Uterine fibroids (UFs) are the most prevalent
gynecologic neoplasm, affecting 70-80% of women over their lifespan. Although UFs are benign they can become life-threatening and require invasive surgeries such as
myomectomy and
hysterectomy. Notwithstanding the significant negative influence UFs have on female reproductive health, very little is known about early events that initiate
tumor development. Several risk factors for UFs have been identified including
vitamin D deficiency,
inflammation,
DNA repair deficiency, and environmental exposures to
endocrine-disrupting chemicals (EDCs). EDCs have come under scrutiny recently due to their role in UF development. Epidemiologic studies have found an association between increased risk for early UF diagnosis and in utero EDC exposure. Environmental exposure to EDCs during uterine development increases UF incidence in a UF animal model. Notably, several studies demonstrated that abnormal myometrial stem cells (MMSCs) are the cell origin for UFs development. Our recent studies demonstrated that early-life EDC exposure reprogrammed the MMSCs toward a pro-
fibroid landscape and altered the DNA repair and
inflammation pathways. Notably,
Vitamin D3 (VITD3) as a natural compound shrank the UF growth concomitantly with the reversion of several abnormal
biological pathways and ameliorated the developmental exposure-induced DNA damage and pro-
inflammation pathway in primed MMSCs. This review highlights and emphasizes the importance of multiple pathway interactions in the context of hypovitaminosis
D at the MMSCs level and provides proof-of-concept information that can help develop a safe, long-term, durable, and non-surgical therapeutic option for UFs.