorter hospital stays and better patient satisfaction [ 45 ].

The vaginal approach is associated with less morbidity than abdominal hysterectomies. Nevertheless, vaginal hysterectomies are usually limited by the size of fibroids and the uterus. Consequently, pretreatment with GnRH analogs has been suggested to facilitate vaginal hysterectomies [ 19 ].

Nowadays, laparoscopic hysterectomy is the typical approach for the majority of patients. However, it often necessitates the morcellation of the uterus, although iatrogenic dissemination caused by the function of the morcellator of benign and potentially malignant tissue in undiagnosed leiomyosarcoma has been discussed. Manual or morcellation in the endo-bag is recommended [ 7 , 84 ]. Nevertheless, a uterine volume of more than 13–14 gestational weeks is considered a relative contraindication for laparoscopic hysterectomies. In such cases, a classic open abdominal approach would be the most appropriate [ 97 ].

Although an abdominal hysterectomy may reduce the chance of spreading unrecognized malignancy from the uterus to other abdominal structures, it is associated with increased rate of different surgery related complications (blood loss, thromboembolism, abdominal wall wound infection, etc.) when compared with minimally invasive approaches. Therefore, it is indicated as the therapy of choice only for large myoma and in women older than 50 years and/or postmenopausal due to their increased risk for uterine malignancy [ 98 ].

4. Conclusions

Symptomatic uterine fibroids require surgical and/or medical therapy according to the FIGO classification, severity of symptoms, patient’s age, infertility and wish to preserve fertility. Currently, the usual treatment for fibroids is surgical intervention, such as hysterectomy and/or fertility-sparing myomectomy performed via hysteroscopy, laparoscopy or laparotomy.

Other minimally invasive techniques, such as uterine artery embolization and occlusion, myolysis, magnetic resonance–guided focused ultrasound surgery, radiofrequency ablation of fibroids and endometrial ablation can provide excellent clinical outcomes in the appropriately selected patient but are less often used in everyday practice. Moreover, these procedures are not suggested for very large fibroid and uterus sizes, large numbers of fibroids or submucosal and pedunculated subserosal fibroids because of the risk of necrosis with expulsion. In addition, these procedures are also not recommended if future pregnancy is desired because of the effect of necrosis (coagulative or ischemic) on the uterus caused by these procedures, and the effect of the degenerated fibroids on implantation, placentation and uterine contractility remain unknown.

Medicamentous treatment options for fibroids are restricted, and available medications are generally used for short-term treatment of fibroid-induced bleeding. Progestogens and COCs provide a brief symptom improvement but do not reduce fibroid size. GnRH agonists are highly effective in suppressing bleeding and reducing fibroid size, but because of their side effects, they cannot be used for long periods. Recently, there is growing evidence that SPRMs can be very efficient for uterine fibroids in symptomatic women. Studies showed that they could be administered intermittently long-term with good results on bleeding and fibroid size reduction. Novel medical treatments, although still under investigation, seem to be good preoperative treatment options as well as an alternative to surgical intervention for fertility preservation.

Finally, it should be pointed out that, based on the fact that fibroid development and growth is an interplay between genetic, epigenetic, hormonal, lifestyle and environmental factors, uterine fibroid management should be individualized according to the medical condition and patient symptoms and wishes ( Table 2 ).

Key points for uterine fibroma treatment.

Author Contributions

Conceptualization, J.M., J.D. and M.D.; Methodology-investigation: M.M, M.A., K.I. and J.B.; Methodology—validation: S.B.; Study design, J.M., S.B. and M.D., Writing—original draft preparation: M.M., M.A., J.B. and D.M.S.; Writing—review and editing: J.M., J.D., D.D.M., V.A., J.S., U.Š. and M.D. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable for studies not involving humans or animals.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article.

Conflicts of Interest

The authors declare no conflicts of interest.

Funding Statement

This research received no external funding.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

