Development Of Fibroids Research Articles

Effect of Progestin-Dominant Combined Oral Contraception on Uterine Fibroid Development

Effect of Progestin-Dominant Combined Oral Contraception on Uterine Fibroid Development

Activin A in Inflammation, Tissue Repair, and Fibrosis: Possible Role as Inflammatory and Fibrotic Mediator of Uterine Fibroid Development and Growth.

AbstractThe growth factor activin A belongs to the transforming growth factor-β superfamily and was initially isolated as an inducer of follicle-stimulating hormone secretion. Activin A was later found to play roles in cell proliferation, differentiation, apoptosis, and metabolism. More recently, activin A has also been recognized as a novel player in mediating inflammation, immunity, wound repair, and fibrosis. Elevated levels of activin A during inflammation are responsible for the increased production of extracellular matrix in different pathological conditions, including fibroids. Our group has demonstrated a profibrotic role of activin A in leiomyoma growth. Uterine leiomyoma can be considered as a fibrotic disorder that initiates from myometrial smooth muscle layer of uterus in reproductive-age women and that is driven by a strong inflammatory component. In fertile women, transient inflammation is a physiological and essential process during menstruation, ovulation, and parturition. However, tissue injury from extravasated menstrual blood and/or an altered response to harmful stimuli, such as pathogens, damaged cells, or irritants, can establish chronic inflammation in the uterus, ultimately leading to dysregulated tissue repair. Myofibroblasts are key cells in normal repair and the chronic tissue remodeling characteristic for fibrosis and uterine leiomyoma. In this review, we discuss the role of activin A in inflammation, tissue repair, and fibrosis and we elaborate the hypothesis that it plays a central role in myofibroblast activation and leiomyoma development and growth.

Chlamydia trachomatis Seroprevalence and Ultrasound-Diagnosed Uterine Fibroids in a Large Population of Young African-American Women.

Reproductive tract infections have long been hypothesized to increase the risk of uterine fibroids. Few studies have been conducted, even for the common infection genital Chlamydia trachomatis (gCT), and only with self-reported gCT data. Our investigation used micro-immunofluorescence serology for gCT to characterize past exposure. We used cross-sectional enrollment data from a prospective fibroid study carried out in the Detroit, Michigan, area; ultrasound examinations systematically screened for fibroids. Participants were African-American women aged 23-34 years (recruited in 2010-2012). Age- and multivariable-adjusted logistic regression models were used to estimate odds ratios. A total of 1,587 women (94% of participants) had unequivocal gCT serology results; 22% had fibroids. Those who were seropositive for gCT were less likely to have fibroids (age-adjusted odds ratio = 0.68, 95% confidence interval: 0.54, 0.87; multivariable-adjusted odds ratio = 0.80, 95% confidence interval: 0.62, 1.03). Inverse associations were similar across categories of fibroid size, number, and total volume. Participant groups likely to have had multiple or severe infections (multiple serovar groups, more sex partners, clinically diagnosed chlamydia) all showed statistically significantly reduced odds of fibroids. A protective association of gCT with fibroids was unexpected but plausible. gCT infection might increase immune surveillance and eliminate early lesions. Further investigation on the relationship between fibroid development and reproductive tract infections is needed.

Uterine Fibroids Review: Understanding their Origins to Better Understand their Future Treatments

