Coenzyme Q-10 reduced the aberrant production of extracellular matrix proteins in uterine leiomyomas through transforming growth factor beta 3.

Objective: To evaluate the impact of coenzyme Q-10 (CoQ-10) on the dysregulated synthesis of extracellular matrix proteins mediated by transforming growth factor beta 3 (TGF-β3) in uterine leiomyomas.

Design: Laboratory study.

Setting: University.

Simvastatin induces degradation of the extracellular matrix in human leiomyomata: novel in vitro, in vivo, and patient level evidence of matrix metalloproteinase involvement.

Objectives: To assess the effect of simvastatin on uterine leiomyoma growth and extracellular matrix (ECM) deposition.

Design: Laboratory analysis of human leiomyoma cell culture, xenograft in a mouse model, and patient tissue from a clinical trial.

Setting: Academic research center.

Curcumin inhibits human leiomyoma xenograft tumor growth and induces dissolution of the extracellular matrix.

Objective: To determine whether a curcumin-supplemented diet would prevent and/or treat uterine leiomyoma growth in our mouse xenograft model.

Design: Animal study.

Setting: Laboratory study.

Relugolix and elagolix directly inhibit leiomyoma extracellular matrix production in 2-dimesnional and 3-dimensional cell cultures.

Objective: To determine the effect relugolix and elagolix have on the production of extracellular matrix (ECM) proteins in human leiomyoma cells.

Design: Laboratory study.

Setting: University hospital.

Carcinoembryonic antigen-related cell adhesion molecule 1: a key regulatory protein involved in leiomyoma growth.

Objective: To assess and characterize the role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in the development of uterine leiomyoma.

Design: Laboratory study.

Setting: Academic research center.

Three-dimensional human leiomyoma xenografts induce angiogenesis by inducing hypoxia inducible factor-1 alpha.

Objective: To characterize the method by which angiogenesis occurred in three-dimensional (3D) leiomyoma xenografts, and to assess the impact of hypoxia on two-dimensional (2D) and 3D myometrial and leiomyoma cells and leiomyoma xenografts in vivo.

Design: Laboratory study.

Setting: Academic research.

Simvastatin modulates estrogen signaling in uterine leiomyoma via regulating receptor palmitoylation, trafficking and degradation.

Uterine leiomyomas or fibroids are the most common tumors of the female reproductive tract. Estrogen (E), a steroid-derived hormone, and its receptors (ERs), particularly ER-α, are important drivers for the development and growth of leiomyomas. We previously demonstrated that simvastatin, a drug used for hyperlipidemia, also possesses anti-leiomyoma properties.

Cross-talk between Janus kinase-signal transducer and activator of transcription pathway and transforming growth factor beta pathways and increased collagen1A1 production in uterine leiomyoma cells.

Objective: To characterize the potential interaction between interleukin-6 (IL6), Janus kinase (JAK)-signal transducer and activator of transcription (STAT)-3 (JAK/STAT3) pathway, and Transforming growth factor beta (TGFβ)-3 , and to determine whether such cross-talk was a contributing factor in the dysregulation of type I collagen production in leiomyomas.

Design: Laboratory study.

Setting: University research laboratory.

Characterization of the role of Activator Protein 1 signaling pathway on extracellular matrix deposition in uterine leiomyoma.

Objective: To characterize the role Activator Protein 1 (AP 1) family members play in mediating extracellular matrix deposition in uterine leiomyoma.

Design: Laboratory study.

Setting: University research laboratory.

Simvastatin ameliorates altered mechanotransduction in uterine leiomyoma cells.

Background: Uterine leiomyomas, the most common tumors of the female reproductive system, are characterized by excessive deposition of disordered stiff extracellular matrix and fundamental alteration in the mechanical signaling pathways. Specifically, these alterations affect the normal dynamic state of responsiveness to mechanical cues in the extracellular environment. These mechanical cues are converted through integrins, cell membrane receptors, to biochemical signals including cytoskeletal signaling pathways to maintain mechanical homeostasis.

NAV3, a Tumor Suppressor Gene, Is Decreased in Uterine Leiomyoma Tissue and Cells.

NAV 3 is a tumor suppressor of unknown function in leiomyomas. The objective of this study is to assess NAV3 expression and its potential role in human uterine leiomyomas. NAV3 protein expression was examined in patient leiomyoma and patient-matched myometrial tissue samples by Western blot and immunohistochemistry.

Steroid hormones and hormone antagonists regulate the neural marker neurotrimin in uterine leiomyoma.

Objective: To characterize the role of steroid hormone and antihormone exposure on neurotrimin (NTM) expression in human leiomyoma and myometrial tissue and cells.

Design: Laboratory study of placebo and ulipristal acetate (UPA)-treated patient tissue. In vitro assessment of immortalized myometrial and leiomyoma cell lines after hormone and antihormone exposure.

Development and Validation of Hormonal Impact of a Mouse Xenograft Model for Human Uterine Leiomyoma.

Multiple in vivo animal models for uterine leiomyoma do not adequately represent human disease based on etiology, molecular phenotype, or limited fixed life span. Our objective was to develop a xenograft model with sustained growth, by transplanting a well-established actively growing three-dimensional (3D) cell culture of human leiomyoma and myometrium in NOD/SCID ovariectomized female mice. We demonstrated continued growth to at least 12 weeks and the overexpression of extracellular matrix (ECM).

Ulipristal acetate decreases active TGF-β3 and its canonical signaling in uterine leiomyoma via two novel mechanisms.

