Endometrial Angiogenesis of Abnormal Uterine Bleeding and Infertility in Patients with Uterine Fibroids-A Systematic Review

Abstract

Uterine fibroids are the most common benign tumors in women, with abnormal uterine bleeding (AUB) as the main reported symptom. Additionally, an association between fibroids and infertility has been established, especially if the fibroid protrudes in the uterine cavity. Hormonal therapy is associated with side-effects and as well as hysterectomy, which is incompatible with a desire to conceive. To improve treatment, it is essential to unravel the etiology of fibroid-related symptoms. We aim to evaluate endometrial angiogenesis in women with fibroids, with and without AUB, and the influence of pharmaceutical therapies in these patients. Furthermore, we explore the possible role of altered angiogenesis in patients with fibroids and infertility. We performed a systematic review according to PRISMA-guidelines (PROSPERO: CRD42020169061), and included 15 eligible studies. Endometrial expression of vascular endothelial growth factor (VEGF) and adrenomedullin was increased in patients with fibroids. This suggests aberrant angiogenesis, potentially involving disturbed vessel maturation, resulting in immature and fragile vessels. Treatment with gonadotropin-releasing hormone agonist, ulipristal acetate, and continuous oral contraception pills reduced several angiogenic parameters, including VEGF. If infertile and fertile patients with fibroids were compared, a significant decreased expression of the bone morphogenetic protein/Smad-protein pathway was found, possibly caused by the increased expression of transforming growth factor-beta. For future therapeutic development, these different angiogenic pathways could be of interest as possible targets to treat fibroid-related symptoms.

Keywords: abnormal uterine bleeding; angiogenic proteins; endometrium; female; infertility; leiomyoma; menorrhagia; neovascularization; pathologic; physiologic.

Figure 1

Different types of angiogenesis. Created with BioRender.com.

Figure 2

PRISMA 2009 flow diagram for the two searches that were carried out for this systematic review [33]. (a) Search I: Endometrial angiogenesis in patients with uterine fibroids; (b) Search II: Endometrial angiogenesis in patients with uterine fibroids and infertility.

Figure 3

Hypoxia-inducible factor (HIF)-pathway and its effect on several pro-angiogenic factors. Adapted from a Middelkoop et al. 2023—Created with BioRender.com [25]. Figure legend: ↑ (upward arrow): indicates an increased process; e.g., an increased vasodilatation; ADM: adrenomedullin; bFGF: basic fibroblast growth factor; BMP(R): bone morphogenetic protein (receptor); CLR: calcitonin receptor-like receptor; c-Src: cellular Src; EC: endothelial cell; ECM: extracellular matrix; eNOS: endothelial nitric oxide synthase; FGF-R: FGF-receptor; HIFα/β: Hypoxia inducible factor; MMP: matrix metalloproteinases; NO: nitric oxide; PLC-γ: Phosphoinositide phospholipase C—pathway; PI3K: phosphoinositide 3-kinase—pathway; RAMP: receptor-activity-modifying proteins; Smad: Suppressor of mothers against decapentaplegic; TGF-β(R)1/2: transforming growth factor-β (receptor) 1 or 2; VEGF(R): vascular endothelial growth factor (receptor).

Figure 4

The effect of several angiogenic pathways on implantation. Figure legend: BMP(R): Bone morphogenetic protein (receptor); EC: endothelial cell; E(R): Estrogen (receptor); eNOS: endothelial nitric oxide synthase; LIF: leukemia inhibitory factor; NO: nitric oxide; P(R): progesterone (receptor); Smad: Suppressor of mothers against decapentaplegic; TGF-β: transforming growth factor; TGF-β(R): transforming growth factor-β (receptor); VEGF-A/R: vascular endothelial growth factor-A/receptor.