Uterine Fibroids: Bridging Genomic Defects and Chronic Inflammation

Abstract

Uterine fibroids (UF; aka leiomyoma, myomas) are the most common benign tumors of female reproductive tract. They are highly prevalent, with 70 to 80% of women burdened by the end of their reproductive years. Fibroids are a leading cause of pelvic pain, abnormal vaginal bleeding, pelvic bulk symptoms, miscarriage, and infertility. They are the leading indication for hysterectomy, and costs exceed 34 billion dollars annually in the United States alone. Recently, somatic mutations in exons 1 and 2 of Med12 gene emerged as common UF driver mutations. Unfortunately, the detailed etiology of UF is not fully realized. Particularly, very little is known about possible dysregulation of inflammatory and immune processes and their possible contribution to UF pathogenesis. The notion on possible impact of altered estrogen and progesterone signaling in UF on inflammatory responses and DNA repair machinery that can conceivably lead to tumor-specific somatic mutation is indeed an intriguing concept which has some foundation in available observation in other hormonally responsive tissues. This review highlights and summarizes our current knowledge on the convergence of such pathways and their relevance for UF pathogenesis.

The Role of Tumor Necrosis Factor α in the Biology of Uterine Fibroids and the Related Symptoms

“…MED12 is also related to endocrine and growth factor pathways [12]. A possible impact of altered signaling in UF pathophysiology on inflammatory responses and genomic repair mechanisms is being extensively researched [101]. UFs growth is mostly hormone-dependent and progesterone is believed to be the most important hormone in this complicated process [12,23,24].…”

“…In cultured UF cells, the treatment with progesterone inhibited the expression of insulin-like growth factor 1 (IGF-1) and the TNF-α, and augmented the expression of apoptosis-inhibiting Bcl-2 protein [123], which is consistent with other reports in the literature. Progesterone is a steroid hormone with anti-inflammatory and mitogenic activity [101,124]. Natural killer (NK) cell activity is suppressed under the influence of progesterone [125].…”

“…Progesterone regulates uterine NK cells through a glucocorticoid receptor mediated process and steroidal antiprogestogens (e.g., mifepristone) could abolish the inhibitory effect of this hormone [126]. Elevated levels of progesterone have an effect on increased TGF-β and decreased TNF-α production [7,29,101]. Progesterone, being the main steroid hormone responsible for the formation and growth of UFs, should lead to a decrease in TNF-α concentration.…”

Alpha-Tocopherol Serum Levels Are Increased in Caucasian Women with Uterine Fibroids: A Pilot Study

“…Steroid hormones, estrogen, and progesterone are considered to be the most important links in the pathophysiology of UFs [ 3 , 4 , 10 , 11 ], whereas progesterone is currently believed to be the key factor in the processes occurring within the UFs [ 3 , 4 , 12 ]. The risk factors for the development of UFs are better known than their etiology [ 1 ] and include elevated BMI values [ 1 , 13 , 14 ], positive family history [ 1 , 4 , 14 ], genetics [ 15 , 16 ], black race [ 17 , 18 ] hypovitaminosis D [ 14 , 19 , 20 ], soybean and food additives consumption [ 1 ], and elevated serum TGF- β 3 (transforming growth factor beta 3) levels [ 14 , 19 , 21 ]. Obviously, the list of the abovementioned risk factors is not complete and further research in this area is necessary.…”

“…Transformation of uterine smooth muscle cells into abnormal, immortal cells, which are capable of clonal division, is the major component of all pathways leading to the formation of a fibroid tumor [ 3 , 11 , 16 , 22 ]. According to recent studies, mutations, especially those in the MED12 gene [ 3 , 15 , 23 ], and oxidative stress [ 24 , 25 ] are of key factors in this regard.…”