Despite the high prevalence and the enormous impact the uterine fibroids has on the healthcare system and the economy, there is no effective medical treatment available to eliminate fibroids. This is due in part to the fact that very little is known about their pathophysiology; in order to look for and potentially find treatments capable of eliminating fibroids, we must gain a deep understanding of the mechanisms behind their initiation, stimulation, and growth. In this article, we comprehensively review current knowledge of the pathogenesis of uterine fibroids, with the aim of better understanding their origin, as well as discussing the action of already existing medical treatments in order to highlight ways that potential future therapies may be able to target the disease. A literature search was performed in PubMed to find articles related to the etiopathogenesis of fibroids and their treatments. Myomas comprise areas of disordered smooth muscle fascicles characterized by an excess of acellular extracellular matrix (ECM) with a dysregulated phenotype. Although the initial event is believed to be smooth muscle cell proliferation, it is thought that a complex signaling system is also necessary. Non-hormonal factors may be responsible for initiating the development of uterine fibroids, although hormonal stimulation is an essential factor for their growth Recent studies have confirmed that the different cell types contained in fibroids are all clonally derived from a parental cell with implied multipotent stem cell properties. Ethnicity also strongly influences the development and clinical severity of fibroids. Many Growth factors and their respective receptors have been implicated in fibroid growth. The available evidence continues to reinforce the importance of progesterone in the development of fibroids. The Ulipristal Acetate mediated volume reduction is due to a series of multifactorial and successive events that lead to a low proliferation rate.

Relationship between Diet, Physical Activity and the Development of Uterine Fibroids

Relationship between Diet, Physical Activity and the Development of Uterine Fibroids

Developmental Exposure to Endocrine Disruptors Expands Murine Myometrial Stem Cell Compartment as a Prerequisite to Leiomyoma Tumorigenesis.

Despite the high prevalence and major negative impact of uterine fibroids (UFs) on women's health, their pathogenesis remains largely unknown. While tumor-initiating cells have been previously isolated from UFs, the cell of origin for these tumors in normal myometrium has not been identified. We isolated cells with Stro1/CD44 surface markers from normal myometrium expressing stem cell markers Oct-4/c-kit/nanog that exhibited the properties of myometrial stem/progenitor-like cells (MSCs). Using a murine model for UFs, we showed that the cervix was a hypoxic "niche" and primary site (96%) for fibroid development in these animals. The pool size of these MSCs also responded to environmental cues, contracting with age and expanding in response to developmental environmental exposures that promote fibroid development. Translating these findings to women, the number of MSCs in unaffected human myometrium correlated with risk for developing UFs. Caucasian (CC) women with fibroids had increased numbers of MSCs relative to CC women without fibroids, and African-American (AA) women at highest risk for these tumors had the highest number of MSCs: AA-with fibroids > CC-with fibroids > AA-without fibroids > CC-without fibroids. These data identify Stro1+ /CD44+ MSCs as MSC/progenitor cell for UFs, and a target for ethnic and environmental factors that increase UF risk. Stem Cells 2017;35:666-678.

ПОСТГІСТЕРЕКТОМІЧНІ ПОРУШЕННЯ ТА ОСОБЛИВОСТІ ОЦІНКИ ЯКОСТІ ЖИТТЯ.

В останні роки відмічається розвиток міоми матки у жінок з нереалізованою репродуктивною функцією, причому зростає частка поєднаних форм гіперпластичних процесів репродуктивної системи – у 20–25 % жінок у віці до 30 років і у 60 % – у віці старше 40 років. Мета – оцінка окремих показників метаболічного гомеостазу у пацієнток з міомою матки після оперативного її оздоровлення та оцінка показників якості життя. Проведено комплексне обстеження і оперативне лікування 40 жінок репродуктивного віку з міомою матки, яким виконано гістеректомію зі збереженням придатків. У контрольну групу ввійшли 20 соматично здорових жінок. Використано загальноприйняті клініко-лабораторні обстеження, лабораторну оцінку гормонального статусу, ліпідного профілю, оцінку характеру розподілу жирової тканини і ступеня ожиріння за індексом маси тіла, ультразвукове дослідження (УЗД) органів малого таза, печінки, нирок, щитоподібної залози, молочних залоз. Якість життя вивчали на основі комплексної оцінки, з використанням модифікованої шкали SF-36 та дослідженням таких важливих показників, як енергійність, сон, емоційні реакції, соціальна ізоляція, фізична активність, больові відчуття. Усі види статистичної обробки виконано за допомогою стандартного пакета «Statistica for Windows – 6,0». Загалом, при аналізі показників гормонального профілю у жінок із проявами постгістеректомічного синдрому через 5 років після операції встановлено у 36,66 % випадків статистично достовірне підвищення рівня пролактину, у 40,00 % – гіпоестрогенію та у 46,66 % пацієнток – ознаки гіперандрогенії, підтверджені лабораторними критеріями. Зміна якості життя у пацієнток із гіперпластичними процесами матки у післяопераційному періоді проявлялася: зниженням фізичної активності у 43,33 % випадків, ростом сексуальних дисфункцій – у 36,66 %, пригніченням психічного стану, конфліктною спрямованістю соціальної поведінки, ослабленням ролевих функцій та суб’єктивним погіршенням загального здоров’я та якості життя у 51,66 % випадків. Віддалені наслідки після оперативного втручання супроводжуються прогресивною гіпоестрогенією із погіршенням функції яєчників, що відображалося у зменшенні їх об’єму при ультразвуковому дослідженні, зменшенні числа та розмірів фолікулів, погіршенні кровопостачання яєчників, зниженні кровотоку в басейні внутрішньої здухвинної артерії та суб’єктивним погіршенням загального здоров’я та якості життя.

