Uterine polyps, adenomyosis, leiomyomas, and endometrial receptivity

Classification and Reporting Systems for Adenomyosis

Background Adenomyosis commonly occurs with abnormal uterine bleeding (AUB) and is associated with subfertility and a higher miscarriage rate. Recent evidence showed abnormal vascularization in the endometrium in patients with adenomyosis, suggesting a role of angiogenesis in the pathophysiology of AUB and subfertility in adenomyosis and providing a possible treatment target. Objective and rationale We hypothesized that the level of abnormal vascularization and expression of angiogenic markers is increased in the ectopic and eutopic endometrium of adenomyosis patients in comparison with the endometrium of control patients. This was investigated through a search of the literature. Search methods A systematic search was performed in PubMed and Embase until February 2019. Combinations of terms for angiogenesis and adenomyosis were applied as well as AUB, subfertility or anti-angiogenic therapy. The main search was limited to clinical studies carried out on premenopausal women. Original research articles focusing on markers of angiogenesis in the endometrium of patients with adenomyosis were included. Studies in which no comparison was made to control patients or which were not published in a peer-reviewed journal were excluded. A second search was performed to explore the therapeutic potential of targeting angiogenesis in adenomyosis. This search also included preclinical studies. Outcomes A total of 20 articles out of 1669 hits met our selection criteria. The mean vascular density (MVD) was studied by quantification of CD31, CD34, von Willebrand Factor (vWF) or factor-VIII-antibody-stained microvessels in seven studies. All these studies reported a significantly increased MVD in ectopic endometrium, and out of the six articles that took it into account, four studies reported a significantly increased MVD in eutopic endometrium compared with control endometrium. Five articles showed a significantly higher vascular endothelial growth factor expression in ectopic endometrium and three articles in eutopic endometrium compared with control endometrium. The vascular and pro-angiogenic markers α-smooth muscle actin, endoglin, S100A13, vimentin, matrix metalloproteinases (MMPs), nuclear factor (NF)-kB, tissue factor (TF), DJ-1, phosphorylated mammalian target of rapamycin, activin A, folli- and myostatin, CD41, SLIT, roundabout 1 (ROBO1), cyclooxygenase-2, lysophosphatidic acid (LPA) 1,4-5, phospho signal transducer and activator of transcription 3 (pSTAT3), interleukin (IL)-6, IL-22 and transforming growth factor-β1 were increased in ectopic endometrium, and the markers S100A13, MMP-2 and -9, TF, follistatin, myostatin, ROBO1, LPA1 and 4-5, pSTAT3, IL-6 and IL-22 were increased in eutopic endometrium, compared with control endometrium. The anti-angiogenic markers E-cadherin, eukaryotic translation initiation factor 3 subunit and gene associated with retinoic-interferon-induced mortality 19 were decreased in ectopic endometrium and IL-10 in eutopic endometrium, compared with control endometrium. The staining level of vWF and two pro-angiogenic markers (NF-κB nuclear p65 and TF) correlated with AUB in patients with adenomyosis. We found no studies that investigated the possible relationship between markers of angiogenesis and subfertility in adenomyosis patients. Nine articles reported on direct or indirect targeting of angiogenesis in adenomyosis-either by testing hormonal therapy or herbal compounds in clinical studies or by testing angiogenesis inhibitors in preclinical studies. However, there are no clinical studies on the effectiveness of such therapy for adenomyosis-related AUB or subfertility. Wider implications The results are in agreement with our hypothesis that increased angiogenesis is present in the endometrium of patients with adenomyosis compared with the endometrium of control patients. It is likely that increased angiogenesis leads to fragile and more permeable vessels resulting in adenomyosis-related AUB and possibly subfertility. While this association has not sufficiently been studied yet, our results encourage future studies to investigate the exact role of angiogenesis in the etiology of adenomyosis and related AUB or subfertility in women with adenomyosis in order to design curative or preventive therapeutic strategies.

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Role of angiogenesis in adenomyosis-associated abnormal uterine bleeding and subfertility: a systematic review.