• 1. Giuliani E., As-Sanie S., Marsh E.E. Epidemiology and management of uterine fibroids. Int. J. Gynaecol. Obstet. Off. Organ Int. Fed. Gynaecol. Obstet. 2020;149:3–9. doi: 10.1002/IJGO.13102. [ DOI ] [ PubMed ] [ Google Scholar ]
• 2. Mohammadi R., Tabrizi R., Hessami K., Ashari H., Nowrouzi-Sohrabi P., Hosseini-Bensenjan M., Asadi N. Correlation of low serum vitamin-D with uterine leiomyoma: A systematic review and meta-analysis. Reprod. Biol. Endocrinol. RBE. 2020;18:85. doi: 10.1186/S12958-020-00644-6. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 3. Farris M., Bastianelli C., Rosato E., Brosens I., Benagiano G. Uterine fibroids: An update on current and emerging medical treatment options. Ther. Clin. Risk Manag. 2019;15:157–178. doi: 10.2147/TCRM.S147318. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 4. Munro M.G., Critchley H.O., Fraser I.S. The flexible FIGO classification concept for underlying causes of abnormal uterine bleeding. Semin. Reprod. Med. 2011;29:391–399. doi: 10.1055/S-0031-1287663. [ DOI ] [ PubMed ] [ Google Scholar ]
• 5. Metwally M., Raybould G., Cheong Y.C., Horne A.W. Surgical treatment of fibroids for subfertility. Cochrane Database Syst. Rev. 2020;1:CD003857. doi: 10.1002/14651858.CD003857.PUB4. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 6. Cianci S., Gulino F.A., Palmara V., La Verde M., Ronsini C., Romeo P., Occhipinti S., Incognito G.G., Capozzi V.A., Restaino S., et al. Exploring Surgical Strategies for Uterine Fibroid Treatment: A Comprehensive Review of Literature on Open and Minimally Invasive Approaches. Medicina. 2023;60:64. doi: 10.3390/MEDICINA60010064. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 7. Multinu F., Casarin J., Hanson K.T., Angioni S., Mariani A., Habermann E.B., Shannon K.L.T. Practice Patterns and Complications of Benign Hysterectomy following the FDA Statement Warning against the Use of Power Morcellation. JAMA Surg. 2018;153:e180141. doi: 10.1001/JAMASURG.2018.0141. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 8. De La Cruz M.S.D., Buchanan E.M. Uterine Fibroids: Diagnosis and Treatment. Am. Fam. Physician. 2017;95:100–107. [ PubMed ] [ Google Scholar ]
• 9. Ali M., Chaudhry Z.T., Al-Hendy A. Successes and failures of uterine leiomyoma drug discovery. Expert Opin. Drug Discov. 2018;13:169–177. doi: 10.1080/17460441.2018.1417381. [ DOI ] [ PubMed ] [ Google Scholar ]
• 10. Kuznetsova M.V., Tonoyan N.M., Trubnikova E.V., Zelensky D.V., Svirepova K.A., Adamyan L.V., Trofimov D.Y., Sukhikh G.T. Novel Approaches to Possible Targeted Therapies and Prophylaxis of Uterine Fibroids. Diseases. 2023;11:156. doi: 10.3390/DISEASES11040156. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 11. Barseghyan M., Chae-Kim J., Catherino W.H. The efficacy of medical management of leiomyoma-associated heavy menstrual bleeding: Amini review. F&S Rep. 2023;5:4–8. doi: 10.1016/J.XFRE.2023.10.003. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 12. Chwalisz K., Taylor H. Current and Emerging Medical Treatments for Uterine Fibroids. Semin. Reprod. Med. 2017;35:510–522. doi: 10.1055/S-0037-1606302. [ DOI ] [ PubMed ] [ Google Scholar ]
• 13. Sohn G.S., Cho S.H., Kim Y.M., Cho C.H., Kim M.R., Lee S.R. Current medical treatment of uterine fibroids. Obstet. Gynecol. Sci. 2018;61:192–201. doi: 10.5468/OGS.2018.61.2.192. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 14. Sangkomkamhang U.S., Lumbiganon P., Pattanittum P. Progestogens or progestogen-releasing intrauterine systems for uterine fibroids (other than preoperative medical therapy) Cochrane Database Syst. Rev. 2020;11:CD008994. doi: 10.1002/14651858.CD008994.PUB3. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 15. Zapata L.B., Whiteman M.K., Tepper N.K., Jamieson D.J., Marchbanks P.A., Curtis K.M. Intrauterine device use among women with uterine fibroids: A systematic review. Contraception. 2010;82:41–55. doi: 10.1016/J.CONTRACEPTION.2010.02.011. [ DOI ] [ PubMed ] [ Google Scholar ]
• 16. Chung Y.J., Chae B., Kwak S.H., Song J.Y., Lee A.W., Jo H.H., Lew Y.O., Kim J.H., Kim M.R. Comparison of the inhibitory effect of gonadotropin releasing hormone (GnRH) agonist, selective estrogen receptor modulator (SERM), antiprogesterone on myoma cell proliferation in vitro. Int. J. Med. Sci. 2014;11:276–281. doi: 10.7150/ijms.7627. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 17. Hilario S.G., Bozzini N., Borsari R., Baracat E.C. Action of aromatase inhibitor for treatment of uterine leiomyoma in perimenopausal patients. Fertil. Steril. 2009;91:240–243. doi: 10.1016/J.FERTNSTERT.2007.11.006. [ DOI ] [ PubMed ] [ Google Scholar ]
• 18. Sayyah-Melli M., Bidadi S., Taghavi S., Ouladsahebmadarek E., Jafari-Shobeiri M., Ghojazadeh M., Rahmani V. Comparative study of vaginal danazol vs diphereline (a synthetic GnRH agonist) in the control of bleeding during hysteroscopic myomectomy in women with abnormal uterine bleeding: A randomized controlled clinical trial. Eur. J. Obstet. Gynecol. Reprod. Biol. 2016;196:48–51. doi: 10.1016/J.EJOGRB.2015.10.021. [ DOI ] [ PubMed ] [ Google Scholar ]
• 19. Lethaby A., Puscasiu L., Vollenhoven B. Preoperative medical therapy before surgery for uterine fibroids. Cochrane Database Syst. Rev. 2017;11:CD000547. doi: 10.1002/14651858.CD000547.PUB2. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 20. Bryant-Smith A.C., Lethaby A., Farquhar C., Hickey M. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst. Rev. 2018;4:CD000249. doi: 10.1002/14651858.CD000249.PUB2. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 21. Rogers P.A.W., Martinez F., Girling J.E., Lederman F., Cann L., Farrell E., Tresserra F., Patel N. Influence of different hormonal regimens on endometrial microvascular density and VEGF expression in women suffering from breakthrough bleeding. Hum. Reprod. 2005;20:3341–3347. doi: 10.1093/HUMREP/DEI239. [ DOI ] [ PubMed ] [ Google Scholar ]
• 22. Donnez J., Dolmans M.M. Fibroids and medical therapy: Bridging the gap from selective progesterone receptor modulators to gonadotropin-releasing hormone antagonist. Fertil. Steril. 2020;114:739–741. doi: 10.1016/J.FERTNSTERT.2020.07.028. [ DOI ] [ PubMed ] [ Google Scholar ]
• 23. Melis G.B., Neri M., Piras B., Paoletti A.M., Ajossa S., Pilloni M., Marotto M.F., Corda V., Saba A., Giancane E., et al. Vilaprisan for treating uterine fibroids. Expert Opin. Investig. Drugs. 2018;27:497–505. doi: 10.1080/13543784.2018.1471134. [ DOI ] [ PubMed ] [ Google Scholar ]
• 24. Ekanem E., Talaulikar V. Medical therapy for fibroids: What next for ulipristal acetate? Adv. Ther. 2021;38:137–148. doi: 10.1007/S12325-020-01555-Z. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 25. Bartels C.B., Cayton K.C., Chuong F.S., Holthouser K., Mehr S.A., Abraham T., Segars J.H. An Evidence-based Approach to the Medical Management of Fibroids: A Systematic Review. Clin. Obstet. Gynecol. 2016;59:30–52. doi: 10.1097/GRF.0000000000000171. [ DOI ] [ PubMed ] [ Google Scholar ]
• 26. Faustino F., Martinho M., Reis J., Aguas F. Update on medical treatment of uterine fibroids. Eur. J. Obstet. Gynecol. Reprod. Biol. 2017;216:61–68. doi: 10.1016/J.EJOGRB.2017.06.047. [ DOI ] [ PubMed ] [ Google Scholar ]
• 27. Ferrero S., Scala C., Vellone V.G., Paudice M., Vitale S.G., Cianci A., Barra F. Preoperative Treatment with Ulipristal Acetate before Outpatient Hysteroscopic Myomectomy. Gynecol. Obstet. Investig. 2020;85:178–183. doi: 10.1159/000505604. [ DOI ] [ PubMed ] [ Google Scholar ]
• 28. Mara M., Boudova B., Lisa Z., Andrasova M., Dundr P., Kuzel D. Laparoscopic myomectomy after or without pre-treatment with ulipristal acetate. Minim. Invasive Ther. Allied Technol. MITAT Off. J. Soc. Minim. Invasive Ther. 2021;30:55–62. doi: 10.1080/13645706.2019.1674337. [ DOI ] [ PubMed ] [ Google Scholar ]
• 29. Vitale S.G., Ferrero S., Caruso S., Barra F., Marín-Buck A., Vilos G.A., Vitagliano A., Torok P., Ciebiera M., Cianci A. Ulipristal Acetate Before Hysteroscopic Myomectomy: A Systematic Review. Obstet. Gynecol. Surv. 2020;75:127–135. doi: 10.1097/OGX.0000000000000764. [ DOI ] [ PubMed ] [ Google Scholar ]
• 30. Szydłowska I., Marciniak A., Nawrocka-Rutkowska J., Ryi A., Starczewski A. Predictive Factors of Response to Selective Progesterone Receptor Modulator (Ulipristal Acetate) in the Pharmacological Treatment of Uterine Fibroids. Int. J. Environ. Res. Public Health. 2020;17:798. doi: 10.3390/IJERPH17030798. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 31. Angioni S., D Alterio M.N., Daniilidis A. Highlights on Medical Treatment of Uterine Fibroids. Curr. Pharm. Des. 2021;27:3821–3832. doi: 10.2174/1381612826666210101152820. [ DOI ] [ PubMed ] [ Google Scholar ]
• 32. Kumar P., Sharma A. Gonadotropin-releasing hormone analogs: Understanding advantages and limitations. J. Hum. Reprod. Sci. 2014;7:170–174. doi: 10.4103/0974-1208.142476. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 33. Moroni R.M., Martins W.P., Ferriani R.A., Vieira C.S., Nastri C.O., Candido Dos Reis F.J., Brito L.G. Add-back therapy with GnRH analogues for uterine fibroids. Cochrane Database Syst. Rev. 2015;2015:CD010854. doi: 10.1002/14651858.CD010854.PUB2. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 34. Archer D.F., Stewart E.A., Jain R.I., Feldman R.A., Lukes A.S., North J.D., Soliman A.M., Gao J., Ng J.W., Chwalisz K. Elagolix for the management of heavy menstrual bleeding associated with uterine fibroids: Results from a phase 2a proof-of-concept study. Fertil. Steril. 2017;108:152–160.e4. doi: 10.1016/J.FERTNSTERT.2017.05.006. [ DOI ] [ PubMed ] [ Google Scholar ]
• 35. Telek S.B., Gurbuz Z., Kalafat E., Ata B. Oral Gonadotropin-Releasing Hormone Antagonists in the Treatment of Uterine Myomas: A Systematic Review and Network Meta-analysis of Efficacy Parameters and Adverse Effects. J. Minim. Invasive Gynecol. 2022;29:613–625. doi: 10.1016/J.JMIG.2021.12.011. [ DOI ] [ PubMed ] [ Google Scholar ]
• 36. Zeybek B., Costantine M., Kilic G.S., Borahay M.A. Therapeutic Roles of Statins in Gynecology and Obstetrics: The Current Evidence. Reprod. Sci. 2018;25:802–817. doi: 10.1177/1933719117750751. [ DOI ] [ PubMed ] [ Google Scholar ]
• 37. Malik M., Britten J., Borahay M., Segars J., Catherino W.H. Simvastatin, at clinically relevant concentrations, affects human uterine leiomyoma growth and extracellular matrix production. Fertil. Steril. 2018;110:1398–1407.e1. doi: 10.1016/J.FERTNSTERT.2018.07.024. [ DOI ] [ PubMed ] [ Google Scholar ]
• 38. Shen Z., Li S., Sheng B., Shen Q., Sun L.Z., Zhu H., Zhu X. The role of atorvastatin in suppressing tumor growth of uterine fibroids. J. Transl. Med. 2018;16:53. doi: 10.1186/S12967-018-1430-X. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 39. Laughlin-Tommaso S.K. Non-surgical Management of Myomas. J. Minim. Invasive Gynecol. 2018;25:229–236. doi: 10.1016/J.JMIG.2017.08.642. [ DOI ] [ PubMed ] [ Google Scholar ]
• 40. Chittawar P.B., Kamath M.S. Review of nonsurgical/minimally invasive treatments and open myomectomy for uterine fibroids. Curr. Opin. Obstet. Gynecol. 2015;27:391–397. doi: 10.1097/GCO.0000000000000223. [ DOI ] [ PubMed ] [ Google Scholar ]
• 41. Akturk H., Dura M.C., Gursoy B., Ikizoglu F., Gol E., Alsalamin W.O.I., Ekin M. Comparison of Recurrence and Quality of Life between Myoma Embolization and Myomectomy. Cureus. 2023;15:e40372. doi: 10.7759/CUREUS.40372. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 42. Manyonda I., Belli A.M., Lumsden M.A., Moss J., McKinnon W., Middleton L.J., Cheed V., Wu O., Sirkeci F., Daniels J.P., et al. Uterine-Artery Embolization or Myomectomy for Uterine Fibroids. N. Engl. J. Med. 2020;383:440–451. doi: 10.1056/NEJMOA1914735. [ DOI ] [ PubMed ] [ Google Scholar ]
• 43. Cappelli A., Mosconi C., Cocozza M.A., Brandi N., Bartalena L., Modestino F., Galaverni M.C., Vara G., Paccapelo A., Pizzoli G., et al. Uterine Artery Embolization for the Treatment of Symptomatic Uterine Fibroids of Different Sizes: A Single Center Experience. J. Pers. Med. 2023;13:906. doi: 10.3390/JPM13060906. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 44. Ukybassova T., Terzic M., Dotlic J., Imankulova B., Terzic S., Shauyen F., Garzon S., Guo L., Sui L. Evaluation of Uterine Artery Embolization on Myoma Shrinkage: Results from a Large Cohort Analysis. Gynecol. Minim. Invasive Ther. 2019;8:165–171. doi: 10.4103/GMIT.GMIT_50_19. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 45. Asgari Z., Salehi F., Hoseini R., Abedi M., Montazeri A. Ultrasonographic Features of Uterine Scar after Laparoscopic and Laparoscopy-Assisted Minilaparotomy Myomectomy: A Comparative Study. J. Minim. Invasive Gynecol. 2020;27:148–154. doi: 10.1016/J.JMIG.2019.03.026. [ DOI ] [ PubMed ] [ Google Scholar ]
• 46. Ludwig P.E., Huff T.J., Shanahan M.M., Stavas J.M. Pregnancy success and outcomes after uterine fibroid embolization: Updated review of published literature. Br. J. Radiol. 2020;93:20190551. doi: 10.1259/BJR.20190551. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 47. Carranco R.C., Vigeras A., Ribeiro R., Zomer M.T., Kondo W. Laparoscopic Variants of Temporary Uterine Artery Ligation. J. Minim. Invasive Gynecol. 2020;27:811–812. doi: 10.1016/J.JMIG.2019.08.026. [ DOI ] [ PubMed ] [ Google Scholar ]
• 48. Peng Y., Cheng J., Zang C., Chen X., Wang J. Comparison of Laparoscopic Myomectomy with and without Uterine Artery Occlusion in Treatment of Symptomatic Multiple Myomas. Int. J. Gen. Med. 2021;14:1719–1725. doi: 10.2147/IJGM.S310864. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 49. MacKoul P., Baxi R., Danilyants N., van der Does L.Q., Haworth L.R., Kazi N. Laparoscopic-Assisted Myomectomy with Bilateral Uterine Artery Occlusion/Ligation. J. Minim. Invasive Gynecol. 2019;26:856–864. doi: 10.1016/J.JMIG.2018.08.016. [ DOI ] [ PubMed ] [ Google Scholar ]