Influence of Diet on Development of Fibroids and Endometriosis, Analysis of the National Health and Nutrition Examination Survey

Influence of Diet on Development of Fibroids and Endometriosis, Analysis of the National Health and Nutrition Examination Survey

Characteristics of Uterine Hyperplastic Processes in Women with Obesity

Introduction. Analysis of uterine leiomyoma incidence indicates not only its growth but also the increase in the number of women of early reproductive age. However, the problem of trigger mechanisms for its development is still uncertain and actual.The objective of the research was to assess the characteristic features of hyperplastic processes in uterus on the background of dishormonal and metabolic disorders.Materials and methods. 60 women of reproductive age with uterine leiomyoma participated in the clinical trial. They gave their informed written consent. The control group consisted of 20 healthy women of reproductive age. Statistical analysis was conducted using material package “STATISTICA for Windows®-6.0” and methods of odds ratio (OR) calculating and its 95% Confidential Interval (95% CI).Results and their discussion. According to the results of the research the main factors contributing to uterine fibroid development in women with obesity were determined. They included: the age of 30-45 years, instrumental intervention in the womb (abortion, diagnostic curettage, etc. (OR = 8.2; 95% CI: 5.1-13.5)); chronic inflammatory diseases of genitalia (OR = 7.9; 2.9-21.9); hormonal imbalances (fibro-cystic breast disease, thyroid disorders (OR = 8.61; 3.1-23.8), liver and gastrointestinal tract disorders (OR = 5.8; 2.1-15.9) sexual disorders and stress inductive factors (OR = 2.6; 1.4-7.1) (usually fibroids occur in 1-2 years after severe stress). There is a significant percentage of adenomyosis and endometrial hyperplastic processes. Growth of tumors in women with obesity increases to 35-40 years of age, and is associated not only with a progressive decrease in the functional activity of the ovaries, their sensitivity to gonadotrophic stimulation, but also with chronic functional exertion of regulation systems on the background of metabolic disorders of hemostasis and homeostasis in this category of women.Conclusions. One of the most significant risk factors for hyperplastic processes of the reproductive organs is obesity and associated metabolic disorders. In case of metabolic disorders activity and hepatocytes on the background of obesity the number of combined forms of hyperplastic processes in the uterus increases by 1.9 times. The main risk factor for fibroids in obese women is hepatocytes dysfunction on the background of a high percentage of hepatobiliary pathology, endocrine pathology – 68.3% (thyroid dysfunction, fibro-cystic breast changes). Morphological and histological structure of endometrium in obese women leads to the growth of endometrial polyps (36.66%).

Myometrial progesterone hyper-responsivness is associated with increased risk for the development of human uterine fibroids

Myometrial progesterone hyper-responsivness is associated with increased risk for the development of human uterine fibroids

Herpes Simplex Virus Type 2 Seroprevalence and Ultrasound-Diagnosed Uterine Fibroids in a Large Population of Young African-American Women.

