cholecalciferol and Leiomyoma

Uterine leiomyomas, or fibroids, are the most common benign tumor in reproductive aged women. Affected women may remain asymptomatic or may report symptoms related to abnormal uterine bleeding, infertility, or pelvic pain and pressure. Depending on a patient's symptomatology and reproductive plans, treatment options include expectant management, medical management (hormonal and non-hormonal), or surgical management (myomectomy or hysterectomy). In those wishing to defer surgical management, non-hormonal therapies such as non-steroidal anti-inflammatory drugs and tranexamic acid have been shown to decrease menstrual blood loss. In patients with more symptomatic leiomyomas, hormonal therapies such as gonadotropin-releasing hormone agonists and selective progesterone receptor modulators are effective at reducing leiomyoma volume, uterine size, and menstrual blood loss. This manuscript will detail the available and emerging hormonal and non-hormonal treatments for symptomatic uterine leiomyomas.

Topics: Antifibrinolytic Agents; Aromatase Inhibitors; Cabergoline; Cholecalciferol; Contraceptive Agents, Female; Contraceptives, Oral, Hormonal; Contraceptives, Oral, Synthetic; Danazol; Dopamine Agonists; Ergolines; Estrenes; Estrogen Antagonists; Female; Gestrinone; Gonadotropin-Releasing Hormone; Humans; Intrauterine Devices, Medicated; Leiomyoma; Levonorgestrel; Mifepristone; Norpregnadienes; Oximes; Patient Care Planning; Selective Estrogen Receptor Modulators; Somatostatin; Tranexamic Acid; Uterine Neoplasms; Vitamins

To provide a detailed summary of current scientific knowledge on uterine fibroids (leiomyomas) in vitro and in in vivo animal models, as well as to postulate the potential role of vitamin D3 as an effective, inexpensive, safe, long-term treatment option for uterine fibroids.. PubMed search articles were used to identify the most relevant studies on uterine fibroids, as well as effects of vitamin D3 on uterine fibroid cells and fibroid tumor growth in in vivo animal models.. University research laboratory.. Not applicable.. None.. Despite numerous publications available on uterine fibroids, information about the role that vitamin D3 plays in the regulation of uterine fibroids is limited. Most of the recent vitamin D3-related studies on uterine fibroids were published from our group. Recent studies have demonstrated that vitamin D deficiency plays a significant role in the development of uterine fibroids. Our recent studies have demonstrated that vitamin D3 reduces leiomyoma cell proliferation in vitro and leiomyoma tumor growth in in vivo animal models. These results postulate the potential role of vitamin D3 for an effective, safe, nonsurgical medical treatment option for uterine fibroids.. This article reviews human and animal studies and uncovers new possibilities for understanding the vitamin D-based therapeutic option for an effective, safe, long-term treatment of uterine fibroids. On the basis of these results, a clinical trial with vitamin D3 or a hypocalcemic analog, paricalcitol, may be warranted for nonsurgical medical treatment of uterine fibroids.

Topics: Animals; Antineoplastic Agents; Black or African American; Cholecalciferol; Dietary Supplements; Ergocalciferols; Female; Humans; Leiomyoma; Risk Factors; Signal Transduction; Treatment Outcome; Uterine Neoplasms; Vitamin D; Vitamin D Deficiency

One of the many factors involved in the development of uterine fibroids is vitamin D deficiency. One aspect of this deficiency is decreased serum concentration of calcidiol-25(OH)D, a metabolite of D3 vitamin. The active form of vitamin D3, which arises after numerous enzymatic reactions, is calcitriol-1,25(OH)2D3; this compound is transported to various body tissues. Vitamin D possesses extra-genomic effects due to its influence on various signaling pathways, i.e., through activating tyrosine kinases and by genomic effects via binding to a specific nuclear receptor, vitamin D receptor (VDR). The vitamin D/VDR complex regulates the expression of genes and is involved in the pathogenesis of fibroids. Numerous studies have shown that vitamin D supplementation reduces fibroid size. It has also been shown that the expression of VDR in myoma tissue is significantly lower than in the uterine muscle tissue at the tumor periphery. However, the expression of VDR in non-myoma uterine muscle has not previously been investigated. Our VDR expression studies were performed immunohistochemically with tissue microarrays (TMA) in three tissue groups: 98 uterine myoma tissues, 98 uterine tissues (tumor margin), and 12 tissues of normal uterine muscle (i.e., without fibroids). A statistical analysis showed significantly lower VDR expression in uterine muscle at the periphery of the fibroid than in healthy uterine muscle. Lower expression of VDR at the periphery of the myoma compared to that in normal uterine muscle may indicate potential for new myomas. This observation and the described reduction in the size of fibroids after vitamin D supplementation supports the hypothesis of causal development of uterine fibroids and may be useful for the prevention of re-development in the event of their excision from the uterus.

