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

Certainly, here is a detailed summary of the text, organized into two major sections:

### 1. **Estrogen and Progesterone in Uterine Fibroids** The passage begins by explaining the role of estrogen and progesterone in uterine fibroids, which were historically understood to be estrogen-dependent.

**a.** **Estrogen Signaling Pathways:** - Uterine fibroids are linked with reproductive age, and the estrogen signaling pathway plays a significant role in these tumors. - Genomic and nongenomic factors are involved in this signaling, including the Ras-Raf-MEK-MAPK and PI3K-PIP3-Akt-mTOR pathways. - Aberrations in estrogen receptors (ERs) and signaling pathways are crucial in the development of uterine fibroids.

**b.** **Role of Progesterone:** - Recent findings suggest that estrogen induces the expression of progesterone receptors, enabling progesterone receptor ligands to act on their target cells. - Progesterone and progesterone receptors are essential in uterine fibroid growth and development. - The proliferation of uterine fibroid cells increases upon exposure to both estradiol and progesterone. - Steroids, including estradiol and progesterone, are required for tumor growth, and selective progesterone receptor modulators (SPRMs) support this process.

### 2. **Extracellular Matrix (ECM) and Growth Factors in Uterine Fibroids** The passage delves into the role of ECM and growth factors in the formation and development of uterine fibroids.

**a.** **ECM Characteristics:** - Abundant disorganized ECM deposition is typical in uterine fibroids, contributing to the stiffness of the tumor. - Glycosaminoglycans and cross-linked interstitial collagens result in an ECM-rich rigid structure, causing abnormal bleeding and pelvic pain. - ECM stiffness affects mechanotransduction, with β-catenin being a clear example of proteins responding to mechanical signals in uterine fibroids. - Uterine fibroids can be divided into 4 stages based on ECM content, and excessive collagen results in nutrient deprivation and activates pathways contributing to phenotypic transformation.

**b.** **Impact of Growth Factors:** - Growth factors, cytokines, steroid hormones, and microRNAs affect ECM accumulation, influencing the fibrotic nature of the disease. - ECM also acts as a reservoir of profibrotic growth factors, enhancing stability and signaling duration, making the understanding of ECM composition vital for therapeutic development.

**c.** **Potential Treatments:** - Various drugs targeting ECM have been explored, including GnRH agonist, GnRH antagonists, SPRMs, vitamin D, and collagenase from Clostridium histolyticum. - A phase I clinical trial demonstrated the safety of collagenase injections, which significantly reduced uterine fibroid tissue stiffness. - Reducing fibroid stiffness could lead to the disturbance of mechanotransduction pathways, resulting in ECM remodeling and a decrease in fibroid size.

Overall, the passage presents a comprehensive overview of the significant role played by estrogen, progesterone, ECM, and growth factors in the formation, development, and potential treatment of uterine fibroids. Understanding these complex mechanisms is essential for developing new therapies and insights into the disease's origins and progression.

Certainly. Below is a detailed summary of the provided text, which covers the topic of DNA Damage and Repair, specifically in the context of uterine fibroids, including related pathways and therapeutic avenues.

### DNA Damage in the Uterus Women are exposed to various exogenous and endogenous factors causing DNA damage in internal organs, including the uterus. Endogenous factors like hormonal changes can induce DNA damage through oxidative stress, which might lead to increased susceptibility to tumors, including breast cancer.

**Repeated DNA Damage:** Regular damages and lack of proper repair can create a chronic inflammatory environment, conducive to uterine fibroid development. However, the exact biological mechanisms remain unknown.

### Defective DNA Damage Response Pathways **DNA Repair Genes Downregulated:** Uterine fibroids show defects in DNA damage response and repair gene expression. DNA repair genes are downregulated in uterine fibroid tumors compared to normal myometrium, implying impaired DNA repair capacity linked to genomic integrity and fibroid initiation.