BACKGROUND Adenomyosis is a benign gynecological disorder associated with subfertility, pelvic pain and abnormal uterine bleeding that have significant consequences for the health and quality of life of women. Histologically, it is defined as the presence of ectopic endometrial islets within the myometrium. Its pathogenesis has not yet been elucidated and several pieces of the puzzle are still missing. One process involved in the development of adenomyosis is the increased capacity of some endometrial cells to infiltrate the myometrium. Moreover, the local and systemic immune systems are associated with the onset of the disease and with maintaining it. Numerous observations have highlighted the activation of immune cells and the release of immune soluble factors in adenomyosis. The contribution of immunity occurs in conjunction with hormonal aberrations and activation of the epithelial to mesenchymal transition (EMT) pathway, which promotes migration of endometrial cells. Here, we review current knowledge on the immunological changes in adenomyosis, with the aim of further elucidation of the pathogenesis of this disease. OBJECTIVE AND RATIONALE The objective was to systematically review the literature regarding the role of the immune system in development of adenomyosis in the inner and the outer myometrium, in humans. SEARCH METHODS A systematic review of published human studies was performed in MEDLINE, EMBASE and Cochrane Library databases from 1970 to February 2019 using the combination of Medical Subject Headings (MeSH): Adenomyosis AND ('Immune System' OR 'Gonadal Steroid Hormones'), and free-text terms for the following search terms (and their variants): Adenomyosis AND (immunity OR immune OR macrophage OR 'natural killer cell' OR lymphocyte* OR leucocyte* OR HLA OR inflammation OR 'sex steroid' OR 'epithelial to mesenchymal transition' OR 'EMT'). Studies in which no comparison was made with control patients, without adenomyosis (systemic sample and/or eutopic endometrium), were excluded. OUTCOMES A total of 42 articles were included in our systematic review. Changes in innate and adaptive immune cell numbers were described in the eutopic and/or ectopic endometrium of women with adenomyosis compared to disease-free counterparts. They mostly described an increase in lymphocyte and macrophage cell populations in adenomyosis eutopic endometrium compared to controls. These observations underscore the immune contributions to the disease pathogenesis. Thirty-one cytokines and other markers involved in immune pathways were studied in the included articles. Pro-inflammatory cytokines (interleukin (IL) 6, IL1β, interferon (IFN) α, tumor necrosis factor α, IFNγ) as well as anti-inflammatory or regulatory mediators (IL10, transforming growth factor β…) were found to be elevated in the eutopic endometrium and/or in the ectopic endometrium of the myometrium in women with adenomyosis compared to controls. Moreover, in women affected by adenomyosis, immunity was reported to be directly or indirectly linked to sex steroid hormone aberrations (notably changes in progesterone receptor in eutopic and ectopic endometrium) in three studies and to EMT in four studies. WIDER IMPLICATIONS The available literature clearly depicts immunological changes that are associated with adenomyosis. Both systemic and local immune changes have been described in women affected by adenomyosis, with the coexistence of changes in inflammatory as well as anti-inflammatory signals. It is likely that these immune changes, through an EMT mechanism, stimulate the migration of endometrial cells into the myometrium that, together with an endocrine imbalance, promote this inflammatory process. In light of the considerable impact of adenomyosis on women's health, a better understanding of the role played by the immune system in adenomyosis is likely to yield new research opportunities to better understand its pathogenesis.

Immunological changes associated with adenomyosis: a systematic review.

Endometrial causes of recurrent pregnancy losses: endometriosis, adenomyosis, and chronic endometritis.

In this study, we aimed to clarify the inflammatory cytokine profile of endometrium in patients with adenomyosis during the implantation window after ovarian stimulation. Eighteen patients with adenomyosis and 24 control patients undergoing in vitro fertilization treatment were included in this prospective case-control study. Regular gonadotropin-releasing hormone antagonist protocol was used for ovarian stimulation. Endometrial samples were obtained 7 days after human chorionic gonadotropin (hCG) injection (hCG + 7). Cytokine levels in endometrium secretions from women with and without adenomyosis were assayed by multiplex immunoassay, levels of interleukin (IL) 6 (25.9 ± 6.6 vs 12.4 ± 3.4 pg/mL; P = .001), IL-10 (10.4 ± 2.9 vs 15.6 ± 4.2 pg/mL; P = .001), IL-17 (11.9 ± 3.0 vs 14.2 ± 3.9 pg/mL; P = .046), interferon-γ (11.7 ± 3.5 vs 8.0 ± 3.4 pg/mL; P = .001), and monocyte chemoattractant protein-1 (MCP-1; 37.1 ± 6.5 vs 16.4 ± 3.2 pg/mL; P = .001) were significantly different between patients with adenomyosis and control groups, respectively. Immunohistochemistry and quantitative real-time polymerase chain reaction showed that CD-68+, IL-6, and MCP-1 expression were higher and IL-10 was lower in adenomyosis endometrium epithelia compared to controls. In conclusion, within the implantation window of ovarian stimulation cycles, macrophages, IL-6, IL-10, and MCP-1 are expressed differently in the endometrium of women with adenomyosis, which may correlate with compromised endometrium receptivity. We postulated that cytokines of endometrial secretions expressed differently in patients with adenomyosis may contribute to impaired endometrium receptivity in these patients.

N. Zhihong

Papers

Cytokine Profiling in the Eutopic Endometrium of Adenomyosis During the Implantation Window After Ovarian Stimulation