Extracellular matrix remodeling and inflammatory pathway in human endometrium: insights from uterine leiomyomas

Governini, Laura; Marrocco, Camilla; Semplici, Bianca; Pavone, Valentina; Belmonte, Giuseppe; Luisi, Stefano; Luddi, Alice; Piomboni, Paola

doi:10.1016/j.fertnstert.2021.06.023

Cited by 15 publications

(9 citation statements)

References 33 publications

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“…This inflammatory environment attracts cytokines such as interleukins (ILs [ 11 , 63 ], or ‘signal transducer and activator of transcription’ (STAT) genes. Both ILs and STAT genes are suggested to play a role in angiogenesis [ 11 , 46 , 63 ].…”

Section: Resultsmentioning

confidence: 99%

“…These specific fibroids make close contact with the endometrium and induce impression of the uterine cavity, but the differences were not statistically significant. They did report significantly increased IL-1β/6/10 levels in the endometrium of uterine fibroids that indirect may result in increased cell proliferation and angiogenesis due to increased inflammation [ 46 ].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

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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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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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“…After the evaluation of the full text, 12 studies were excluded [23][24][25][26][27][28][29][30][31][32][33][34] ; three studies [35][36][37] were included in the present meta-analysis (Figure 1).…”

Section: Study Selectionmentioning

confidence: 99%

Impact of FIGO type 3 uterine fibroids on in vitro fertilization outcomes: A systematic review and meta‐analysis

Favilli

Etrusco

Chiàntera

et al. 2023

Intl J Gynecology & Obste

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BackgroundThe effect of FIGO (the International Federation of Gynecology & Obstetrics) type 3 myomas on in vitro fertilization (IVF) is uncertain.ObjectivesTo evaluate whether FIGO type 3 myomas affect IVF outcomes, through a systematic review and meta‐analysis (CRD42022379700).Search strategyElectronic databases were searched until November 15, 2022.Selection criteriaStudies evaluating the effects of FIGO type 3 myomas on IVF outcome.Data collection and analysisPooled results were expressed as odds ratios (OR) with 95% confidence intervals (CI). Heterogeneity was assessed using Higgins I2. Sources of heterogeneity were explored with sensitivity and subgroup analyses.Main resultsIn total, 1020 patients were included: 324 with FIGO type 3 myomas and 696 controls (without myomas). A pooled data analysis showed a significantly lower live birth rate (OR 2.16, 95% CI 1.55–3.01, I2 = 0%, P < 0.00001), clinical pregnancy rate (OR 2.06, 95% CI 1.52–2.81, I2 = 0%, P < 0.00001), and implantation rate (OR 1.77, 95% CI 1.35–2.32, I2 = 0%, P < 0.00001) in women with untreated myomas compared with controls. The number and size of fibroids correlated with a worsening of IVF outcomes.ConclusionsFIGO type 3 myomas are significantly associated with a lower implantation rate, cumulative pregnancy rate, and live birth rate. Furthermore, their deleterious effect on the outcome of IVF increases further with increasing size and number. Nevertheless, no firm conclusions could be drawn about the potential benefits of surgery for FIGO type 3 uterine fibroids on IVF outcomes.

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“…ULs may alter uterine vascular perfusion, gamete migration, as well as negatively influence the expression of myometrial/endometrial genes involved in regulating endometrial receptivity throughout implantation and embryonic development. [18][19][20][21][22] Furthermore, similarly to intramural ULs, FIGO type 3 ULs may contribute to an increase in myometrial peristalsis, potentially affecting sperm migration and blastocyst implantation, as well as an enlargement and/or deformity of the uterine cavity. In addition, the proximity to the endometrium impairs the junctional zone and facilitates the passage of pleiotropic cytokines into the uterine cavity (Figure 3).…”

Section: The Peculiar C a S E Of Fi G O T Ype Myoma : The " Hyb Rid" ...mentioning

confidence: 99%

“…Specifically, the authors reported a differential expression and localization of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in the endometrium of women with type 3 ULs, as well as a derangement in the expression of key molecules involved in the inflammatory pathway. 22 Notably, the analysis was conducted on a small sample of patients (n = 18 per study group) with large ULs (>3 cm) during the proliferative phase F I G U R E 3 Putative detrimental effects on fertility linked to type 3 uterine leiomyoma.…”

Section: Fi G O T Ype 3 Myoma S and Infertilit Y: What Do We K Now ?mentioning

confidence: 99%

The challenge of FIGO type 3 leiomyomas and infertility: Exploring therapeutic alternatives amidst limited scientific certainties

Favilli,

Mazzon,

Etrusco

et al. 2023

Intl J Gynecology & Obste

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Uterine leiomyomas (ULs) are non‐cancerous tumors composed of smooth muscle cells that develop within the myometrium and represent the most prevalent pathological condition affecting the female genital tract. Despite the volume of available research, many aspects of ULs remain unresolved, making it a “paradoxical disease” where the increase in available scientific literature has not been matched by an increase in solid evidence for clinical management. Fertility stands at the top of the list of clinical issues where the role of ULs is still unclear. The leiomyoma subclassification system, released by the International Federaion of Gynecology and Obstetrics (FIGO) in 2008, introduced a new and more effective way of categorizing uterine fibroids. The aim was to go beyond the traditional classification “subserosal, intramural and submucosal”, facilitating a detailed examination of individual ULs impact on the female reproductive system. The “type 3 UL” is a special type of myoma, characterized by its complete myometrial development while encroaching the endometrium. It is a unique “hybrid” between a submucous and an intramural UL, that may exert a detrimental “double hit” mechanism, which is of particular interest in patients wishing pregnancy. To date, no robust evidence is available regarding the management of type 3 ULs. The aim of this narrative review is to provide a comprehensive overview of the physiopathological mechanisms that type 3 UL may exert on fertility, and to present new perspectives that may help us to better understand both the need for and the methods of treating this unique type of fibroid.

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Extracellular matrix remodeling and inflammatory pathway in human endometrium: insights from uterine leiomyomas

Cited by 15 publications

References 33 publications

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

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

Impact of FIGO type 3 uterine fibroids on in vitro fertilization outcomes: A systematic review and meta‐analysis

The challenge of FIGO type 3 leiomyomas and infertility: Exploring therapeutic alternatives amidst limited scientific certainties

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