• 50. Tranoulis A., Georgiou D., Alazzam M., Borley J. Combined Laparoscopic Uterine Artery Occlusion and Myomectomy versus Laparoscopic Myomectomy: A Direct-Comparison Meta-Analysis of Short- and Long-Term Outcomes in Women with Symptomatic Leiomyomas. J. Minim. Invasive Gynecol. 2019;26:826–837. doi: 10.1016/J.JMIG.2019.02.004. [ DOI ] [ PubMed ] [ Google Scholar ]
• 51. Gizzo S., Saccardi C., Patrelli T.S., Ancona E., Noventa M., Fagherazzi S., Mozzanega B., D Antona D., Nardelli G.B. Magnetic resonance-guided focused ultrasound myomectomy: Safety, efficacy, subsequent fertility and quality-of-life improvements, a systematic review. Reprod. Sci. 2014;21:465–476. doi: 10.1177/1933719113497289. [ DOI ] [ PubMed ] [ Google Scholar ]
• 52. Ferrari F., Arrigoni F., Miccoli A., Mascaretti S., Fascetti E., Mascaretti G., Barile A., Masciocchi C. Effectiveness of Magnetic Resonance-guided Focused Ultrasound Surgery (MRgFUS) in the uterine adenomyosis treatment: Technical approach and MRI evaluation. Radiol. Med. 2016;121:153–161. doi: 10.1007/s11547-015-0580-7. [ DOI ] [ PubMed ] [ Google Scholar ]
• 53. Jeng C.J., Long C.Y., Chuang L.T. Comparison of magnetic resonance-guided high-intensity focused ultrasound with uterine artery embolization for the treatment of uterine myoma: A systematic literature review and meta-analysis. Taiwan. J. Obstet. Gynecol. 2020;59:691–697. doi: 10.1016/J.TJOG.2020.07.012. [ DOI ] [ PubMed ] [ Google Scholar ]
• 54. Clark N.A., Mumford S.L., Segars J.H. Reproductive impact of MRI-guided focused ultrasound surgery for fibroids: A systematic review of the evidence. Curr. Opin. Obstet. Gynecol. 2014;26:151–161. doi: 10.1097/GCO.0000000000000070. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 55. Berman J.M., Guido R.S., Garza Leal J.G., Pemueller R.R., Whaley F.S., Chudnoff S.G., Banks E., Harris M., Gerardo Garza Leal J., Abbott K., et al. Three-year outcome of the Halt trial: A prospective analysis of radiofrequency volumetric thermal ablation of myomas. J. Minim. Invasive Gynecol. 2014;21:767–774. doi: 10.1016/J.JMIG.2014.02.015. [ DOI ] [ PubMed ] [ Google Scholar ]
• 56. Santalla-Hernandez A., Naveiro-Fuentes M., Benito-Villena R., Villegas-Alcazar J., Lopez-Criado M.S., Lara-Serrano A., Parra J.F., Alcazar J.L., Pelayo-Delgado I. Complications of transvaginal radiofrequency ablation of fibroids: A 5-year experience. Eur. J. Obstet. Gynecol. Reprod. Biol. X. 2023;20:100244. doi: 10.1016/J.EUROX.2023.100244. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 57. Fasciani A., Turtulici G., Pedullà A., Sirito R. Uterine Myoma Position-based Radiofrequency Ablation (UMP-b RFA): 36 months follow-up clinical outcomes. Eur. J. Obstet. Gynecol. Reprod. Biol. 2023;281:23–28. doi: 10.1016/J.EJOGRB.2022.12.006. [ DOI ] [ PubMed ] [ Google Scholar ]
• 58. Vilos G.A., Allaire C., Laberge P.Y., Leyland N., Vilos A.G., Murji A., Chen I. The Management of Uterine Leiomyomas. J. Obstet. Gynaecol. Can. 2015;37:157–178. doi: 10.1016/S1701-2163(15)30338-8. [ DOI ] [ PubMed ] [ Google Scholar ]
• 59. Bofill Rodriguez M., Lethaby A., Grigore M., Brown J., Hickey M., Farquhar C. Endometrial resection and ablation techniques for heavy menstrual bleeding. Cochrane Database Syst. Rev. 2019;1:CD001501. doi: 10.1002/14651858.CD001501.PUB5. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 60. Eisele L., Kochli L., Stadele P., Welter J., Fehr-Kuhn M., Fehr M.K. Predictors of a Successful Bipolar Radiofrequency Endometrial Ablation. Geburtshilfe Frauenheilkd. 2019;79:286–292. doi: 10.1055/A-0733-5798. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 61. Kakinuma T., Kakinuma K., Tanaka H., Ohwada M. Considerations for performing microwave endometrial ablation (MEA)—Three cases with abnormal test results of endometrial tissue discovered by chance when performing MEA. Int. J. Hyperth. Off. J. Eur. Soc. Hyperthermic Oncol. North Am. Hyperth. Group. 2020;37:749–752. doi: 10.1080/02656736.2020.1781267. [ DOI ] [ PubMed ] [ Google Scholar ]
• 62. Sleiman Z., Baba R., Garzon S., Khazaka A. The Significant Risk Factors of Intra-Operative Hemorrhage during Laparoscopic Myomectomy: A Systematic Review. Gynecol. Minim. Invasive Ther. 2019;9:6–12. doi: 10.4103/GMIT.GMIT_21_19. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 63. Wang C.J., Lee C.L., Yuen L.T., Kay N., Han C.M., Soong Y.K. Oxytocin infusion in laparoscopic myomectomy may decrease operative blood loss. J. Minim. Invasive Gynecol. 2007;14:184–188. doi: 10.1016/J.JMIG.2006.09.016. [ DOI ] [ PubMed ] [ Google Scholar ]
• 64. Wang C.J., Yuen L., Han C.M., Kay N., Lee C.L., Soong Y. A transient blocking uterine perfusion procedure to decrease operative blood loss in laparoscopic myomectomy. Chang Gung Med. J. 2008;31:463–468. [ PubMed ] [ Google Scholar ]
• 65. Conforti A., Mollo A., Alviggi C., Tsimpanakos I., Strina I., Magos A., De Placido G. Techniques to reduce blood loss during open myomectomy: A qualitative review of literature. Eur. J. Obs. Gynecol. Reprod. Biol. 2015;192:90–95. doi: 10.1016/j.ejogrb.2015.05.027. [ DOI ] [ PubMed ] [ Google Scholar ]
• 66. Gambacorti-Passerini Z., Gimovsky A.C., Locatelli A., Berghella V. Trial of labor after myomectomy and uterine rupture: A systematic review. Acta Obstet. Gynecol. Scand. 2016;95:724–734. doi: 10.1111/AOGS.12920. [ DOI ] [ PubMed ] [ Google Scholar ]
• 67. Dolmans M.M., Donnez J., Fellah L. Uterine fibroid management: Today and tomorrow. J. Obstet. Gynaecol. Res. 2019;45:1222–1229. doi: 10.1111/JOG.14002. [ DOI ] [ PubMed ] [ Google Scholar ]
• 68. Etrusco A., Laganà A.S., Chiantera V., Vitagliano A., Cicinelli E., Mikuš M., Šprem Goldštajn M., Ferrari F., Uccella S., Garzon S., et al. Feasibility and Surgical Outcomes of Hysteroscopic Myomectomy of FIGO Type 3 Myoma: A Systematic Review. J. Clin. Med. 2023;12:4953. doi: 10.3390/JCM12154953. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 69. Lasmar R.B., Lasmar B.P., Moawad N.S. Hysteroscopic myomectomy. Medicina. 2022;58:1627. doi: 10.3390/MEDICINA58111627. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 70. Piecak K., Milart P. Hysteroscopic myomectomy. Prz. Menopauzalny = Menopause Rev. 2017;16:126–128. doi: 10.5114/PM.2017.72757. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 71. Ciebiera M., Lozinski T., Wojtyła C., Rawski W., Jakiel G. Complications in modern hysteroscopic myomectomy. Ginekol. Pol. 2018;89:398–404. doi: 10.5603/GP.A2018.0068. [ DOI ] [ PubMed ] [ Google Scholar ]
• 72. Xu R., Zhou X., Wang L., Cao Y. Gas embolism during surgical hysteroscopy leading to cardiac arrest and refractory hypokalemia: A case report and review of literature. Medicine. 2023;102:E35227. doi: 10.1097/MD.0000000000035227. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 73. Bortoletto P., Keefe K.W., Unger E., Hariton E., Gargiulo A.R. Incidence and risk factors of intrauterine adhesions after myomectomy. F&S Rep. 2022;3:269–274. doi: 10.1016/J.XFRE.2022.05.007. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 74. Cheng M., Chang W.H., Yang S.T., Huang H.Y., Tsui K.H., Chang C.P., Lee W.L., Wang P.H. Efficacy of Applying Hyaluronic Acid Gels in the Primary Prevention of Intrauterine Adhesion after Hysteroscopic Myomectomy: A Meta-Analysis of Randomized Controlled Trials. Life. 2020;10:285. doi: 10.3390/life10110285. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 75. Takasaki K., Henmi H., Ikeda U., Endo T., Azumaguchi A., Nagasaka K. Intrauterine adhesion after hysteroscopic myomectomy of submucous myomas. J. Obs. Gynaecol. Res. 2023;49:675–681. doi: 10.1111/jog.15499. [ DOI ] [ PubMed ] [ Google Scholar ]
• 76. Dumitrascu M.C., Nenciu C.G., Nenciu A.E., Calinoiu A., Neacsu A., Cirstoiu M., Sandru F. Laparoscopic myomectomy—The importance of surgical techniques. Front. Med. 2023;10:1158264. doi: 10.3389/FMED.2023.1158264. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 77. Palheta M.S., Medeiros F.D.C., Severiano A.R.G. Reporting of uterine fibroids on ultrasound examinations: An illustrated report template focused on surgical planning. Radiol. Bras. 2023;56:86–94. doi: 10.1590/0100-3984.2022.0048. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 78. Gitas G., Alkatout I., Allahqoli L., Rody A., Ertan A.K., Grimbizis G., Baum S. Severe direct and indirect complications of morcellation after hysterectomy or myomectomy. Minim. Invasive Ther. Allied Technol. 2022;31:418–425. doi: 10.1080/13645706.2020.1802292. [ DOI ] [ PubMed ] [ Google Scholar ]
• 79. CNGOF [Update of myoma management: Guidelines for clinical practice—Text of the guidelines] J. Gynecol. Obstet. Biol. Reprod. 2011;40:953–961. doi: 10.1016/j.jgyn.2011.09.025. (In French) [ DOI ] [ PubMed ] [ Google Scholar ]
• 80. Wang Y., Zhang S., Li C., Li B., Ouyang L. Minimally invasive surgery for uterine fibroids. Ginekol. Pol. 2020;91:149–157. doi: 10.5603/GP.2020.0032. [ DOI ] [ PubMed ] [ Google Scholar ]
• 81. Tanos V., Berry K.E., Frist M., Campo R., Dewilde R.L. Prevention and Management of Complications in Laparoscopic Myomectomy. BioMed Res. Int. 2018;2018:8250952. doi: 10.1155/2018/8250952. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 82. Abbas A.M., Michael A., Ali S.S., Makhlouf A.A., Ali M.N., Khalifa M.A. Spontaneous prelabour recurrent uterine rupture after laparoscopic myomectomy. J. Obstet. Gynaecol. J. Inst. Obstet. Gynaecol. 2018;38:1033–1034. doi: 10.1080/01443615.2018.1447913. [ DOI ] [ PubMed ] [ Google Scholar ]
• 83. Guven C.M., Uysal D. In-bag abdominal manual morcellation versus contained power morcellation in laparoscopic myomectomy: A comparison of surgical outcomes and costs. BMC Surg. 2023;23:106. doi: 10.1186/s12893-023-02007-5. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 84. Wu X., Jiang W., Xu H., Ye X., Xu C. Characteristics of uterine rupture after laparoscopic surgery of the uterus: Clinical analysis of 10 cases and literature review. J. Int. Med. Res. 2018;46:3630–3639. doi: 10.1177/0300060518776769. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 85. Luo W., Duan K., Zhang N., Delgado S., Guan Z., Guan X. A comparison of three approaches for laparoscopic single-site (LESS) myomectomy: Conventional, robotic, and hand assisted. J. Robot. Surg. 2021;15:643–649. doi: 10.1007/S11701-020-01151-X. [ DOI ] [ PubMed ] [ Google Scholar ]
• 86. Cianci S., Perrone E., Rossitto C., Fanfani F., Tropea A., Biondi A., Scambia G., Gueli Alletti S. Percutaneous-assisted vs mini-laparoscopic hysterectomy: Comparison of ultra-minimally invasive approaches. Updates Surg. 2021;73:2347–2354. doi: 10.1007/S13304-020-00893-5. [ DOI ] [ PubMed ] [ Google Scholar ]
• 87. Advincula A.P. Robot-assisted laparoscopic myomectomy: Technique & brief literature review. Best Pract. Res. Clin. Obstet. Gynaecol. 2024;93:102452. doi: 10.1016/J.BPOBGYN.2023.102452. [ DOI ] [ PubMed ] [ Google Scholar ]
• 88. Tsakos E., Xydias E.M., Ziogas A.C., Sorrentino F., Nappi L., Vlachos N., Daniilidis A. Multi-Port Robotic-Assisted Laparoscopic Myomectomy: A Systematic Review and Meta-Analysis of Comparative Clinical and Fertility Outcomes. J. Clin. Med. 2023;12:4134. doi: 10.3390/JCM12124134. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 89. Sheng Y., Hong Z., Wang J., Mao B., Wu Z., Gou Y., Zhao J., Liu Q. Efficacy and safety of robot-assisted laparoscopic myomectomy versus laparoscopic myomectomy: A systematic evaluation and meta-analysis. World J. Surg. Oncol. 2023;21:230. doi: 10.1186/S12957-023-03104-8. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 90. Tahapary M., Timmerman S., Ledger A., Dewilde K., Froyman W. Implementation of robot-assisted myomectomy in a large university hospital: A retrospective descriptive study. Facts Views Vis. ObGyn. 2023;15:243. doi: 10.52054/FVVO.15.3.089. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 91. Maccio A., Madeddu C., Caffiero A., Paoletti A.M. Successful pregnancy following myomectomy of a giant uterine myoma: Role of a combined surgical approach. Arch. Gynecol. Obstet. 2012;285:1577–1580. doi: 10.1007/S00404-011-2197-Y. [ DOI ] [ PubMed ] [ Google Scholar ]
• 92. Vargas M.V., Larson K.D., Sparks A., Margulies S.L., Marfori C.Q., Moawad G., Amdur R.L. Association of operative time with outcomes in minimally invasive and abdominal myomectomy. Fertil. Steril. 2019;111:1252–1258.e1. doi: 10.1016/J.FERTNSTERT.2019.02.020. [ DOI ] [ PubMed ] [ Google Scholar ]
• 93. Russo M.L., Gallant T., King C.R. Surgical techniques for mini-laparotomy myomectomy. Fertil. Steril. 2023;120:1262–1263. doi: 10.1016/J.FERTNSTERT.2023.08.973. [ DOI ] [ PubMed ] [ Google Scholar ]
• 94. Mujalda A., Kaur T., Jindal D., Sindhu V., Jindal P., Mujalda J. Giant Cervical Fibroid: A Surgical Challenge. Cureus. 2023;15:e39602. doi: 10.7759/CUREUS.39602. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 95. Martin-Merino E., Garcia Rodriguez L.A., Wallander M.A., Andersson S., Soriano-Gabarro M. The incidence of hysterectomy, uterus-preserving procedures and recurrent treatment in the management of uterine fibroids. Eur. J. Obstet. Gynecol. Reprod. Biol. 2015;194:147–152. doi: 10.1016/J.EJOGRB.2015.08.034. [ DOI ] [ PubMed ] [ Google Scholar ]
• 96. Tebeu P.M., Tayou R., Antaon J.S.S., Mawamba Y.N., Koh V.M., Ngou-Mve-Ngou J.P. Clinical Determinants of Vaginal and Abdominal Hysterectomy for Benign Conditions at the University Teaching Hospital, Yaounde-Cameroon. J. West Afr. Coll. Surg. 2019;9:1–7. doi: 10.4103/jwas.jwas_900_19. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 97. Brito L.G.O., Ueno N.L., Machado M.R. Does Big Mean Evil? Giant, but Benign Uterine Leiomyoma: Case Report and Review of the Literature. Rev. Bras. Ginecol. Obstet. Rev. Fed. Bras. Soc. Ginecol. Obstet. 2021;43:66–71. doi: 10.1055/S-0040-1721351. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 98. Ottarsdottir H., Cohen S.L., Cox M., Vitonis A., Einarsson J.I. Trends in Mode of Hysterectomy After the U.S. Food and Drug Administration Power Morcellation Advisory. Obs. Gynecol. 2017;129:1014–1021. doi: 10.1097/AOG.0000000000002058. [ DOI ] [ PubMed ] [ Google Scholar ]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

