Abstract
Uterine leiomyomas represent the most common benign gynecologic tumor. These hormone-dependent smooth-muscle formations occur with an estimated prevalence of ~70% among women of reproductive age and cause symptoms including pain, abnormal uterine bleeding, infertility, and recurrent abortion. Despite the prevalence and public health impact of uterine leiomyomas, available treatments remain limited. Among the potential causes of leiomyomas, early hormonal exposure during periods of development may result in developmental reprogramming via epigenetic changes that persist in adulthood, leading to disease onset or progression. Recent developments in unbiased high-throughput sequencing technology enable powerful approaches to detect driver mutations, yielding new insights into the genomic instability of leiomyomas. Current data also suggest that each leiomyoma originates from the clonal expansion of a single transformed somatic stem cell of the myometrium. In this review, we propose an integrated cellular and molecular view of the origins of leiomyomas, as well as paradigm-shifting studies that will lead to better understanding and the future development of non-surgical treatments for these highly frequent tumors.
Highlights
Inhibition of estrogen activity has been proposed, mainly by using aromatase inhibitors [38]. These findings show that progesterone and estrogen play a key role in Uterine leiomyomas (uLM) pathogenesis; further research on their involvement is needed to explore new therapeutic approaches that exploit the specific mechanisms of action of these ovarian steroid hormones
DNA methylation and MED12 mutation together constitute a complex regulatory network that affects progesterone/PRmediated RANKL gene expression [120,121], with an important role in activating stem cell proliferation and leiomyoma development [121]. These findings suggest that DNA methylation might play a key role in the pathogenesis of uterine leiomyoma by altering the normal myometrial mRNA expression profile
Uterine leiomyomas display great genetic complexity, ranging from germinal mutations that predispose women to developing uLM, to somatic alterations such as point mutations in the MED12 gene or copy number variants and chromosomal aberrations that affect different regions, to epigenetic alterations, which complicates the utilization and interpretation of multi-omic information related to these tumors
Summary
Uterine leiomyomas (uLM), known as fibroids or uterine myomas, are the most important benign neoplastic threat to women’s health, with an estimated lifetime incidence of up to 70% [1,2,3]. Increased parity seems to reduce the risk of fibroid development, while nulliparity is related to higher risk of uLM This situation may seem ambiguous since there are high levels of circulating estrogens and progesterone of placental origin; this paradox may be due to differentiation of the myometrium during pregnancy [19]. Inhibition of estrogen activity has been proposed, mainly by using aromatase inhibitors [38] These findings show that progesterone and estrogen play a key role in uLM pathogenesis; further research on their involvement is needed to explore new therapeutic approaches that exploit the specific mechanisms of action of these ovarian steroid hormones. These novel fibroid therapies hold immense promise for shifting mainstream treatment of uLM from the surgical domain to the realm of orally administered medicines
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