Hypovitaminosis D exacerbates the DNA damage load in human uterine fibroids, which is ameliorated by vitamin D3 treatment.

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.

Dietary phytochemicals for possible preventive and therapeutic option of uterine fibroids: Signaling pathways as target.

A growing interest has emerged on dietary phytochemicals to control diverse pathological conditions. Unfortunately, dietary phytochemical research in uterine fibroids is still under construction. Uterine fibroids/leiomyomas are benign tumors developing from the myometrium of the uterus in premenopausal women. They may occur in more than 70% of women, and approximately 25% of women show clinically significant symptoms. These include heavy and prolonged menstrual bleeding, pelvic pressure (urinary frequency, incontinence, and difficulty with urination), pelvic pain, pelvic mass, infertility, and reproductive dysfunction. Due to lack of medical treatments surgery has been definitive choice for fibroid management. Moreover, surgery negatively affects women's quality of life, and its associated cost appears to be expensive. The molecular mechanism of fibroids development and growth is not fully elucidated. However, accumulated evidence shows that several signaling pathways, including Smad 2/3, PI3K/AKT/mTOR, ERK 1/2 and ß-catenin are involved in the leiomyoma pathogenesis, indicating that they could serve as targets for prevention and/or treatment of this tumor. Therefore, in this review, we discuss the involvement of signaling pathways in leiomyoma development and growth, and introduce some potential dietary phytochemicals that could modulate those signaling pathways.

Use of dietary phytochemicals to target inflammation, fibrosis, proliferation, and angiogenesis in uterine tissues: promising options for prevention and treatment of uterine fibroids?

Uterine leiomyomas (fibroids, myomas) are the most common benign tumors of female reproductive tract. They are highly prevalent, with 70-80% of women burdened by the end of their reproductive years. Fibroids are a leading cause of pelvic pain, abnormal vaginal bleeding, pressure on the bladder, miscarriage, and infertility. They are the leading indication for hysterectomy, and costs exceed 6 billion dollars annually in the United States. Unfortunately, no long-term medical treatments are available. Dysregulation of inflammatory processes are thought to be involved in the initiation of leiomyoma and extracellular matrix deposition, cell proliferation, and angiogenesis are the key cellular events implicated in leiomyoma growth. In modern pharmaceutical industries, dietary phytochemicals are used as source of new potential drugs for many kinds of tumors. Dietary phytochemicals may exert therapeutic effects by interfering with key cellular events of the tumorigenesis process. At present, a negligible number of phytochemicals have been tested as therapeutic agents against fibroids. In this context, our aim was to introduce some of the potential dietary phytochemicals that have shown anti-inflammatory, antiproliferative, antifibrotic, and antiangiogenic activities in different biological systems. This review could be useful to stimulate the evaluation of these phytochemicals as possible therapies for uterine fibroids.

Vitamin D and female fertility.

PURPOSE OF REVIEW: Apart from the well known effects of vitamin D on maintaining calcium homeostasis and promoting bone mineralization, there is some evidence suggesting that vitamin D also modulates human reproductive processes. We will review the most interesting and relevant studies on vitamin D and female fertility published over the past year. RECENT FINDINGS: In the past year, several observational studies reported a better in-vitro fertilization outcome in women with sufficient vitamin D levels (≥30 ng/ml), which was mainly attributed to vitamin D effects on the endometrium. One randomized controlled trial found an increased endometrial thickness in women with polycystic ovary syndrome (PCOS) receiving vitamin D during intrauterine insemination cycles. Further, vitamin D supplementation had a beneficial effect on serum lipids in PCOS women. Vitamin D treatment improved endometriosis in a rat model and increased vitamin D intake was related to a decreased risk of incident endometriosis. Vitamin D was also favorably associated with primary dysmenorrhea, uterine leiomyoma, and ovarian reserve in late reproductive aged women. SUMMARY: In women undergoing in-vitro fertilization, a sufficient vitamin D level (≥30 ng/ml) should be obtained. Vitamin D supplementation might improve metabolic parameters in women with PCOS. A high vitamin D intake might be protective against endometriosis.