Narrative Review of Chronic Inflammation in Uterine Myoma: Lack of Specialized Pro-Resolving Lipid Mediators (SPMs) and Vitamin D as a Potential Reason for the Development of Uterine Fibroids

Abstract

Uterine leiomyoma (uterine fibroids, UF) are benign myometrium tumors that affect up to 70% of the female population and may lead to severe clinical symptoms. Despite the high prevalence, pathogenesis of UF is not understood and involves cytokines, steroid hormones, and growth factors. Additionally, an increased deposition and remodelling of the extracellular matrix is characteristic for UF. Vitamin D seems to play a new role in UF. Interestingly, hypovitaminosis D correlates with a higher prevalence of myomas and the severity of the myomas. Administration of vitamin D in women with insufficiency (serum level <30 ng/mL) restored the vitamin D status and reduced the mild symptoms of myomas. In addition, inflammatory processes may play a role. In the past years, it has become clear that cessation of inflammation is an active process driven by a class of lipid mediator molecules called specialized pro-resolving mediators (SPM). Inadequate resolution of inflammation is related to several chronic inflammatory diseases and several studies have proven the crucial role of SPMs in improving these diseases. In this review, we will give an overview on processes involved in UF growth and will give an overview on the modern view regarding the concept of inflammation and the role of SPMs in resolution of inflammation, especially in chronic inflammatory diseases.

Keywords: inflammation; specialized pro-resolving mediators (SPMs); uterine myoma; vitamin D.

Figure 1

Biosynthesis of the SPMs, resolvins, protectins, and maresins. EPA, eicosapentaenoic acid; 18-HpEDE, 17-HpDHA, and 14-HPDHA: precursors of the SPMs during biosynthesis; Cox-1/2: cyclooxygenases; and LOX: lipoxygenase Aspirin triggers biosynthesis of 18-HpEDE and 17-HpDHA intermediates via modification of COX enzymes. Maresins are produced by macrophages via a preliminary lipoxygenation step. Further lipoxygenases are required for SPM biosynthesis as depicted (modified from Serhan [48]).

Figure 2

Concomitant initiation and resolution of inflammation. Synthesis of pro-resolving lipid mediator molecules is initiated at the beginning of inflammatory processes. LM: lipid mediator; PUFA: poly-unsaturated fatty acid, PMN: polymorphonuclear neutrophils; and SPM: specialized pro-resolving mediators (maresins, resolvins, protectins, and lipoxins). Modified from Serhan and Levy [54].

Figure 3

Role of SPMs during resolution of inflammation and potential outcome of inflammatory processes. After inflammation is triggered, cells of the innate immune system synthesize eicosanoid lipid mediator (LM) molecules (LT, TX, PG, etc.) from AA and pro-inflammatory cytokines that stimulate the influx of PMNs and monocytes and result in the classical signs of acute inflammation (calor, rubor, tumor, and dolor). At the beginning of inflammation, eicosanoids trigger the lipid mediator (LM) class switch resulting in the synthesis of SPMs from omega-3 PUFAs (see Figure 1 and text). SPMs are crucial for resolution of inflammation. LM: lipid mediator; LT: leukotriene, TX: thromboxane, PG: prostaglandins; PUFA: poly-unsaturated fatty acid, and SPM: specialized pro-resolving mediators (modified from Serhan [48,50]).