**Impaired DNA Repair Capacity in Fibroid Stem Cells:** Human uterine fibroid stem cells show accumulated DNA damage, decreased DNA repair gene expression, and altered signaling. These issues may contribute to mutagenesis and fibroid growth.

**Effects of Germline Mutations and EDCs:** Mutations in specific genes may predispose to uterine fibroids, and the risk may increase with early-life exposure to endocrine-disrupting chemicals (EDCs). Such exposure alters the ability of myometrial stem cells to repair DNA, possibly driving tumor development in adulthood.

**Further Research Required:** Investigation into other types of DNA repair, such as nucleotide excision and base-excision repair of oxidative DNA damage, is necessary in the context of uterine fibroids.

### Wnt/β-Catenin Signaling Pathway The Wnt/β-catenin signaling pathway plays roles in various physiological processes and has been linked to uterine fibroid formation.

**Contrasting β-catenin Expression:** Different studies have shown conflicting results regarding β-catenin expression in uterine fibroids. Mislocalization of β-catenin has been linked to fibroids, with fibroids expressing higher nuclear β-catenin levels.

**Estrogen's Role:** Estrogen activates β-catenin nuclear translocation and enhances responsive gene expression, proposing a paracrine role for the pathway in response to estrogen and progesterone, thus leading to fibroid growth.

**Therapeutic Approaches:** Various compounds like vitamin D3, ICG-001, cordycepin, and XAV939 have been associated with inhibiting the Wnt/β-catenin pathway, decreasing uterine fibroid cell proliferation. Histone deacetylase inhibitors (HDACi) have also shown antiproliferative effects, representing a potential epigenetic-based therapy.

### Conclusion The text summarizes the complex interplay between DNA damage and repair mechanisms, hormonal fluctuations, and signaling pathways like Wnt/β-catenin in the context of uterine fibroids. The impaired DNA repair system and signaling aberrations offer insights into the pathogenesis of uterine fibroids, suggesting avenues for therapeutic interventions. Continued exploration of these mechanisms may pave the way for more effective treatments for uterine fibroids.

Certainly. The text you provided outlines detailed information on several aspects of uterine fibroids, including various pathways and mechanisms implicated in their pathogenesis. Below are detailed summaries of each section:

1. **YAP/TAZ Pathway:** The Hippo pathway, involving YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding domain), connects mechanical stimuli to cellular proliferation. It plays a key role in fibrotic diseases and hormone-regulated organs. Recent studies show elevated YAP/TAZ levels in uterine fibroid cells compared to normal myometrium, along with increased tissue stiffness. The antifibrotic effects of verteporfin (a YAP inhibitor) and nintedanib have been studied, with promising results in reducing cell survival, fibronectin deposition, and Hippo/YAP signaling. More research is encouraged to identify targeted therapeutic strategies.

2. **Rho/ROCK Signaling Pathway:** This pathway involves activation of Rho, which interacts with Rho-kinase (ROCK), leading to increased cell proliferation, reduced apoptosis, and changes in extracellular matrix (ECM) composition. Higher RhoA expression in uterine fibroids compared to normal cells has been noted. Studies have shown that inhibiting integrin-β1 reduces RhoA expression, and Fasudil (a ROCK inhibitor) affects uterine fibroid cells' contraction. Potential antifibrotic effects of these inhibitors are suggested for further exploration.

3. **Epigenetic Regulation:** The formation of uterine fibroids is also influenced by epigenetic processes, including DNA methylation, histone modification, non-coding RNA, and heterochromatinization. Aberrant alterations in genome methylation/demethylation and microRNA synthesis have been observed. Recent studies have begun to investigate long non-coding RNAs, demonstrating their critical role. Understanding the epigenetic regulation of these pathways may provide potential therapies.