Topics: Cholecalciferol; Female; Humans; Immunohistochemistry; Leiomyoma; Receptors, Calcitriol; Vitamin D; Vitamin D Deficiency

Topics: Animals; Cholecalciferol; DNA Damage; Endocrine Disruptors; Female; Leiomyoma; Myometrium; Rats; Stem Cells

Uterine fibroids (UFs) are the most common benign neoplastic threat to women's health and associated with DNA damage and genomic instability. Hypovitaminosis D is a known risk factor for UFs, especially among African Americans. Vitamin D3 has been shown to effectively inhibit UF phenotype, but its mechanisms remain unclear. We hypothesize that Vitamin D3 ameliorates UFs by recovering the damaged DNA repair system, thus inhibits tumor progression. We compared the DNA damage status and Vitamin D receptor (VDR) expression between normal myometrial and UF primary cells. Unrepaired DNA double-strand breaks (DSBs) accumulated but VDR expression decreased in UFs. The RNA and protein levels of key DNA repair members belonging to DNA DSB sensors (MRE11, NBS1, RAD50), mediators and effectors (CHECK2, BRCA1, RAD51) were downregulated in UFs compared with myometrial cells. VDR KD induced DSB accumulation and DNA damage response (DDR) defects in myometrial cells. Using the DNA damage PCR array, the expression of many additional DNA repair genes was downregulated in VDR KD cells. Treatment of UF cells with Vitamin D3 (100 nM) significantly decreased DNA damage and restored DDR concomitant with VDR induction. Notably, the PCR array demonstrated that among 75 downregulated genes after VDR KD, 67 (89.3%) were upregulated after vitamin D3 treatment. These studies demonstrate a novel link between DNA damage and the vitamin D3/VDR axis in UFs. Vitamin D3 suppresses the UF phenotype through orchestrated targeting at multiple molecules in DNA repair pathways, thus offering novel mechanistic insights into the clinical effectiveness of vitamin D3 on UFs.

Topics: Cell Line; Cholecalciferol; DNA; DNA Breaks, Double-Stranded; DNA Repair; Female; Humans; Leiomyoma; Up-Regulation; Uterus; Vitamin D Deficiency

Somatic mutations in the Med12 gene are known to activate Wnt/β-catenin signaling in human uterine fibroids (UFs).. The objective of the study was to examine the role of vitamin D3 in the modulation of Wnt/β-catenin and mammalian target of rapamycin (mTOR) signaling in human UF cells.. Immortalized human UF cells (HuLM) and human primary UF (PUF) cells were treated with increasing concentrations of vitamin D3 and thereafter analyzed using Western blots and immunocytochemistry.. Wnt/β-catenin and mTOR signaling proteins in cultured HuLM and PUF cells were measured.. UF tumors with Med12 somatic mutations showed an up-regulation of Wnt4 and β-catenin as compared with adjacent myometrium. Vitamin D3 administration reduced the levels of Wnt4 and β-catenin in both HuLM and PUF cells. Vitamin D3 also reduced the expression/activation of mTOR signaling in both cell types. In contrast, vitamin D3 induced the expression of DNA damaged-induced transcription 4 (an inhibitor of mTOR) and tuberous sclerosis genes (TSC1/2) in a concentration-dependent manner in HuLM cells. Furthermore, we observed a concentration-dependent reduction of Wisp1 (Wnt induced signaling protein 1) and flap endonuclease 1 proteins in HuLM cells. Additionally, abrogation of vitamin D receptor expression (by silencing) in normal myometrial cells induces Wnt4/β-catenin as well as prompts a fibrotic process including an increase in cell proliferation and increased extracellular matrix production. Together these results suggest that vitamin D3 functions as an inhibitor of Wnt4/β-catenin and mTOR signaling pathways, which may play major roles in fibroid pathogenesis.. Vitamin D3 may have utility as a novel long-term therapeutic and/or preventive option for uterine fibroids.

Topics: beta Catenin; Cell Differentiation; Cell Proliferation; Cholecalciferol; Female; Humans; Leiomyoma; Signal Transduction; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Uterine Neoplasms; Wnt Proteins

Topics: Animals; Apoptosis; bcl-Associated Death Protein; Cell Proliferation; Cholecalciferol; Dose-Response Relationship, Drug; Female; Genes, myc; Humans; Leiomyoma; Proto-Oncogene Proteins c-bcl-2; Rats; Receptors, Calcitriol; Risk Factors; Vitamin D; Women's Health