Morphometric evaluation of endometrial blood vessels

Makhija, Divya; Mathai, Alka Mary; Naik, Ramadas; Kumar, Suneet; Rai, Sharada; Pai, Muktha R; Baliga, Poornima

doi:10.4103/0377-4929.42508

Cited by 14 publications

(8 citation statements)

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“…MVD was investigated in six studies, five of which showed no significant changes in both the proliferative and secretory phases ( Mints et al , 2005 , 2007b , 2010 ; Makhija et al , 2008 ; Andersson et al , 2015 ), while one study that found an increase in MVD in the secretory phase ( Zhang et al , 2010 ). One study found that pericyte coverage of >50% was decreased in the proliferative phase and also in the secretory phase in patients with AUB-E compared to the control group ( Andersson et al , 2015 ).…”

Section: Resultsmentioning

confidence: 99%

Angiogenesis in abnormal uterine bleeding: a narrative review

Middelkoop

Don

Hehenkamp

et al. 2023

Human Reproduction Update

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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.

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Section: Resultsmentioning

confidence: 99%

Angiogenesis in abnormal uterine bleeding: a narrative review

Middelkoop

Don

Hehenkamp

et al. 2023

Human Reproduction Update

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“…Patient populations were considered to be matching for reproductive age and history of hormonal therapy use in accordance with the RoB-assessment. AUB was not described in four studies [ 34 , 35 , 36 , 37 ] and was subjectively defined in five studies, based on patients’ medical history [ 38 , 39 , 40 , 41 , 42 ].…”

Section: Resultsmentioning

confidence: 99%

“…One study found an increase of FGF-R1 in the secretory phase in patients with symptomatic uterine fibroids [ 39 ]. A second study that was classified as poor quality in our RoB analysis ( Supplementary File S2 ) found no differences in MVD, vascular congestion, and vascular dilatation between patients with fibroids compared to normal controls [ 34 ]. VEGF and eNOS were found to be increased in both the proliferative and secretory phases in patients with uterine fibroids in two studies.…”

Section: Resultsmentioning

confidence: 99%

“…However, two studies showed no difference in MVD in patients with and without fibroids and the presence of complaints of AUB did not seem to affect these outcomes [ 34 , 38 ]. Nevertheless, it is important to emphasize that the MVD is not equivalent to the degree of angiogenic activity [ 72 , 73 ].…”

Section: Discussionmentioning

confidence: 99%

“…For example, sprouting angiogenesis increases the MVD and coalescent angiogenesis reduces MVD, while both mechanisms increase blood flow [ 15 , 18 ]. Furthermore, as the MVD is a relative number, the results can be influenced by volume changes in other cell components such as stroma or glandular cells or by shifting of edema [ 34 , 73 ]. For example, if the extravascular component of the endometrium decreases under the influence of medical agents or decreased estradiol levels, this may lead to an unchanged or increase of the MVD, even when the amounts of vessels or their diameters increase.…”

Section: Discussionmentioning

confidence: 99%

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

Don

Middelkoop

Hehenkamp

et al. 2023

IJMS

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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.

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