4. **Inflammation:** Inflammation, especially chronic, plays a role in conditions including uterine fibroids. Factors like obesity, smoking, environmental exposure, and infections may lead to chronic systemic inflammation, thereby initiating tumorous cells and contributing to tumor-intrinsic inflammation. Epidemiological studies have explored associations between reproductive tract infections (RTIs), inflammation, and uterine fibroids, although the findings have been mixed. Genetic studies also reported associations between inflammatory mediator gene polymorphisms (IL-1β, IL-4, TNF-α, IL-6, etc.) and uterine fibroids. The chronically active inflammatory immune system is hypothesized to be involved in uterine fibroid formation, inducing cell proliferation and fibrosis. Ongoing research is focused on cytokines and chemokines, with suggestions for employing high-throughput methods for future research.

The summarized information highlights the complexity of uterine fibroid pathogenesis, emphasizing the interconnected roles of various signaling pathways, epigenetic regulation, and inflammation. It underscores the need for further research to elucidate these mechanisms and develop targeted therapeutic strategies.

Certainly! The information provided discusses several aspects of uterine fibroids and the roles played by Vitamin D pathways and the microbiome. I'll break down the summary into relevant sections.

### Role of Vitamin D Pathway

**General Functionality of Vitamin D:** - Vitamin D works by forming a complex with the vitamin D receptor (VDR). - It has tissue-specific effects on gene expression. - Exhibits antiproliferative, pro-apoptotic activities, and cell differentiation in various diseases.

**Effects on Uterine Fibroids:** - **Anti-fibrotic Effect**: It reduces the expression of TGF-β3-induced ECM proteins, which are overexpressed in uterine fibroids. - **Inhibiting Growth**: Vitamin D inhibits the growth of uterine fibroid cells by downregulating specific proteins and enzymes. - **Reduction of Fibroid Size**: Administration in animal models decreased uterine fibroids. - **Regulating Matrix Metalloproteinases (MMPs)**: Vitamin D affects the expression of MMPs involved in ECM deposition. - **Functioning as Anti-estrogen and Antiprogesterone Agent**: It reduces levels of Wnt/β-catenin, leading to downregulation of mTOR signaling expression. - **Reducing DNA Damage**: Low serum vitamin D levels are associated with increased DNA damage. - **Anti-inflammatory Functions**: It also suppresses inflammation-induced pathology. - **Clinical Trials**: A trial with vitamin D supplementation inhibited uterine fibroid growth.

### Role of the Microbiome

**Intestinal Estrogen Metabolism:** - The gut microbiome plays a significant role in estrogen metabolism, referred to as the estrobolome. - Enzymes in the gut flora influence estrogen reabsorption. - Different bacteria at family and species levels control estrogen content. - Hysterectomy effects on intestinal flora diversity have been studied.

**Female Reproductive Tract Sterility and Uterine Fibroid Microbiome:** - Modern sequencing technologies have revealed that the uterine cavity harbors a unique microbiome. - A pilot study found greater bacterial diversity in uterine fibroid patient samples compared to controls, suggesting a systemic distribution of gut bacteria. - Further studies are needed to understand whether the uterine microbiome plays a role in uterine fibroids' pathogenesis.

**Challenges in Investigations:** - Multiple factors like race, age, BMI, menstrual cycle phase, and others must be considered while conducting studies on uterine fibroids.

### Integration of Multiple Pathways in Uterine Fibroids

- Emphasis on the coincidence of many biological events and multiple abnormal pathways contributing to uterine fibroids. - Interaction of vitamin D3/receptor pathway with β-catenin and DNA repair pathway. - Other pathways and their interaction, including AP1 signaling, ECM activation of β-catenin signaling, MED12 mutations, and others.

### Conclusion

The information presented outlines the multifaceted relationship between Vitamin D, the microbiome, and uterine fibroids. The role of Vitamin D is prominent in influencing uterine fibroids' growth, inflammation, and DNA repair mechanisms. The microbiome, especially the gut flora, plays a role in estrogen metabolism, potentially affecting uterine fibroids. The intricate web of pathways and their interactions underscores the complexity of understanding uterine fibroids and the need for carefully designed, multifactorial studies.

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