For decades reproductive tract infections (RTIs) have been hypothesized to play a role in uterine fibroid development. The few previous studies conducted used self-reported history of RTIs and had inconsistent findings. We investigated this hypothesis further using serological analysis, an immunological measure of past exposure. We focused on herpes simplex virus type 2 (HSV-2) because prior published data have suggested a possible association with fibroids, and serology for HSV-2 is much more sensitive than self-report. We used cross-sectional enrollment data from African-American women enrolled in a prospective study of fibroid incidence and growth (recruited 2010-2012) in the Detroit, Michigan, area. The women were aged 23-34 years and were screened for fibroids using a standardized ultrasound examination at their enrollment. Age- and multivariable-adjusted logistic regression models were used to estimate odds ratios. Of 1,696 participants, 1,658 had blood samples and HSV-2 serology results; 22% of participants with serology results had fibroids. There was no significant association between HSV-2 seropositivity and the presence of fibroids (multivariable-adjusted odds ratio = 0.94, 95% confidence interval: 0.73, 1.20), nor were there any associations with size of the largest fibroid, number of fibroids, or total fibroid volume. Our data provide no evidence for an influence of HSV-2 exposure on fibroid risk in young African-American women. Further study of other serologically measured RTIs is warranted.

Resveratrol inhibits proliferation of myometrial and leiomyoma cells and decreases extracellular matrix-associated protein expression

Uterine fibroids (leiomyomas) are the most common benign tumours in women during their reproductive age. Hyperplasia of uterine smooth muscle cells and abnormal deposition of extracellular matrix (ECM) are responsible for the development of uterine fibroids. Studies have shown that food rich in phytochemicals can prevent or treat leiomyoma. Therefore, the purpose of this study is to demonstrate the inhibitory effects of resveratrol on uterine fibroid cell growth and ECM-associated protein expression. We found that resveratrol inhibited the proliferation of leiomyoma cell line (ELT3) and uterine smooth muscle cell line (UtSMC) and affected the cell morphology of both cell lines, induced cell cycle arrest at S and G2/M phase, regulated cell apoptosis associated protein expression and induced cell apoptosis, and affected ECM-associated mRNA and protein expression. Our results suggest that resveratrol is potentially effective in preventing the hyperplasia of leiomyoma and uterine smooth muscle cells.

CLINICAL AND MORPHOLOGICAL CHARACTERISTICS AND PROGNOSTIC SIGNIFICANCE OF THE CONTENTS OF PD-ECGF, TGF-β, KI67 IN ENDOMETRIUM AT LARGE UTERINE LEIOMYOMA

The endometrium may be the most convenient object of forecasting the development of the large uterine fibroid, as the object is available in the diagnosis of diseases of the uterus, changes in its cytokine profile linked with the growth of uterine fibroid. Immunohistochemically identification of high expression of Ki 67, TGF-, PD-ECGF in the endometrium allows to predict the development of large uterine fibroids.

Early Life Adverse Environmental Exposures Increase the Risk of Uterine Fibroid Development: Role of Epigenetic Regulation.

Uterine Fibroids [UF(s), AKA: leiomyoma] are the most important benign neoplastic threat to women’s health. They are the most common cause of hysterectomy imposing untold personal consequences and 100s of billions of healthcare dollars, worldwide. Currently, there is no long term effective FDA-approved medical treatment available, and surgery is the mainstay. The etiology of UFs is not fully understood. In this regard, we and others have recently reported that somatic mutations in the gene encoding the transcriptional mediator subunit Med12 are found to occur at a high frequency (∼85%) in UFs. UFs likely originate when a Med12 mutation occurs in a myometrial stem cell converting it into a tumor-forming stem cell leading to a clonal fibroid lesion. Although the molecular attributes underlying the mechanistic formation of UFs is largely unknown, a growing body of literature implicates unfavorable early life environmental exposures as potentially important contributors. Early life exposure to EDCs during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life. Neonatal exposure to the EDCs such as diethylstilbestrol (DES) and genistein during reproductive tract development has been shown to increase the incidence, multiplicity and overall size of UFs in the Eker rat model, concomitantly reprogramming estrogen-responsive gene expression. Importantly, EDC exposure represses enhancer of zeste 2 (EZH2) and reduces levels of histone 3 lysine 27 trimethylation (H3K27me3) repressive mark through Estrogen receptor/Phosphatidylinositide 3-kinases/Protein kinase B non-genomic signaling in the developing uterus. Considering the fact that distinct Mediator Complex Subunit 12 (Med12) mutations are detected in different fibroid lesions in the same uterus, the emergence of each Med12 mutation is likely an independent event in an altered myometrial stem cell. It is therefore possible that a chronic reduction in DNA repair capacity eventually causes the emergence of mutations such as Med12 in myometrial stem cells converting them into fibroid tumor-forming stem cells, and thereby leads to the development of UFs. Advancing our understanding of the mechanistic role epigenetic regulation of stem cells plays in mediating risk and tumorigenesis will help in pointing the way toward the development of novel therapeutic options.