• View on publisher site
• PDF (348.6 KB)
• Collections

Similar articles

Cited by other articles, links to ncbi databases.

• Download .nbib .nbib
• Format: AMA APA MLA NLM

Add to Collections

An official website of the United States government

Official websites use .gov A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS A lock ( Lock Locked padlock icon ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

• Publications
• Account settings
• Advanced Search
• Journal List

Literature Review on the Role of Uterine Fibroids in Endometrial Function

Deborah e ikhena , md, serdar e bulun , md.

• Author information
• Article notes
• Copyright and License information

Serdar E. Bulun, Department of Obstetrics and Gynecology, Northwestern University, 250 E Superior Street, St 3-3306, Chicago, IL 60611, USA. Email: [email protected]

Issue date 2018 May.

Uterine fibroids are benign uterine smooth muscle tumors that are present in up to 8 out of 10 women by the age of 50. Many of these women experience symptoms such as heavy and irregular menstrual bleeding, early pregnancy loss, and infertility. Traditionally believed to be inert masses, fibroids are now known to influence endometrial function at the molecular level. We present a comprehensive review of published studies on the effect of uterine fibroids on endometrial function. Our goal was to explore the current knowledge about how uterine fibroids interact with the endometrium and how these interactions influence clinical symptoms. Our review shows that submucosal fibroids produce a blunted decidualization response with decreased release of cytokines critical for implantation such as leukocyte inhibitory factor and cell adhesion molecules. Furthermore, fibroids alter the expression of genes relevant for implantation, such as bone morphogenetic protein receptor type II, glycodelin, among others. With regard to heavy menstrual bleeding, fibroids significantly alter the production of vasoconstrictors in the endometrium, leading to increased menstrual blood loss. Fibroids also increase the production of angiogenic factors such as basic fibroblast growth factor and reduce the production of coagulation factors resulting in heavy menses. Understanding the crosstalk between uterine fibroids and the endometrium will provide key insights into implantation and menstrual biology and drive the development of new and innovative therapeutic options for the management of symptoms in women with uterine fibroids.

Keywords: uterine fibroids, endometrium, endometrial stromal cells, leiomyoma, implantation, menstrual bleeding, infertility, bone morphogenetic receptor type II (BMPR-2), recurrent pregnancy loss

Introduction

Uterine fibroids are the most common gynecologic tumor, present in up to 80% of all women by the age of 50. 1 While most uterine fibroids do not cause symptoms, some women can experience severe symptoms that significantly impact their quality of life. Fibroid symptoms include heavy and irregular menstrual bleeding with accompanying anemia, pelvic pain, dysmenorrhea, dyspareunia, increased urinary frequency, infertility, early pregnancy loss, among others. 2 , 3 Fibroids are the leading indication for hysterectomy in the United States and account for up to US$34.4 billion dollars annually in health-care costs. 4

The effects of fibroids on fertility were formerly believed to be exclusively as a result of their size; however, this perspective has changed as our understanding of fibroid pathogenesis at the molecular level has broadened. Fibroids influence endometrial gene expression through paracrine interactions. Additionally, the effect of fibroids on the endometrium is global and not localized to the endometrium overlying the fibroid itself. 5 We conducted a review of the literature to evaluate and discuss what is currently known about how uterine fibroids interact with the endometrium and how these interactions lead to clinical symptoms, specifically infertility, miscarriage, and heavy menstrual bleeding.

We performed a comprehensive review of the literature on uterine fibroids, the influences they exert on endometrial function, and the potential mechanisms through which these lead to the impaired implantation. PubMed and Google Scholar websites were used to identify relevant articles. Search terms such as “uterine fibroids,” “leiomyoma,” and “endometrium” were used in combination with “implantation,” “heavy menstrual bleeding,” “irregular menses,” “recurrent pregnancy loss,” “miscarriage,” “early pregnancy loss,” “infertility,” “subfertility,” and “fertility outcomes.” References from these articles were used to identify additional sources.

Only reports written in English were included in the literature review. We placed no restrictions on year of publication; we included all publications from the earliest database dates until March 2017. We described and expanded on what is currently known about the relationship between uterine fibroids and the endometrium as it pertains to fertility and menstrual bleeding.

