Angiogenesis in abnormal uterine bleeding: a narrative review

Abstract

Background: Abnormal uterine bleeding (AUB) has a significant socioeconomic impact since it considerably impacts quality of life. Therapeutic options are frequently based on trial and error and do not target disease aetiology. Pathophysiological insight in this disease is required for the development of novel treatment options. If no underlying cause is found for the AUB (e.g. fibroids, adenomyosis, polyps), endometrial-AUB (AUB-E) is usually caused by a primary endometrium disorder. When AUB is induced by prescribed (exogenous) hormones, it is classified as iatrogenic-AUB (AUB-I). Considering vascular modulation and function, AUB-E and AUB-I both could potentially result from abnormal vascularization in the endometrium due to alterations in the process of angiogenesis and vascular maturation.

Objective and rationale: We aim to investigate the fundamental role of angiogenesis and vascular maturation in patients with AUB and hypothesize that aberrant endometrial angiogenesis has an important role in the aetiology of both AUB-E and AUB-I, possibly through different mechanisms.

Search methods: A systematic literature search was performed until September 2021 in the Cochrane Library Databases, Embase, PubMed, and Web of Science, with search terms such as angiogenesis and abnormal uterine bleeding. Included studies reported on angiogenesis in the endometrium of premenopausal women with AUB-E or AUB-I. Case reports, letters, reviews, editorial articles, and studies on AUB with causes classified by the International Federation of Gynecology and Obstetrics as myometrial, oncological, or infectious, were excluded. Study quality was assessed by risk of bias, using the Cochrane tool and the Newcastle-Ottawa Scale.

Outcomes: Thirty-five out of 2158 articles were included. In patients with AUB-E, vascular endothelial growth factor A and its receptors (1 and 2), as well as the angiopoietin-1:angiopoietin-2 ratio and Tie-1, were significantly increased. Several studies reported on the differential expression of other pro- and antiangiogenic factors in patients with AUB-E, suggesting aberrant vascular maturation and impaired vessel integrity. Overall, endometrial microvessel density (MVD) was comparable in patients with AUB-E and controls. Interestingly, patients with AUB-I showed a higher MVD and higher expression of proangiogenic factors when compared to controls, in particular after short-term hormone exposure. This effect was gradually lost after longer-term exposure, while alterations in vessel maturation were observed after both short- and long-term exposures.

Wider implications: AUB-E and AUB-I are most likely associated with aberrant endometrial angiogenesis and impaired vessel maturation. This review supports existing evidence that increased proangiogenic and decreased antiangiogenic factors cause impaired vessel maturation, resulting in more fragile and permeable vessels. This matches our hypothesis and these mechanisms appear to play an important role in the pathophysiology of AUB-E and AUB-I. Exploring the alterations in angiogenesis in these patients could provide treatment targets for AUB.

Keywords: abnormal uterine bleeding; angiogenesis; angiogenic proteins; endometrium; hormone antagonists; hormone substitutes; hormones; metrorrhagia.

Graphical Abstract

Altered expression of pro- and antiangiogenic factors in the endometrium results in aberrant angiogenesis, contributing to endometrial and iatrogenic abnormal uterine bleeding.

Figure 1.

The human endometrial cycle during normal physiological menstruation. During the menstrual cycle, the human endometrium regenerates in a cyclic manner, which involves restoration and remodelling of the vascular morphology of the endometrium under the influence of oestradiol and progesterone. Ang-2: angiopoietin 2; ECs: endothelial cells; HESCs: human endometrial stromal cells; HIF: hypoxia-inducible factor; VEGF: vascular endothelial growth factor. Figure created with BioRender.com

Figure 2.

Angiogenesis in the endometrium of women with normal menstrual bleeding. This figure shows potential mechanisms of angiogenesis in the endometrium during the normal menstrual cycle. ANG1/2: angiopoietin 1/2; FGF: fibroblast growth factor; VEGF: vascular endothelial growth factor.

Figure 3.

Angiogenesis in the endometrium of women with abnormal uterine bleeding. This figure shows a hypothesis on how impaired angiogenesis in the endometrium could cause abnormal uterine bleeding via different angiogenic mechanisms, initiated by a significant imbalance between pro- and antiangiogenic factors. As a consequence of excessive proangiogenic factors, the combination of increased vessel formation and/or impaired vessel maturation could lead to endometrial and/or iatrogenic-AUB. ANG1/2: angiopoietin 1/2; FGF: fibroblast growth factor; VEGF: vascular endothelial growth factor.

Figure 4.

The hypoxia-inducible factor pathway and its effect on several proangiogenic factors. Arrows indicate the direction of change. ADM: adrenomedullin; Ang-1/2: angiotensine-1/2; bFGF: basic fibroblast growth factor; BMP(R): bone morphogenetic protein (receptor); CLR: calcitonin receptor-like receptor; c-Src: cellular Src; EC: endothelial cell; eNOS: endothelial nitric oxide synthase; FGF-R: FGF-receptor; HIFα/β: hypoxia-inducible factor α/β; 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: transforming growth factor; TGF-βR1/2: TGF-β receptor 1 or 2; Tie-1/2: tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains-1/2; VEGF(R): vascular endothelial growth factor (receptor).

Figure 5.

PRISMA 2009 flow diagram for the search carried out for this narrative review.

Figure 6.

Schematic overview of pro- and antiangiogenic parameters assessed in this review. Blue: proangiogenic parameter; red: antiangiogenic parameter. ↑ increase, = no change, ↓ decrease. a/bFGF: acidic/basic fibroblast growth factor; ADM: adrenomedullin; Ang: angiopoietin; AQP: aquaporin; BMP(-R): bone morphogenetic protein (-receptor); CLR: calcitonin receptor-like receptor; CSPG4: cleaved chondroitin sulphate proteoglycan; CXCR4: CX-chemokine receptor4; HIF: hypoxia-inducible factor; EGF(-R): epidermal growth factor (-receptor); eNOS: endothelial nitric oxide synthase; FGF-R1: fibroblast growth factors receptor 1; NO: nitric oxide; PR: progesterone receptor; Smad: Smad proteins; STC-1: stanniocalcin-1; TF: tissue factor; TGF-β1: transforming growth factor-β1; Tie-1/2: tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains-1/2; TP: thymidine phosphorylase; VEGF(-R): vascular endothelial growth factor (-receptor).