Converting of Myometrial Stem Cells to Tumor-Initiating Cells: Mechanism of Uterine Fibroid Development.

Converting of Myometrial Stem Cells to Tumor-Initiating Cells: Mechanism of Uterine Fibroid Development.

Circulating Sex Hormones and Risk of Uterine Fibroids: Study of Women's Health Across the Nation (SWAN).

Estrogen has been implicated in the development of uterine fibroids. However, the contribution of androgen in women is unknown. Our objective was to assess the longitudinal relations of circulating androgens and estradiol (E2) and their joint effects to the risk of developing fibroids. This is a 13-year longitudinal study in the Study of Women's Health Across the Nation. This study was conducted in seven sites across the United States (1997-2013). At baseline, 3240 pre- or early peri-menopausal women with an intact uterus, ages 45-52 years were included; 43.6% completed the follow-up. There were 512 incident and 478 recurrent fibroid cases. We measured near-annual time-varying serum levels of bioavailable E2 and bioavailable T, dichotomized at the median (high vs low). We estimated the conditional odds ratio (OR) of fibroids in the ensuing year using discrete-time proportional odds models adjusted for race/ethnicity/site, age, body mass index, menopausal stage, reproductive factors, smoking, timing of blood draw, and FSH. Women with high T had a statistically significant increased risk of incident fibroids (OR, 1.33; 95% confidence interval [CI], 1.01-1.76; P = .04), but not recurrent fibroids. This risk was further elevated in those with high T and E2 (OR, 1.52; 95% CI, 1.07-2.17; P = .02). High E2 and T was associated with lower risk of recurrent fibroids (OR, 0.50; 95% CI, 0.26-0.96; P = .04). High T with high E2 was associated with an elevated risk of incident fibroids in midlife women who never reported fibroids before baseline. Conversely, the risk of recurrent fibroids was mitigated in women with high E2 and high T.

The Epidemiology and Genetics of Uterine Leiomyoma

Uterine leiomyomas (fibroids) are the most common benign neoplasms in premenopausal women, which confer significant morbidity during the reproductive years and represent a significant public health issue. The incidence of fibroids has been associated with African-American race, early onset of menarche, early parity, and environmental/dietary exposures. These sex steroid-responsive uterine tumors are characterized by de novo transformation of the myometrium into fibroids via excessive formation of the extracellular matrix (ECM). Cytogenic anomalies, mutations in mediator complex subunit 12 (MED 12), and aberrant DNA methylation/demethylation have been observed, but have not been reported as direct mediators of fibroid development. Recent advances in epigenetics have implied a functional role of G protein-coupled receptor 10 (GPR10) overexpression and irregular microRNA expression in the pathobiology of fibroids that require future investigation. Herein, the impact of epidemiologic and genetic factors on the incidence and development of fibroids is reviewed.

Possible involvement of inflammatory/reparative processes in the development of uterine fibroids.