Cellular Origins of Uterine Fibroids

Uterine fibroids are monoclonal tumors believed to arise from a single fibroid stem cell within the myometrium. 6 Three cell populations have been identified in uterine fibroids: fully differentiated fibroid smooth muscle cells, a cell population with intermediate characteristics, and fibroid stem cells. 7 Both myometrium and fibroid tissue have side population cells that possess cell surface markers characteristic of stem cells. 7 , 8 Fibroid stem cells are critical for fibroid growth and expansion. In fact, in a murine model, tumors composed only of fully differentiated or intermediate populations of fibroid cells demonstrate significantly slower growth rates than those tumors composed of fibroid stem cells. 7

It appears that fibroid stem cells occur as a result of a genetic hit to a myometrial stem cell, such as point mutations in the mediator complex subunit 12 ( MED12 ) gene or chromosomal rearrangements that affect the expression of the high-mobility group AT-hook 2 ( HMGA2 ) gene. 6 Chromosomal rearrangements involving HMGA2 on the long arm of chromosome 12 are believed to play a role in the induction of fibroid stem cells and fibroid tumorigenesis, especially in larger tumors. 6 , 9 Additionally, some fibroid stem cells possess MED12 mutations that have not been identified in the myometrial stem cell population. 10 Introduction of a MED12 mutation in murine uterine tissue has been shown to give rise to fibroid-like tumor formation. 11 These findings suggest that a genetic hit may be important for the initiation of fibroid tumors and their growth. Ethnicity and environmental factors are believed to play a role in tumorigenesis. Endocrine-disrupting chemicals (EDCs) have been shown to interfere with growth and differentiation in different stem cell types. Recent studies suggest that exposure to EDCs may lead to genetic alterations in stem cells, which may be important in fibroid tumorigenesis. 12 - 14 With regard to ethnicity, studies reveal that the number of tumor-initiating myometrial stem cells is directly correlated with the likelihood of developing uterine fibroids, with the highest number being present in African American women with uterine fibroids and the lowest in Caucasian women without uterine fibroids. 15

Fibroids are hormonally responsive tumors. Mature fibroid cells possess estrogen receptors, and estradiol is associated with increased proliferation of uterine fibroid smooth muscle cells. 16 , 17 Uterine fibroids not only respond to systemic steroids but also to local steroids biosynthesized by aromatase within the fibroid itself. 18 Despite the hormonally dependent nature of fibroids, fibroid stem cells express low levels of estrogen and progesterone receptors, suggesting that steroid hormones utilize a paracrine mechanism to exert their tropic effects on fibroid stem cells ( Figure 1 ).

Illustration of stem cell populations in the myometrium and fibroid tissue. Stem cells are self-renewing and are involved in the proliferation of both normal myometrium and fibroid tissue. It is thought that a genetic hit, such as a mutation in the MED12 gene, can lead to the transformation of a myometrial stem cell into a fibroid stem cell. Fibroids are hormone-responsive tissues. However, fibroid stem cells, which are mainly responsible for proliferation and fibroid growth, are devoid of estrogen and progesterone receptors. Thus, stem cell replication and growth is likely regulated via paracrine signals, which lead to fibroid growth. ERα indicates estrogen receptor alpha; PR, progesterone receptor.

An important signaling pathway implicated in promoting fibroid growth is the wingless-type Mouse Mammary Tumor Virus (MMTV) integration site Wingless Type (WNT)/β-catenin pathway. 19 Because β-catenin targets the MED12 subunit, mutations in the MED12 gene can lead to alterations in the interactions between MED12 and β-catenin leading to inhibition of β-catenin transactivation in response to WNT signaling. 20 In the WNT/β-catenin pathway, secreted WNT proteins bind to frizzled family cell surface receptors, leading to decreased β-catenin degradation in the cytoplasm and a subsequent increase in nuclear β-catenin. 2 , 21 In the murine model, increased β-catenin level seen with increasing parity is correlated with the number of fibroid-like tumors present in the uteri of such mice, which exhibit both histologic and molecular characteristics of fibroids. 22 However, in this study, it was unclear whether the increased β-catenin level or the increased parity of these mice is the primary driver of the increase in fibroid-like tumors. Recent data show that MED12 knockdown in human fibroid cells leads to decreased cell proliferation via downregulation of the WNT/β-catenin signaling pathway. 23

Additionally, activation of the WNT/β-catenin pathway leads to increased levels of transforming growth factor β3 (TGF-β3). Fibroid cells secrete markedly elevated levels of TGF-β3 in a steroid-responsive manner when compared to myometrial cells. 24 Transforming growth factor β3 has also been shown to play a key role in cell proliferation and deposition of extracellular matrix. 22 Taylor and colleagues have demonstrated that TGF-β3 secreted by fibroid cells exerts paracrine effects on endometrial stromal cells (ESCs) and epithelial cells. 5 , 25 , 26

Clinical Fertility Outcomes in the Presence of Uterine Fibroids

One in every 10 women seeking fertility treatment has uterine fibroids. 27 - 29 The effect of uterine fibroids on infertility is largely dependent on the location of the fibroid, with submucosal and intramural fibroids having the most significant impact.

Submucosal fibroids

Submucosal fibroids, which impinge into the uterine cavity, have been associated with impaired reproductive outcomes. In 2008, Klatsky et al performed a systematic review showing that women with submucosal fibroids had lower implantation rates (3.0%-11.5% vs 14%-30%) and a higher incidence of early pregnancy loss (47% vs 22%) compared to women without fibroids. 30 - 33 A meta-analysis by Pritts et al found that women with submucosal fibroids had significantly lower implantation rates, pregnancy rates, ongoing pregnancies, and live birth rates. In this meta-analysis, submucosal fibroids were associated with an increased risk of spontaneous abortion. 34 Although most of these data are from retrospective or prospective cohort studies, the consensus is to surgically remove submucosal fibroids in a woman who is actively pursuing pregnancy, regardless of other symptoms.

Intramural fibroids

Fibroids located within the wall of the myometrium are known as intramural fibroids. The data on the relationship between intramural fibroids and infertility are inconclusive at best. A meta-analysis by Pritts et al found higher rates of spontaneous abortions and significantly lower rates of implantation, ongoing pregnancies, and live births in women with intramural fibroids. 34 In 2017, Christopoulos et al showed decreased pregnancy rates after in vitro fertilization (IVF) in women with noncavity-distorting fibroids. Sagi-Dain and colleagues observed a similar trend in recipients of donor oocytes with uterine fibroids. 35 , 36 However, in this study, oocyte recipients with intramural fibroids received a significant lower percent of good quality embryos and this was not controlled for in the results. However, other studies show data to the contrary. Klatsky et al also studied pregnancy rates in recipients of donor oocytes and noted no difference in implantation or clinical pregnancy rates between women with and without uterine fibroids. 37 Additionally, the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation clinical trial by the Reproductive Medicine Network showed no difference in conception and live birth rates in women with noncavity-distorting intramural fibroids. 38 Given the conflicting data, there is still some debate about the clinical effect of noncavity-distorting intramural fibroids. Current data suggest that if a clinical effect is present, it may be unmasked by and as a result more clinically relevant for IVF cycles than with ovarian stimulation and intrauterine insemination.

In addition to the controversy on fibroid location, there is still some debate as to whether the degree of the detrimental effect of uterine fibroids’ endometrial function correlates with the size of the fibroid. A 2008 meta-analysis by Pritts et al both show no difference in effect due to fibroid size or number on outcomes. 34 However, fibroid size was only reported by 5 of the studies included in this meta-analysis.

The effect of myomectomy

These observations, specifically in the case of submucosal fibroids, raise the question of whether myomectomy leads to an improvement in fertility and early pregnancy outcomes. A 2013 Cochrane review concluded that hysteroscopic myomectomy improves clinical pregnancy rates with timed intercourse from a baseline of 21% to 39%. 39 Although these findings suggest that hysteroscopic myomectomy provides a clinical benefit in the presence of a submucosal fibroid, more data from randomized controlled trials with larger populations are needed to better understand the effect of hysteroscopic myomectomy on endometrial function and implantation.

Effect of Uterine Fibroids on the Endometrium and Implantation

The narrow time period during which the endometrium is receptive to implantation of the embryo is known as the window of implantation (WOI). The WOI occurs between 7 and 10 days following the luteinizing hormone surge and it is when the endometrium prepares for the attachment of the blastocyst. 40 The steps necessary for successful implantation are apposition, adhesion, and invasion. A complex series of interactions between various processes are necessary for these steps to occur and any aberrations can result in recurrent implantation failure, early pregnancy loss, or infertility. The effects of uterine fibroids on implantation are summarized in Figure 2 and described in detail below.

Diagram summarizing the effects of submucosal and intramural fibroids on implantation. BMP2 indicates bone morphogenetic protein 2; HOXA10, Homeobox A10; IL-1β, interleukin 1 beta; IL-11, interleukin 11; LIF, leukemia inhibitory factor; TGF-β3, transforming growth factor beta 3; VEGF, vascular endothelial growth factor.

Cell adhesions molecules, homeobox genes, and other gene expression

Transcription factors known as homeobox genes, specifically homeobox A10 ( HOXA10 ) and homeobox A11 ( HOXA11 ), are expressed in the female reproductive system and are important for implantation. 41 In mice, HOXA10 expression increased during the WOI. Knockout mice for HOXA10 are infertile due to implantation failure, specifically embryos from HOXA10 knockout mice are able to grow normally in wild-type mice, demonstrating that the defect lies with endometrial receptivity and not with the embryos themselves. 42

The HOXA10 expression is decreased in the endometrium of women with submucosal fibroids. This decrease in HOXA10 expression is most prominent in the endometrium overlying the submucosal fibroid but is also observed throughout the endometrium. 5

Decreased expression of HOXA10 and the cell adhesion molecule E-cadherin have been described in the endometrium of women with noncavity-distorting intramural uterine fibroids during the WOI. 43 In fact, 68.8% of women with fibroids have low mid-secretory phase HOXA10 protein expression. 44 Furthermore, it appears that this decrease in HOXA10 expression reverses following myomectomy. Interestingly, the same study failed to show any improvement in HOXA10 expression following myomectomy for submucosal fibroids. 45 Bone morphogenetic protein type II (BMP2) mediates HOXA10 expression; thus, increased endometrial resistance to BMP2 may contribute to the low HOXA10 expression in the endometrium of these patients 25 ( Figure 2 ).

Ben-Nagi and colleagues evaluated levels of glycodelin, osteopontin, interleukin (IL) 6, IL-10, and tumor necrosis factor (TNF) α in uterine flushings of women with and without submucosal fibroids during the WOI. They found lower levels of glycodelin and IL-10 in uterine flushings from the mid-luteal endometrium of women with uterine fibroids and no differences in osteopontin, IL-6, and TNFα compared to women without fibroids. 46 However, this was a study of uterine flushings and the accuracy of the correlation between uterine flushings and secretions from ESCs is unclear.

Horcajadas et al performed gene expression analysis on endometrial tissue from women with or without intramural uterine fibroids during the WOI. They identified 3 genes that are dysregulated in women with intramural fibroids >5 cm compared to controls: glycodelin and aldehyde dehydrogenase 3 family member B2. 47 Glycodelin was dysregulated in women with intramural fibroids <5 cm. This suggests that larger fibroids may have a more profound effect on endometrial gene expression; however, additional studies are needed to better elucidate this point.

The rise in progesterone following ovulation is responsible for decidualization of the endometrium, which is marked by increasing amounts of prostaglandins and vascular endothelial growth factor (VEGF). 48 These prostaglandins and VEGF increase vessel permeability in endometrial blood vessels allowing for extravasation of polymorphonuclear cells, which also produce cytokines important for implantation, including leukocyte inhibitory factor (LIF).

