Eur J Pain. 2016 Aug;20(7):1044-57.

Sciatic endometriosis induces mechanical hypersensitivity, segmental nerve damage, and robust local inflammation in rats.

Chen S1,2Xie W2Strong JA2Jiang J1Zhang JM2.

 

Abstract

BACKGROUND:

Endometriosis is a common cause of pain including radicular pain. Ectopic endometrial tissue may directly affect peripheral nerves including the sciatic, which has not been modelled in animals.

METHODS:

We developed a rat model for sciatic endometriosis by grafting a piece of autologous uterine tissue around the sciatic nerve. Control animals underwent a similar surgery but received a graft of pelvic fat tissue.

RESULTS:

The uterine grafts survived and developed fluid-filled cysts; the adjacent nerve showed signs of swelling and damage. Mechanical and cold hypersensitivity and allodynia of the ipsilateral hindpaw developed gradually over the first 2 weeks after the surgery, peaked at 2-5 weeks, and was almost resolved by 7 weeks. Control animals showed only minor changes in these pain behaviours. Histological signs of inflammation in the uterine graft and in the adjacent nerve were observed at 3 weeks but were resolving by 7 weeks. In vivo fibre recording showed increased spontaneous activity, especially of C-fibres, in sciatic nerve proximal to the uterine graft. Several pro-inflammatory cytokines including interluekin-18, VEGF, fractalkine, and MIP-1α, were elevated in the uterine graft plus sciatic nerve samples, compared to samples from normal nerve or nerve plus fat graft. Growth associated protein 43 (GAP43), a marker of regenerating nerve fibres, was observed in the adjacent sciatic nerve as well as in the uterine graft.

CONCLUSIONS:

This model shared many features with other rat models of endometriosis, but also had some unique features more closely related to neuropathic pain models.

WHAT DOES THIS STUDY/REVIEW ADD:

Some especially painful forms of endometriosis are essentially neuropathic, because peripheral nerves are directly affected by nearby ectopic endometrial tissue. We modelled endometriosis by implanting autologous uterine tissue around rat sciatic nerve. We observed mechanical and cold pain behaviours along with signs of inflammation and nerve damage and increased pro-inflammatory cytokines at the implant site. Pain behaviours correlated with signs of nerve inflammation and damage rather than with cyst survival.

 

 

Hum Reprod. 2016 Feb;31(2):355-69.

Transforming growth factor β1 signaling coincides with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice.

Shen M1Liu X2Zhang H3Guo SW4.

 

Abstract

STUDY QUESTION:

Do platelets have any role in the development of adenomyosis?

SUMMARY ANSWER:

Activated platelets coincide with the release of transforming growth factor (TGF)-β1 and induction of the TGF-β/Smad signaling pathway as well as evidence of epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT) in a mouse model of adenomyosis, resulting ultimately in fibrosis, as in adenomyosis.

WHAT IS KNOWN ALREADY:

Both EMT and FMT are known to play vital roles in fibrogenesis in general and in endometriosis in particular. EMT has been implicated in the development of adenomyosis, but this was based primarily on cross-sectional observation. It is unclear as to whether adenomyotic lesions and their microenvironment have the machinery to promote EMT and FMT, resulting ultimately in fibrosis. There has not been any published study on the role of platelets in the development of adenomyosis, even though adenomyotic lesions undergo repeated cycles of tissue injury and repair, which implicates the involvement of platelets and constitutes an environment conducive for fibrogenesis.

STUDY DESIGN, SIZE, DURATION:

Adenomyosis was induced in 28 female ICR mice by neonatal dosing of tamoxifen. Another 32 were neonatally dosed without tamoxifen. These mice were sacrificed serially and their tissue samples were subsequently evaluated.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Female ICR mice with and without induced adenomyosis were sacrificed in batch at 5, 10, 15, 42 and 60 days of age. The depth of myometrial infiltration of endometrial tissues was assessed and immunohistochemistry analysis of biomarkers of EMT and FMT, as well as TGF-β1, phosphorylated Smad3 (p-Smad3) and markers of proliferation, angiogenesis and extracellular matrix (ECM) deposits was performed in ectopic (for adenomyotic mice) and eutopic (controls) endometrial tissue samples. Masson trichrome and Van Gieson stainings were performed to quantify the extent of fibrosis in lesions. Progesterone receptor isoform B (PR-B) staining also was performed.

MAIN RESULTS AND THE ROLE OF CHANCE:

While TGF-β1 immunoreactivity was consistently low in control endometrium, its level was increased dramatically starting from Day 10, along with the extent of platelet aggregation. Staining for TGF-β1 and p-Smad3 increased progressively as adenomyosis progressed, along with markers for proliferation, angiogenesis and ECM deposits. Consistently, staining of vimentin (a marker for stromal or mesenchymal cells) was also increased while that of E-cadherin (a marker for epithelial cells) was reduced. PR-B staining also decreased progressively. Starting from Day 42, α-SMA staining, a marker for myofibroblasts, was elevated in lesions, while in control endometrium, it was negative. Concomitantly, the extent of fibrosis also was increased.

LIMITATIONS, REASONS FOR CAUTION:

This study is limited by the use of histochemistry and immunohistochemistry analyses only and the lack of intervention.

WIDER IMPLICATIONS OF THE FINDINGS:

Like their endometriotic counterpart, adenomyotic lesions and their microenvironment may contain all the necessary molecular machinery to promote fibrogenesis. Platelet-induced activation of the TGF-β/Smad signaling pathway may be a driving force in EMT and FMT in the development of adenomyosis, leading to fibrosis. This study provides the first piece of evidence that adenomyotic lesions are wounds that undergo repeated injury and healing, and as such, platelets play critical roles in the development of adenomyosis. It suggests the potential for the use of anti-platelet therapy in the treatment of adenomyosis, and also opens a new venue for developing novel biomarkers for diagnostic or prognostic purposes.

