PDF(Pubmed)
Abstract：
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.
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.
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.
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.
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.
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.
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.
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.
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.
摘要：
背景：异常子宫出血（AUB）具有显著的社会经济影响，因为它相当影响生活质量。治疗选择通常基于试验和错误，而不是针对疾病的病因。这种疾病的病理生理学见解对于开发新的治疗方案是必需的。如果没有发现AUB的潜在原因(例如肌瘤，子宫腺肌病,息肉)，子宫内膜AUB（AUB-E）通常由原发性子宫内膜疾病引起。当AUB由处方（外源）激素诱导时，它被分类为医源性AUB(AUB-I)。考虑到血管调制和功能，AUB-E和AUB-I都可能是由于血管生成和血管成熟过程中的改变引起的子宫内膜异常血管形成。
目的：我们旨在研究血管生成和血管成熟在AUB患者中的基本作用，并假设异常的子宫内膜血管生成在AUB-E和AUB-I的病因学中具有重要作用。可能是通过不同的机制。
方法：在Cochrane图书馆数据库中进行了系统的文献检索，直到2021年9月，Embase,PubMed,和WebofScience,搜索项，如血管生成和异常子宫出血。纳入的研究报道了绝经前女性AUB-E或AUB-I的子宫内膜血管生成。病例报告,信件,reviews,社论文章,以及由国际妇产科联合会分类为子宫肌层的原因的AUB研究，肿瘤学，或传染性，被排除在外。研究质量通过偏倚风险来评估，使用Cochrane工具和纽卡斯尔-渥太华量表。
结果：2158篇文章中有35篇被纳入。在AUB-E患者中，血管内皮生长因子A及其受体（1和2），以及血管生成素-1：血管生成素-2的比例和Tie-1，均显着增加。一些研究报道了AUB-E患者中其他促血管生成因子和抗血管生成因子的差异表达，提示异常血管成熟和血管完整性受损。总的来说,AUB-E患者和对照组的子宫内膜微血管密度(MVD)相当.有趣的是,与对照组相比，AUB-I患者显示出更高的MVD和更高的促血管生成因子表达，特别是短期激素暴露后。这种效果在长期暴露后逐渐消失，而在短期和长期暴露后观察到血管成熟的改变。
结论：AUB-E和AUB-I很可能与子宫内膜血管生成异常和血管成熟受损有关。这篇综述支持现有证据表明，促血管生成因子增加和抗血管生成因子减少会导致血管成熟受损。导致更脆弱和可渗透的血管。这符合我们的假设，这些机制似乎在AUB-E和AUB-I的病理生理学中起重要作用。探索这些患者中血管生成的改变可以为AUB提供治疗靶标。
目的：我们旨在研究血管生成和血管成熟在AUB患者中的基本作用，并假设异常的子宫内膜血管生成在AUB-E和AUB-I的病因学中具有重要作用。可能是通过不同的机制。
方法：在Cochrane图书馆数据库中进行了系统的文献检索，直到2021年9月，Embase,PubMed,和WebofScience,搜索项，如血管生成和异常子宫出血。纳入的研究报道了绝经前女性AUB-E或AUB-I的子宫内膜血管生成。病例报告,信件,reviews,社论文章,以及由国际妇产科联合会分类为子宫肌层的原因的AUB研究，肿瘤学，或传染性，被排除在外。研究质量通过偏倚风险来评估，使用Cochrane工具和纽卡斯尔-渥太华量表。
结果：2158篇文章中有35篇被纳入。在AUB-E患者中，血管内皮生长因子A及其受体（1和2），以及血管生成素-1：血管生成素-2的比例和Tie-1，均显着增加。一些研究报道了AUB-E患者中其他促血管生成因子和抗血管生成因子的差异表达，提示异常血管成熟和血管完整性受损。总的来说,AUB-E患者和对照组的子宫内膜微血管密度(MVD)相当.有趣的是,与对照组相比，AUB-I患者显示出更高的MVD和更高的促血管生成因子表达，特别是短期激素暴露后。这种效果在长期暴露后逐渐消失，而在短期和长期暴露后观察到血管成熟的改变。
结论：AUB-E和AUB-I很可能与子宫内膜血管生成异常和血管成熟受损有关。这篇综述支持现有证据表明，促血管生成因子增加和抗血管生成因子减少会导致血管成熟受损。导致更脆弱和可渗透的血管。这符合我们的假设，这些机制似乎在AUB-E和AUB-I的病理生理学中起重要作用。探索这些患者中血管生成的改变可以为AUB提供治疗靶标。