Another effect of progesterone and estrogen on ESCs is the secretion of decidual markers such as prolactin and insulin-like growth factor-binding protein 1, which are associated with IL-11. 49 , 50 IL-11 is essential for implantation. 51 Both LIF and IL-11 are pleiotropic cytokines belonging to the IL-6 family and have been noted to be essential for embryo implantation in the murine model. Both LIF and IL-11 bind to ligand-specific receptors, LIFR and IL-11R, and share the same signal transduction target, gp130. The gp130 signaling pathway is important for embryo implantation, 41 , 52 with inactivation of gp130 in a murine model resulting in implantation failure. 53

The LIF-deficient mice show a complete failure of implantation due to defective decidualization. Interestingly, embryos from LIF-deficient mice are unable to implant in the endometrium of LIF-deficient mice, but they are able to implant in the endometrium of wild-type mice. 54 In humans, LIF expression increases in the luteal phase and peaks during the implantation window; however, in the presence of submucosal fibroids, the luteal phase increase in LIF protein expression is blunted. 55 Clinically, deregulation of LIF production in the secretory endometrium has been associated with unexplained infertility and recurrent abortions. 56

Interleukin 11 is essential for sustained decidualization. The IL-11-deficient mice are able to begin decidualization but cannot sustain or complete the decidual response, thus leading to pregnancy loss by day 8. 51 , 57 In humans, IL-11 plays a role in the regulation of trophoblast invasion, and low levels of IL-11 are associated with decreased numbers of uterine natural killer (NK) cells in the secretory endometrium. 58 , 59 The production of IL-11 is decreased during the WOI in the presence of submucosal fibroids. 55 Because of its known role in trophoblast invasion and decidualization, reduction in IL-11 may lead to defective implantation; however, further study is needed to determine the clinical correlation.

Growth factors

Progesterone induces the secretion of BMP2 and its downstream target wingless-type MMTV integration site family, member 4 (WNT4) by ESCs. 60 This occurs via decidual signals from TGF-β3 family proteins such as heparin-binding epidermal growth factor. 61 The endometrium in BMP2-deficient mice is unable to undergo decidual differentiation due to the absence of BMP2 production. 62 , 63 Furthermore, although embryo attachment is possible in BMP2-deficient mice, impaired decidual differentiation leads to defective implantation and pregnancy loss. 60 , 63 When exposed to progesterone, WNT4 knockout mice have defective implantation as a result of impaired ESC survival and decidualization. 64 The activation of BMP2 in response to progesterone appears to be necessary for WNT4 activation and subsequently implantation.

In humans, BMP2 resistance is one of the proposed mechanisms by which submucosal fibroids impair implantation. Submucosal fibroids secrete high levels of TGF-β3, which downregulates BMP receptor type II expression in ESC and subsequently leads to ESC resistance to BMP2. 25 This resistance to BMP2 negatively affects cell proliferation and differentiation, causing impaired decidualization and implantation site formation. 63 Given the essential role of BMP2 and its downstream targets in decidualization and successful implantation, endometrial resistance to BMP2 in the presence of uterine fibroids has the potential to result in suboptimal decidualization and defective implantation. Clinically, this may manifest as a higher incidence of spontaneous abortions and a lower rate of implantation.

Immune cells

The progesterone-dependent increase in VEGF and prostaglandin secretion seen with decidualization promotes extravasation of immune cells into the endometrium. These cells consist mainly of macrophages and NK cells. 65 Macrophages produce cytokines, such as LIF, which as described above are essential for implantation. 58 , 66 Furthermore, macrophages play an integral role in trophoblast invasion and placental development. 67

The NK cells are the principal immune cells present during the WOI and are important for immune tolerance, angiogenesis, trophoblast migration, and invasion. 68 The NK cells produce pro-angiogenic factors such as VEGF and placental growth factor, which regulate maternal–uterine vasculature remodeling and trophoblast invasion. 69 , 70 Mice deficient in NK cells are still fertile, but their pregnancies are marked by fetal loss, severe intrauterine growth restriction, and preeclampsia. 71

Mid-secretory endometrium of women with uterine fibroids compared to women without fibroids show an increase in macrophage density and a decrease in the density of NK cells 72 ( Figure 2 ). These abnormalities in macrophage and NK cell density result in altered endometrial function and may impede endometrial receptivity to implantation.

Mechanical stretch, uterine wall contractility, and implantation

Uterine fibroids can place tremendous stress and stretch on the nearby myometrium and overlying endometrium, proportionate to the size and location of the fibroid. This increase in uterine stretch results in abnormal gene expression. 73 - 75

These abnormalities in gene expression, together with the physical presence of fibroids, contribute to impaired uterine contractility. Recent studies have implicated uterine contractility in implantation. Abnormal uterine contractions and peristalsis during the mid-luteal phase have been observed on cine magnetic resonance imaging of women with uterine fibroids. 76 Yoshino et al further described lower pregnancy rates in women with intramural fibroids and a higher frequency of uterine peristalsis during the WOI. In that study, 10 of the 29 women with intramural fibroids in the low-frequency peristalsis group achieved pregnancy compared to none of the 22 women in the high-frequency peristalsis group. 77 Although it was a small study, the data suggest that abnormal uterine peristalsis may play a role in implantation and pregnancy outcomes in women with intramural fibroids. However, additional larger studies are needed before these clinical relevance of these data can be determined.

Heavy Menstrual Bleeding and Dysmenorrhea Associated With Uterine Fibroids

Abnormal uterine bleeding is one of the most common symptoms in women with uterine fibroids. Normal menses occurs every 24 to 35 days. The American Congress of Obstetrics and Gynecology (ACOG) defines heavy menstrual bleeding as diagnosed when bleeding exceeds 80 mL, however, for clinical purposes, any level of menstrual bleeding which causes distress to the patient is managed as heavy menstrual bleeding. 78 The quantity of bleeding experienced with each menses depends on a complex interplay of vasoconstriction, angiogenesis, and coagulation. The most common type of abnormal uterine bleeding observed with fibroids is excessive menstrual bleeding that is frequently accompanied by dysmenorrhea. 2

Endothelin-1 (ET-1) and prostaglandin F 2alpha (PGF 2α ) are the 2 most important vasoconstrictors involved in menstruation. 79 Endothelin-1 is a potent vasoconstrictor that stimulates mitogenesis and myometrial contraction. 80 In the endometrium, ET-1 plays a role in spiral arteriole vasoconstriction and thus blood flow. Significantly higher levels of ET-1 are expressed in the endometrium compared to the myometrium and fibroid tissue. Endothelin-1 exerts its effects via its receptors ET A -R and ET B -R. Higher levels of ET A -R are found in fibroid tissue relative to the myometrium, but the opposite is observed for ET B -R. The alterations in receptor levels suggest that ET function is aberrant in the presence of uterine fibroids. 81 The altered myometrial expression of ET A -R and ET B -R may result in abnormal uterine contractions leading to defective vasoconstriction and increased menstrual blood flow, especially in the setting of intramural fibroids. Consistent with these data, the endometrial stroma in women with fibroids and heavy menstrual bleeding have been shown to have dilated endometrial stromal venous spaces compared to normal controls. This supports the idea that defective vasoconstriction is one of the mechanisms by which heavy menstrual bleeding occurs. 82 Prostaglandin F 2alpha receptors are present in normal myometrium and regulate uterine contractions. Uterine fibroids have increased PGF 2α production, which is accompanied by disordered uterine contraction and may play a role in the greater menstrual blood loss observed in women with uterine fibroids. 65

When compared to normal endometrium, fibroids overexpress basic fibroblast growth factor (bFGF), an important regulator of angiogenesis. 83 Concurrently, the endometrial stroma of women with uterine fibroids expresses increased levels of basic fibroblast growth factor receptor 1 (FGFR1). 83 The combined increase in the expression of bFGF and FGFR1 may play a role in abnormal angiogenesis and excess bleeding during menses observed in women with uterine fibroids ( Figure 3 ).

Diagram summarizing the effects of submucosal and intramural fibroids on bleeding. ATIII indicates antithrombin III; bFGF, basic fibroblast growth factor; BMPR-2, bone morphogenetic receptor type II; ET-1, endothelin-1; FGFR1, basic fibroblast growth factor receptor 1; PAI1, plasminogen activator inhibitor 1; PGF2α, prostaglandin F 2-alpha; TGF-β3, transforming growth factor beta 3; TM, thrombomodulin.

As described previously, fibroids secrete TGF-β3. Increased TGF-β3 secretion impedes production of coagulation and thrombosis factors, such as thrombomodulin, antithrombin III, and plasminogen activator inhibitor 1. Therefore, disproportionately higher levels of TGF-β3 secreted by fibroids inhibit expression of genes related to fibrinolytic and anticoagulant activity, which results in heavy menstrual bleeding ( Figure 3 ).

Our understanding of the intricate communication between uterine fibroids and the endometrium continues to grow. Although a clear link exists between uterine fibroids and heavy menstrual bleeding, a causative relationship between uterine fibroids and fertility is less clear given that both conditions are relatively common. There is consensus that submucosal fibroids, which distort the uterine cavity, are associated with infertility and early pregnancy loss and should be removed in patients with infertility. In contrast, the clinical significance of intramural fibroids remains controversial.

Submucosal and intramural fibroids both exert significant effects on endometrial gene expression and function. The downstream effects of excessive TGF-β3 secretion from uterine fibroids influence the entire endometrium. This leads to decreased production of transcription factors necessary for implantation during the WOI and aberrant production of coagulation factors during menses. Fibroids also exert their effect on the endometrium through altered gene expression and changes to the immune environment and vasoconstrictive factors.

Despite the significant strides that have been made in this field in recent years, further study is warranted to better understand the crosstalk between uterine fibroids and the endometrium. Such knowledge has the potential to lead to new therapeutic options for the management of symptomatic uterine fibroids.

Authors’ Note: DEI designed the review, performed the literature search, and wrote the manuscript. SEB designed the manuscript, supervised and performed revisions, and critically discussed and reviewed the complete manuscript.

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the NIH grants, POI-HD57877 and R37-HD38691 (to S.E.B) and the Friends of Prentice (to D.E.I).