Uterine leiomyomas are benign tumors in the smooth muscle layer of the uterus. The most common histological type is the "usual leiomyoma", characterized by overexpression of ECM proteins, whereas the "cellular type" has higher cellular content. Our objective is to investigate the involvement of inflammatory and reparative processes in leiomyoma pathobiology. Using a morphological approach, we investigate the presence of inflammatory cells. Next, we determine the localization of the ECM, the presence/absence of fibrotic cells via α-sma and desmin and the immunohistochemical profile of the mesenchymal cells with respect to CD34. Finally, we explore the effect of inflammatory mediators (TNF-α, IL-1β, IL-6, IL-15, GM-CSF and IFN-γ) on pro-fibrotic factor activin A mRNA expression in vitro. Higher numbers of macrophages were found inside and close to leiomyomas as compared to the more distant myometrium. Cellular leiomyomas showed more macrophages and mast cells than the "usual type". Inside the fibroid tissue, we found cells positive for α-sma, but negative for desmin and a large amount of collagen surrounding the nodule, suggestive of myofibroblasts producing ECM. In the myometrium and leiomyomas of the "usual type", we identified numerous CD34+ fibroblasts, which are known to give rise to myofibroblasts upon loss of CD34 expression. In leiomyomas of the "cellular type", stromal fibroblasts were CD34-negative. Finally, we found that TNF-α increased activin A mRNA in myometrial and leiomyoma cells. In conclusion, this study demonstrates the presence of inflammatory cells in uterine leiomyomas, which may contribute to excessive ECM production, tissue remodeling and leiomyoma growth.

Clinicopathological Study of Uterine Leiomyomas: A Multicentric Study in Rural Population

Leiomyoma of uterus forms the most common type of benign tumor of uterus and also the most common pelvic tumor in women. The symptomatology continues to be variable. Surgery has for long been the main mode of therapy for the myomas. For women who wish to retain the uterus for future pregnancies or other reasons, myomectomy is preferred. Recent trend has been toward nonsurgical approaches like GnRH hormone analogs/agonists, RU 486, or selective uterine artery embolization, laparoscopic cryoablation, radiofrequency thermal ablation, and MRGUs. This multicentric study was an attempt to analyze the clinicopathological spectrum in cases of leiomyoma of the uterus at Cheluvamba Hospital, Adichunchanagiri Institute of Medical Sciences, and to know regarding the pattern of presentation, pathological correlation, with type of fibroid, and endometrial and ovarian changes. A clinical study of 100 cases of fibroid uterus was conducted in the Cheluvamba Hospital, attached to Mysore Medical College and Research Institute, Mysore, and Adichunchanagiri Institute of medical sciences, BG Nagara, Mandya from November 2008 to August 2012. The cases are selected by random allocation. On admission, detailed history, clinical examination, and investigations were recorded. Leiomyoma is the most common benign tumor of the uterus and commonly affects the women of child-bearing age, most commonly in the third decade, 55%. The most common mode of presentation was menstrual disturbances (76%), among which menorrhagia was seen in 54% of the cases. Primary infertility was seen in 15% of the patients. Intramural fibroids were the most common variety occurring in 60% of the cases. Endometrial pattern was proliferative in 66.3%. Cystic ovaries were seen in 8% of the patients, adenomyosis in 16% indicating hyperestrogenism. Fibromyoma (leiomyoma) is the most common benign tumor of the pelvis. It commonly affects the women of child-bearing age, mostly in the third decade and is most commonly seen in multipara. The most common mode of presentation is menstrual disturbances. Intramural fibroid is the most common variety. The proliferative and hyperplastic endometrium was commonly reported. The presence of proliferative endometrium, adenomyosis, and cystic ovaries all are indicative of hyperestrogenic state associated with development of fibroids.

Early life exposure to genistein permanently decreases myometrial DNA repair capacity, which may contribute to increased risk of uterine fibroid development

Environmental exposures during sensitive windows of development can reprogram normal physiological responses and alter disease susceptibility later in life. Genistein is a phytoestrogen and belongs to the category of isoflavones. Our previous studies demonstrated that neonatal exposure to the genistein increases uterine fibroid tumor incidence and multiplicity in Eker rats (Greathouse et al., 2012). However, the detailed mechanism regarding xenoestrogen-induced promotion of fibroid development is largely unknown.