Understanding the Impact of Uterine Fibroids on Human Endometrium Function

Abstract

Uterine fibroids (leiomyomas) are the most common benign gynecological tumors in women of reproductive age worldwide. They cause heavy menstrual bleeding, usually leading to severe anemia, pelvic pain/pressure, infertility, and other debilitating morbidities. Fibroids are believed to be monoclonal tumors arising from the myometrium, and recent studies have demonstrated that fibroids actively influence the endometrium globally. Studies suggest a direct relationship between the number of fibroids removed and fertility problems. In this review, our objective was to provide a complete overview of the origin of uterine fibroids and the molecular pathways and processes implicated in their development and growth, which can directly affect the function of a healthy endometrium. One of the most common characteristics of fibroids is the excessive production of extracellular matrix (ECM) components, which contributes to the stiffness and expansion of fibroids. ECM may serve as a reservoir of profibrotic growth factors such as the transforming growth factor β (TGF-β) and a modulator of their availability and actions. Fibroids also elicit mechanotransduction changes that result in decreased uterine wall contractility and increased myometrium rigidity, which affect normal biological uterine functions such as menstrual bleeding, receptivity, and implantation. Changes in the microRNA (miRNA) expression in fibroids and myometrial cells appear to modulate the TGF-β pathways and the expression of regulators of ECM production. Taken together, these findings demonstrate an interaction among the ECM components, TGF-β family signaling, miRNAs, and the endometrial vascular system. Targeting these components will be fundamental to developing novel pharmacotherapies that not only treat uterine fibroids but also restore normal endometrial function.

Keywords: endometrial receptivity; endometrium; heavy menstrual bleeding; implantation; subfertility; transforming growth factor beta; uterine fibroids.

FIGURE 1

Factors implicated in uterine fibroid (UF) development and growth may influence the endometrial biology. Extracellular matrix (ECM) components, microRNAs (miRNAs), growth factors, cytokines, and chemokines are involved in UF development. These factors may also affect endometrial cell growth and function and vessel remodeling, thereby contributing to the increased incidence of reproductive complications such as heavy and irregular menses and infertility. In addition, we propose that UFs may impact the endometrial microbiome composition.

FIGURE 2

The presence of uterine fibroids (UFs) may interfere with the endometrial pathways involved in the menstrual cycle, leading to heavy menstrual bleeding. Balance among hormones, growth factors, cytokines, and other factors regulates the cyclic endometrial growth and bleeding. Transforming growth factor-beta (TGF-β), its receptors (TGF-βR), and downstream SMADs are important for endometrial remodeling during menses, and excessive levels of these factors may suppress the gene expressions of the fibrinolytic and anticoagulant components. Prostaglandin F2α (PGF2α) and endothelin-1 (ET-1) are involved in spiral artery vasoconstriction and myometrial constriction during the menstruation period. Vascular endothelial growth factor (VEGF), the most specific endothelial cell growth factor, and platelet-derived growth factor (PDGF) play a role in endometrial angiogenesis, an essential process of endometrial renewal. Nitric oxide (NO) is produced downstream of ET-1 and VEGF signaling, and it is a potent vasodilator. Tumor necrosis factor-alpha (TNF-α) contributes to the process of menstrual shedding and bleeding through the induction of apoptosis. White arrows within circles indicate uterine changes due to UFs presence, which may dysregulate normal endometrium activity, causing excessive endometrium development and, eventually, heavy menstrual bleeding.

FIGURE 3

Effect of uterine fibroids (UFs) on heavy menstrual bleeding. The presence of UFs causes alterations in the endometrial vascular architecture and function, contributing to increased and prolonged menstrual bleeding. UFs influence the production of angiogenic factors such as VEGF, VEGFA, ET-1, EGF, and PDGF, among others, which support increased angiogenesis. EGF, epidermal growth factor; ET-1, endothelin 1; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor; VEGFA, vascular endothelial growth factor A.

FIGURE 4

Effect of uterine fibroids (UFs) on endometrial receptivity and implantation. The presence of UFs impacts endometrial gene expression, contributing to failure in endometrial receptivity. In addition, submucosal UFs can distort the uterine cavity, which interferes with embryo implantation and placentation, likely affecting fertility. ALDH3A2, aldehyde dehydrogenase 3 family member 2; BMP2, bone morphogenetic protein 2; HOX10, homeobox gene 10; IL-11, interleukin 11; LIF, leukemia inhibitory factor; MCP-1, monocyte chemoattractant protein-1; TGF-β3, transforming growth factor beta 3.

FIGURE 5

Proposed model of future directions in the uterine fibroid (UF) field. The presence of UFs causes alterations in the healthy endometrial microbiome and changes in the exosome content, leading to increased factors involved in cell proliferation, angiogenesis, and inflammation, among others. This creates a vicious cycle contributing to increased and prolonged heavy menstrual bleeding in women with UFs.