• 1. Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003;188(1):100–107. [ DOI ] [ PubMed ] [ Google Scholar ]
• 2. ACOG Practice Bulletin. Alternatives to hysterectomy in the management of leiomyomas. Obstet Gynecol. 2008;112(2 pt 1):387–400. [ DOI ] [ PubMed ] [ Google Scholar ]
• 3. Zimmermann A, Bernuit D, Gerlinger C, Schaefers M, Geppert K. Prevalence, symptoms and management of uterine fibroids: an international internet-based survey of 21,746 women. BMC Womens Health. 2012;12:6. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 4. Cardozo ER, Clark AD, Banks NK, Henne MB, Stegmann BJ, Segars JH. The estimated annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol. 2012;206(3):211.e1-e9. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 5. Rackow BW, Taylor HS. Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity. Fertil Steril. 2010;93(6):2027–2034. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 6. Bulun SE. Uterine fibroids. N Engl J Med. 2013;369(14):1344–1355. [ DOI ] [ PubMed ] [ Google Scholar ]
• 7. Yin P, Ono M, Moravek MB, et al. Human uterine leiomyoma stem/progenitor cells expressing CD34 and CD49b initiate tumors in vivo. J Clin Endocrinol Metab. 2015;100(4):E601–E606. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 8. Ono M, Maruyama T, Masuda H, et al. Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells. Proc Natl Acad Sci U S A. 2007;104(47):18700–18705. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 9. Mas A, Cervello I, Fernandez-Alvarez A, et al. Overexpression of the truncated form of high mobility group A proteins (HMGA2) in human myometrial cells induces leiomyoma-like tissue formation. Mol Hum Reprod. 2015;21(4):330–338. [ DOI ] [ PubMed ] [ Google Scholar ]
• 10. Ono M, Qiang W, Serna VA, et al. Role of stem cells in human uterine leiomyoma growth. PLoS One. 2012;7(5):e36935. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 11. Mittal P, Shin YH, Yatsenko SA, Castro CA, Surti U, Rajkovic A. Med12 gain-of-function mutation causes leiomyomas and genomic instability. J Clin Invest. 2015;125(8):3280–3284. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 12. Yang Q, Diamond MP, Al-Hendy A. Early life adverse environmental exposures increase the risk of uterine fibroid development: role of epigenetic regulation. Front Pharmacol. 2016;7:40. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 13. Katz TA, Yang Q, Trevino LS, Walker CL, Al-Hendy A. Endocrine-disrupting chemicals and uterine fibroids. Fertil Steril. 2016;106(4):967–977. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 14. Yang Q, Diamond MP, Al-Hendy A. Converting of myometrial stem cells to tumor-initiating cells: mechanism of uterine fibroid development. Cell Stem Cells Regen Med. 2016;2(1) PMID: 28042616. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 15. Mas A, Stone L, O’Connor PM, et al. Developmental exposure to endocrine disruptors expands murine myometrial stem cell compartment as a prerequisite to leiomyoma tumorigenesis. Stem Cells. 2017;35(3):666–678. [ DOI ] [ PubMed ] [ Google Scholar ]
• 16. Andersen J, DyReyes VM, Barbieri RL, Coachman DM, Miksicek RJ. Leiomyoma primary cultures have elevated transcriptional response to estrogen compared with autologous myometrial cultures. J Soc Gynecol Investig. 1995;2(3):542–551. [ DOI ] [ PubMed ] [ Google Scholar ]
• 17. Pedeutour F, Quade BJ, Weremowicz S, Dal Cin P, Ali S, Morton CC. Localization and expression of the human estrogen receptor beta gene in uterine leiomyomata. Genes Chromosomes Cancer. 1998;23(4):361–366. [ DOI ] [ PubMed ] [ Google Scholar ]
• 18. Bulun SE, Simpson ER, Word RA. Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissues and cells in culture. J Clin Endocrinol Metab. 1994;78(3):736–743. [ DOI ] [ PubMed ] [ Google Scholar ]
• 19. Rocha PP, Scholze M, Bleiss W, Schrewe H. Med12 is essential for early mouse development and for canonical WNT and WNT/PCP signaling. Development. 2010;137(16):2723–2731. [ DOI ] [ PubMed ] [ Google Scholar ]
• 20. Kim S, Xu X, Hecht A, Boyer TG. Mediator is a transducer of WNT/beta-catenin signaling. J Biol Chem. 2006;281(20):14066–14075. [ DOI ] [ PubMed ] [ Google Scholar ]
• 21. Mosimann C, Hausmann G, Basler K. Beta-catenin hits chromatin: regulation of WNT target gene activation. Nat Rev Mol Cell Biol. 2009;10(4):276–286. [ DOI ] [ PubMed ] [ Google Scholar ]
• 22. Tanwar PS, Lee HJ, Zhang L, et al. Constitutive activation of beta-catenin in uterine stroma and smooth muscle leads to the development of mesenchymal tumors in mice. Biol Reprod. 2009;81(3):545–552. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 23. Al-Hendy A, Laknaur A, Diamond MP, Ismail N, Boyer TG, Halder SK. Silencing Med12 gene reduces proliferation of human leiomyoma cells mediated via WNT/beta-catenin signaling pathway. Endocrinology. 2017;158(3):592–603. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 24. Arici A, Sozen I. Transforming growth factor-beta3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation. Fertil Steril. 2000;73(5):1006–1011. [ DOI ] [ PubMed ] [ Google Scholar ]
• 25. Doherty LF, Taylor HS. Leiomyoma-derived transforming growth factor-beta impairs bone morphogenetic protein-2-mediated endometrial receptivity. Fertil Steril. 2015;103(3):845–852. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 26. Sinclair DC, Mastroyannis A, Taylor HS. Leiomyoma simultaneously impair endometrial BMP-2-mediated decidualization and anticoagulant expression through secretion of TGF-beta3. J Clin Endocrinol Metab. 2011;96(2):412–421. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 27. Cook H, Ezzati M, Segars JH, McCarthy K. The impact of uterine leiomyomas on reproductive outcomes. Minerva Ginecol. 2010;62(3):225–236. [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 28. Guo XC, Segars JH. The impact and management of fibroids for fertility: an evidence-based approach. Obstet Gynecol Clin North Am. 2012;39(4):521–533. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 29. Surrey ES, Minjarez DA, Stevens JM, Schoolcraft WB. Effect of myomectomy on the outcome of assisted reproductive technologies. Fertil Steril. 2005;83(5):1473–1479. [ DOI ] [ PubMed ] [ Google Scholar ]
• 30. Klatsky PC, Tran ND, Caughey AB, Fujimoto VY. Fibroids and reproductive outcomes: a systematic literature review from conception to delivery. Am J Obstet Gynecol. 2008;198(4):357–366. [ DOI ] [ PubMed ] [ Google Scholar ]
• 31. Casini ML, Rossi F, Agostini R, Unfer V. Effects of the position of fibroids on fertility. Gynecol Endocrinol. 2006;22(2):106–109. [ DOI ] [ PubMed ] [ Google Scholar ]
• 32. Eldar-Geva T, Meagher S, Healy DL, MacLachlan V, Breheny S, Wood C. Effect of intramural, subserosal, and submucosal uterine fibroids on the outcome of assisted reproductive technology treatment. Fertil Steril. 1998;70(4):687–691. [ DOI ] [ PubMed ] [ Google Scholar ]
• 33. Farhi J, Ashkenazi J, Feldberg D, Dicker D, Orvieto R, Ben Rafael Z. Effect of uterine leiomyomata on the results of in-vitro fertilization treatment. Hum Reprod. 1995;10(10):2576–2578. [ DOI ] [ PubMed ] [ Google Scholar ]
• 34. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril. 2009;91(4):1215–1223. [ DOI ] [ PubMed ] [ Google Scholar ]
• 35. Christopoulos G, Vlismas A, Salim R, Islam R, Trew G, Lavery S. Fibroids that do not distort the uterine cavity and IVF success rates: an observational study using extensive matching criteria. BJOG. 2017;124(4):615–621. [ DOI ] [ PubMed ] [ Google Scholar ]
• 36. Sagi-Dain L, Ojha K, Bider D, et al. Pregnancy outcomes in oocyte recipients with fibroids not impinging uterine cavity. Arch Gynecol Obstet. 2017;295(2):497–502. [ DOI ] [ PubMed ] [ Google Scholar ]
• 37. Klatsky PC, Lane DE, Ryan IP, Fujimoto VY. The effect of fibroids without cavity involvement on ART outcomes independent of ovarian age. Hum Reprod. 2007;22(2):521–526. [ DOI ] [ PubMed ] [ Google Scholar ]
• 38. Styer AK, Jin S, Liu D, et al. Association of uterine fibroids and pregnancy outcomes after ovarian stimulation-intrauterine insemination for unexplained infertility. Fertil Steril. 2017;107(3):756–62.e3. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 39. Bosteels J, Kasius J, Weyers S, Broekmans FJ, Mol BW, D’Hooghe TM. Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. Cochrane Database Syst Rev. 2013;(1):CD009461 PMID: 23440838. [ DOI ] [ PubMed ] [ Google Scholar ]
• 40. Achache H, Revel A. Endometrial receptivity markers, the journey to successful embryo implantation. Hum Reprod Update. 2006;12(6):731–746. [ DOI ] [ PubMed ] [ Google Scholar ]
• 41. Dey SK, Lim H, Das SK, et al. Molecular cues to implantation. Endocr Rev. 2004;25(3):341–373. [ DOI ] [ PubMed ] [ Google Scholar ]
• 42. Satokata I, Benson G, Maas R. Sexually dimorphic sterility phenotypes in HOXA10-deficient mice. Nature. 1995;374(6521):460–463. [ DOI ] [ PubMed ] [ Google Scholar ]
• 43. Makker A, Goel MM, Nigam D, et al. Endometrial expression of homeobox genes and cell adhesion molecules in infertile women with intramural fibroids during window of implantation. Reprod Sci. 2017;24(3):435–444. [ DOI ] [ PubMed ] [ Google Scholar ]
• 44. Matsuzaki S, Canis M, Darcha C, Pouly JL, Mage G. HOXA-10 expression in the mid-secretory endometrium of infertile patients with either endometriosis, uterine fibromas or unexplained infertility. Hum Reprod. 2009;24(12):3180–3187. [ DOI ] [ PubMed ] [ Google Scholar ]
• 45. Unlu C, Celik O, Celik N, Otlu B. Expression of endometrial receptivity genes increase after myomectomy of intramural leiomyomas not distorting the endometrial cavity. Reprod Sci. 2016;23(1):31–41. [ DOI ] [ PubMed ] [ Google Scholar ]
• 46. Ben-Nagi J, Miell J, Mavrelos D, Naftalin J, Lee C, Jurkovic D. Endometrial implantation factors in women with submucous uterine fibroids. Reprod Biomed Online. 2010;21(5):610–615. [ DOI ] [ PubMed ] [ Google Scholar ]
• 47. Horcajadas JA, Goyri E, Higon MA, et al. Endometrial receptivity and implantation are not affected by the presence of uterine intramural leiomyomas: a clinical and functional genomics analysis. J Clin Endocrinol Metab. 2008;93(9):3490–3498. [ DOI ] [ PubMed ] [ Google Scholar ]
• 48. Fritz MA, Speroff L. Clinical Gynecologic Endocrinology and Infertility. 8th ed Philadelphia, PA: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2011. [ Google Scholar ]
• 49. Dimitriadis E, Stoikos C, Baca M, Fairlie WD, McCoubrie JE, Salamonsen LA. Relaxin and prostaglandin E(2) regulate interleukin 11 during human endometrial stromal cell decidualization. J Clin Endocrinol Metab. 2005;90(6):3458–3465. [ DOI ] [ PubMed ] [ Google Scholar ]
• 50. Karpovich N, Klemmt P, Hwang JH, et al. The production of interleukin-11 and decidualization are compromised in endometrial stromal cells derived from patients with infertility. J Clin Endocrinol Metab. 2005;90(3):1607–1612. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 51. Gellersen B, Brosens JJ. Cyclic decidualization of the human endometrium in reproductive health and failure. Endocr Rev. 2014;35(6):851–905. [ DOI ] [ PubMed ] [ Google Scholar ]
• 52. Kishimoto T, Taga T, Akira S. Cytokine signal transduction. Cell. 1994;76(2):253–262. [ DOI ] [ PubMed ] [ Google Scholar ]
• 53. Ernst M, Inglese M, Waring P, et al. Defective gp130-mediated signal transducer and activator of transcription (STAT) signaling results in degenerative joint disease, gastrointestinal ulceration, and failure of uterine implantation. J Exp Med. 2001;194(2):189–203. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 54. Stewart CL, Kaspar P, Brunet LJ, et al. Blastocyst implantation depends on maternal expression of leukaemia inhibitory factor. Nature. 1992;359(6390):76–79. [ DOI ] [ PubMed ] [ Google Scholar ]
• 55. Hasegawa E, Ito H, Hasegawa F, et al. Expression of leukemia inhibitory factor in the endometrium in abnormal uterine cavities during the implantation window. Fertil Steril. 2012;97(4):953–958. [ DOI ] [ PubMed ] [ Google Scholar ]
• 56. Hambartsoumian E. Endometrial leukemia inhibitory factor (LIF) as a possible cause of unexplained infertility and multiple failures of implantation. Am J Reprod Immunol. 1998;39(2):137–143. [ DOI ] [ PubMed ] [ Google Scholar ]
• 57. Robb L, Li R, Hartley L, Nandurkar HH, Koentgen F, Begley CG. Infertility in female mice lacking the receptor for interleukin 11 is due to a defective uterine response to implantation. Nat Med. 1998;4(3):303–308. [ DOI ] [ PubMed ] [ Google Scholar ]
• 58. Zenclussen AC, Hammerling GJ. Cellular regulation of the uterine microenvironment that enables embryo implantation. Front Immunol. 2015;6:321. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 59. Paiva P, Salamonsen LA, Manuelpillai U, Dimitriadis E. Interleukin 11 inhibits human trophoblast invasion indicating a likely role in the decidual restraint of trophoblast invasion during placentation. Biol Reprod. 2009;80(2):302–310. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 60. Li Q, Kannan A, Das A, et al. WNT4 acts downstream of BMP2 and functions via beta-catenin signaling pathway to regulate human endometrial stromal cell differentiation. Endocrinology. 2013;154(1):446–457. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 61. Paria BC, Ma W, Tan J, et al. Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors. Proc Natl Acad Sci U S A. 2001;98(3):1047–1052. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 62. Li Q, Kannan A, Wang W, et al. Bone morphogenetic protein 2 functions via a conserved signaling pathway involving WNT4 to regulate uterine decidualization in the mouse and the human. J Biol Chem. 2007;282(43):31725–31732. [ DOI ] [ PubMed ] [ Google Scholar ]
• 63. Lee KY, Jeong JW, Wang J, et al. Bmp2 is critical for the murine uterine decidual response. Mol Cell Biol. 2007;27(15):5468–5478. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 64. Franco HL, Dai D, Lee KY, et al. WNT4 is a key regulator of normal postnatal uterine development and progesterone signaling during embryo implantation and decidualization in the mouse. FASEB J. 2011;25(4):1176–1187. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 65. Miura S, Khan KN, Kitajima M, et al. Differential infiltration of macrophages and prostaglandin production by different uterine leiomyomas. Hum Reprod. 2006;21(10):2545–2554. [ DOI ] [ PubMed ] [ Google Scholar ]
• 66. Jensen AL, Collins J, Shipman EP, Wira CR, Guyre PM, Pioli PA. A subset of human uterine endometrial macrophages is alternatively activated. Am J Reprod Immunol. 2012;68(5):374–386. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 67. Helige C, Ahammer H, Moser G, et al. Distribution of decidual natural killer cells and macrophages in the neighbourhood of the trophoblast invasion front: a quantitative evaluation. Hum Reprod. 2014;29(1):8–17. [ DOI ] [ PubMed ] [ Google Scholar ]
• 68. Lee SK, Kim CJ, Kim DJ, Kang JH. Immune cells in the female reproductive tract. Immune Netw. 2015;15(1):16–26. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 69. Tayade C, Hilchie D, He H, et al. Genetic deletion of placenta growth factor in mice alters uterine NK cells. J Immunol. 2007;178(7):4267–4275. [ DOI ] [ PubMed ] [ Google Scholar ]
• 70. Wang C, Umesaki N, Nakamura H, et al. Expression of vascular endothelial growth factor by granulated metrial gland cells in pregnant murine uteri. Cell Tissue Res. 2000;300(2):285–293. [ DOI ] [ PubMed ] [ Google Scholar ]
• 71. King A. Uterine leukocytes and decidualization. Hum Reprod Update. 2000;6(1):28–36. [ DOI ] [ PubMed ] [ Google Scholar ]
• 72. Kitaya K, Yasuo T. Leukocyte density and composition in human cycling endometrium with uterine fibroids. Hum Immunol. 2010;71(2):158–163. [ DOI ] [ PubMed ] [ Google Scholar ]
• 73. Rogers R, Norian J, Malik M, et al. Mechanical homeostasis is altered in uterine leiomyoma. Am J Obstet Gynecol. 2008;198(4):474.e1-e11. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 74. Payson M, Malik M, Siti-Nur Morris S, Segars JH, Chason R, Catherino WH. Activating transcription factor 3 gene expression suggests that tissue stress plays a role in leiomyoma development. Fertil Steril. 2009;92(2):748–755. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 75. Norian JM, Owen CM, Taboas J, et al. Characterization of tissue biomechanics and mechanical signaling in uterine leiomyoma. Matrix Biol. 2012;31(1):57–65. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 76. Orisaka M, Kurokawa T, Shukunami K, et al. A comparison of uterine peristalsis in women with normal uteri and uterine leiomyoma by cine magnetic resonance imaging. Eur J Obstet Gynecol Reprod Biol. 2007;135(1):111–115. [ DOI ] [ PubMed ] [ Google Scholar ]
• 77. Yoshino O, Hayashi T, Osuga Y, et al. Decreased pregnancy rate is linked to abnormal uterine peristalsis caused by intramural fibroids. Hum Reprod. 2010;25(10):2475–2479. [ DOI ] [ PubMed ] [ Google Scholar ]
• 78. National Institute for Health and Clinical Excellence. Heavy Menstrual Bleeding: Assessment and Management. NICE Guidelines (CG44) 2007. Available at: https://www.nice.org.uk/guidance/cg44 [ PubMed ] [ Google Scholar ]
• 79. Maybin JA, Critchley HO. Menstrual physiology: implications for endometrial pathology and beyond. Hum Reprod Update. 2015;21(6):748–761. [ DOI ] [ PMC free article ] [ PubMed ] [ Google Scholar ]
• 80. Masaki T. Endothelins: homeostatic and compensatory actions in the circulatory and endocrine systems. Endocr Rev. 1993;14(3):256–268. [ DOI ] [ PubMed ] [ Google Scholar ]
• 81. Pekonen F, Nyman T, Rutanen EM. Differential expression of mRNAs for endothelin-related proteins in human endometrium, myometrium and leiomyoma. Mol Cell Endocrinol. 1994;103(1-2):165–170. [ DOI ] [ PubMed ] [ Google Scholar ]
• 82. Farrer-Brown G, Beilby JO, Tarbit MH. Venous changes in the endometrium of myomatous uteri. Obstet Gynecol. 1971;38(5):743–751. [ PubMed ] [ Google Scholar ]
• 83. Anania CA, Stewart EA, Quade BJ, Hill JA, Nowak RA. Expression of the fibroblast growth factor receptor in women with leiomyomas and abnormal uterine bleeding. Mol Hum Reprod. 1997;3(8):685–691. [ DOI ] [ PubMed ] [ Google Scholar ]
• View on publisher site
• PDF (297.2 KB)
• Collections