Objective: To characterize the effect of ulipristal acetate (UPA) treatment on transforming growth factor (TGF) canonical and noncanonical signaling pathways in uterine leiomyoma tissue and cells. UPA decreased extracellular matrix in surgical specimens; we characterize the mechanism in this study.

Design: Laboratory study.

Ulipristal Acetate Mediates Decreased Proteoglycan Expression Through Regulation of Nuclear Factor of Activated T-Cells (NFAT5).

Nuclear factor of activated T-cells (NFAT5) is a tissue specific, osmoadaptive transcription factor essential for the control of hydration homeostasis in mammalian cells. Nuclear factor of activated T-cells regulates osmolyte transporters aldo-keto reductase family 1 member B1 (AKR1B1) and solute carrier family 5 member 3 (SLC5A3) to maintain fluid equilibrium in cells. The osmotic potential of the extracellular matrix of leiomyomas is attributed to the role of proteoglycans.

Simvastatin, at clinically relevant concentrations, affects human uterine leiomyoma growth and extracellular matrix production.

Objective: To observe the antifibroid effects of therapeutic concentrations of simvastatin, which interferes with cholesterol biosynthesis, a known precursor of five major classes of steroid hormones, including progesterone and estrogen, which play a major role in the development and growth of uterine leiomyomas.

Design: Two-dimensional and three-dimensional cell culture study of immortalized human leiomyoma and patient-matched myometrium cells treated with simvastatin.

Setting: University laboratory.

A-Kinase Anchoring Protein 13 (AKAP13) Augments Progesterone Signaling in Uterine Fibroid Cells.

Context: Uterine leiomyomata (fibroids) are prevalent sex hormone‒dependent tumors with an altered response to mechanical stress. Ulipristal acetate, a selective progesterone receptor (PR) modulator, significantly reduces fibroid size in patients. However, PR signaling in fibroids and its relationship to mechanical signaling are incompletely understood.

A Comprehensive Review of the Pharmacologic Management of Uterine Leiomyoma.

Uterine leiomyomata are the most common benign tumors of the gynecologic tract impacting up to 80% of women by 50 years of age. It is well established that these tumors are the leading cause for hysterectomy with an estimated total financial burden greater than $30 billion per year in the United States. However, for the woman who desires future fertility or is a poor surgical candidate, definitive management with hysterectomy is not an optimal management plan.

Ulipristal Acetate and Extracellular Matrix Production in Human Leiomyomas In Vivo: A Laboratory Analysis of a Randomized Placebo Controlled Trial.

In a prior randomized controlled study, patients treated with ulipristal acetate (UPA) or placebo for 3 months had a decrease in leiomyoma size. A total of 10 patients' tissue samples (5 placebo and 5 treated with 10 mg/d UPA) that underwent hysterectomy and tissue preservation were identified from this study. Quantitative real-time reverse transcriptase polymerase chain reaction and Western blotting were used to assess fold gene and protein expression of extracellular membrane (ECM) proteins: collagen 1A (COL1A), fibronectin (FN1), and versican (VCAN) of the samples.

Mifepristone inhibits extracellular matrix formation in uterine leiomyoma.

Objective: To characterize the efficacy of mifepristone treatment on extracellular matrix (ECM) production in leiomyomas.

Design: Laboratory study.

Setting: University research laboratory.

Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones.

Objective: To determine the effect of GnRH analogues (GnRH-a) leuprolide acetate (LA) and cetrorelix acetate on gonadal hormone-regulated expression of extracellular matrix in uterine leiomyoma three-dimensional (3D) cultures.

Design: Laboratory study.

Setting: University research laboratory.

Alternative therapies in management of leiomyomas.

Leiomyomas are benign soft-tissue neoplasms that arise from smooth muscle. Relief of symptoms (abnormal uterine bleeding, pain, pressure) is the major goal in management of women with significant symptoms. For symptomatic myomas, hysterectomy is a definitive solution; however, there are emerging less-invasive options.

Leiomyoma cells in 3-dimensional cultures demonstrate an attenuated response to fasudil, a rho-kinase inhibitor, when compared to 2-dimensional cultures.

Uterine leiomyomata are common benign tumors in women of reproductive age and demonstrate an attenuated response to mechanical signaling that involves Rho and integrins. To further characterize the impairment in Rho signaling, we studied the effect of Rho-kinase inhibitor, fasudil, on extracellular matrix production, in 2-dimensional (2D) and 3-dimensional (3D) cultures of leiomyoma and myometrial cells. Leiomyoma 2D cultures demonstrated a rapid decrease in gene transcripts and protein for fibronectin, procollagen 1A, and versican.

Liarozole inhibits transforming growth factor-β3--mediated extracellular matrix formation in human three-dimensional leiomyoma cultures.

Objective: To investigate the impact of liarozole on transforming growth factor-β3 (TGF-β3) expression, TGF-β3 controlled profibrotic cytokines, and extracellular matrix formation in a three-dimensional (3D) leiomyoma model system.

Design: Molecular and immunohistochemical analysis in a cell line evaluated in a three-dimensional culture.

Setting: Laboratory study.

Integrin β1 regulates leiomyoma cytoskeletal integrity and growth.

Uterine leiomyomas are characterized by an excessive extracellular matrix, increased mechanical stress, and increased active RhoA. Previously, we observed that mechanical signaling was attenuated in leiomyoma, but the mechanisms responsible remain unclear. Integrins, especially integrin β1, are transmembrane adhesion receptors that couple extracellular matrix stresses to the intracellular cytoskeleton to influence cell proliferation and differentiation.