Similar articles

Cited by other articles, links to ncbi databases.

• Download .nbib .nbib
• Format: AMA APA MLA NLM

Add to Collections

Current medical treatment of uterine fibroids

Affiliations.

• 1 Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
• 2 Institute of Women's Life Medical Science, Yonsei University College of Medicine, Seoul, Korea.
• 3 Department of Obstetrics and Gynecology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.
• 4 Department of Obstetrics and Gynecology, Keimyung University School of Medicine, Daegu, Korea.
• 5 Department of Obstetrics and Gynecology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea.
• 6 Department of Obstetrics and Gynecology, Ewha Womans University College of Medicine, Seoul, Korea.
• PMID: 29564309
• PMCID: PMC5854898
• DOI: 10.5468/ogs.2018.61.2.192

Uterine fibroids (leiomyomas or myomas), benign monoclonal tumors, are the most common benign tumors in women. Heavy or prolonged menstrual bleeding, abnormal uterine bleeding, resultant anemia, pelvic pain, infertility, and/or recurrent pregnancy loss are generally associated with uterine fibroids. Although curative treatment of this tumor relies on surgical therapies, medical treatments are considered the first-line treatment to preserve fertility and avoid or delay surgery. The aim of this review is to provide available and emerging medical treatment options for symptomatic uterine fibroids. Literature review and consensus of expert opinion. Many uterine fibroids are asymptomatic and require no intervention, although it is advisable to follow-up patients to document stability in size and growth. Fibroid-associated symptoms include heavy menstrual bleeding and pain or pelvic discomfort. The association between infertility and fibroids increases with age. Treatment options for symptomatic uterine fibroids - include medical, surgical, and radiologically guided interventions. Various medical therapies are now available for women with uterine fibroids, although each therapy has its own advantages and disadvantages. Currently, gonadotrophin-releasing hormone (GnRH) agonists and selective progesterone receptor modulators (SPRMs) are the most effective medical therapies, with the most evidence to support their reduction of fibroid volume and symptomatic improvement in menstrual bleeding. The choice of treatment depends on the patient's personal treatment goals, as well as efficacy and need for repeated interventions.

Keywords: GnRH receptor; Uterine fibroids.

Publication types