STUDY FUNDING/COMPETING INTERESTS:

Support for data collection and analysis was provided by grants from the National Science Foundation of China. None of the authors has anything to disclose.

 

 

Am J Reprod Immunol. 2016 Apr;75(4):461-73.

1,25-Dihydroxy Vitamin D3 Modulates Endometriosis-Related Features of Human Endometriotic Stromal Cells.

Delbandi AA1,2Mahmoudi M2Shervin A3Zarnani AH1,4.

 

Abstract

PROBLEM:

We aimed to evaluate modulatory effects of vitamin D3 on endometriosis-related features of endometriotic stromal cells.

METHOD OF STUDY:

The effect of vitamin D3 on adhesion, invasion, proliferation, apoptosis, cytokine production, and angiogenesis potential of the eutopic (EuESCs), ectopic (EESCs), and control (CESCs) stromal cells from 25 women with and 20 women without endometriosis was investigated.

RESULTS:

In all groups, vitamin D3 significantly increased cell adhesion (P = 0.0013-0.042), while decreased invasion (P = 0.026-0.031) and proliferation (P = 0.0013-0.039) of EESCs and EuESCs. Such treatment also resulted in a significant decrease in IL-6 production by EESCs (P = 0.039), but had no significant effect on the IL-8 production. This vitamin also caused significant decrease in Bcl-2 gene expression by EuESCs (P = 0.04) and Bcl-xL by EESCs (P = 0.044-0.009). In addition, vitamin D3 treatment reduced VEGF-A gene expression by EESCs (P = 0.046-0.009).

CONCLUSION:

Based on substantial favourable in vitro effects of vitamin D3 in endometriosis-related features of human endometriotic stromal cells, further investigations on therapeutic potential of this hormone in endometriosisare warranted.

 

 

Reprod Sci. 2016 Jun;23(6):795-802

Use of Neutrophil-to-Lymphocyte Ratio Combined With CA-125 to Distinguish Endometriomas From Other Benign Ovarian Cysts.

Tokmak A1Yildirim G2Öztaş E2Akar S2Erkenekli K2Gülşen P2Yilmaz N2Uğur M2.

 

Abstract

PURPOSE:

The objective of this study was to evaluate the diagnostic value of the neutrophil-to-lymphocyte ratio (NLR) compared to CA-125 in patients with endometriomas.

METHODS:

This study was designed as a retrospective comparative study. A total of 807 women who underwent surgery due to benign ovarian cysts between January 2008 and January 2013 were included in the study. The NLR and CA-125 levels were assessed separately and together, with a receiver-operating characteristic curve analysis for the diagnosis of endometriomas.

RESULTS:

The mean serum levels of NLR, CA-125, and combined markers were significantly higher in the study group (all P < .001). According to the highest Youden index, the cutoff values were found to be 23.7 IU/mL for CA-125 at 75% sensitivity and 81% specificity and 1.89 for NLR at 70% sensitivity and 74% specificity. The cutoff value for the combined marker was 41.0 with 80% sensitivity and 82% specificity. There was a positive correlation between NLR and CA-125 (P < .001). Neutrophil-to-lymphocyte ratio was also positively correlated with the endometriosis score (P < .001).

CONCLUSIONS:

Although NLR is a simple and easily applicable marker, CA-125 is superior for differentiating endometriomas from other benign ovarian cysts. The combination of these 2 markers improves diagnostic accuracy.

 

 

Best Pract Res Clin Obstet Gynaecol. 2016 Aug;35:51-62.

Bowel complications in endometriosis surgery.

Oliveira MA1Pereira TR2Gilbert A3Tulandi T3de Oliveira HC2De Wilde RL4.

 

Abstract

Endometriosis surgery by laparoscopy or laparotomy can be associated with various types of intestinal complications that may occur in the immediate postoperative period or later. They include bowel anastomotic dehiscence, rectovaginal fistula, anastomotic bleeding, intra-abdominal infections, wound infections, bowel stricture, intestinal obstruction, chronic constipation, and diarrhea. There is growing evidence that bowel injuries can be repaired by primary closure in two layers even without previous bowel preparation. Surgical treatments of deep bowel endometriosis include conservative surgery (including shaving technique or discoid resection) or a more radical approach such as bowel resection that is associated with increased complications. Good perfusion and no tension at the anastomosis site are essential when segmental resection is performed. Early recognition of bowel complications during surgery or in the immediate postoperative period is fundamental to decreased morbidity and mortality. This chapter will deal with the prevention of bowel complication in minimally invasive surgery for endometriosis.

 

 

Cochrane Database Syst Rev. 2015 Dec 23;(12)

Urinary biomarkers for the non-invasive diagnosis of endometriosis.

Liu E1Nisenblat VFarquhar CFraser IBossuyt PMJohnson NHull ML.

 

Abstract

BACKGROUND:

About 10% of reproductive-aged women suffer from endometriosis which is a costly chronic disease that causes pelvic pain and subfertility. Laparoscopy is the ‘gold standard’ diagnostic test for endometriosis, but it is expensive and carries surgical risks. Currently, there are no simple non-invasive or minimally-invasive tests available in clinical practice that accurately diagnoses endometriosis.

OBJECTIVES:

  1. To provide summary estimates of the diagnostic accuracy of urinary biomarkers for the diagnosis of pelvic endometriosiscompared to surgical diagnosis as a reference standard.2. To assess the diagnostic utility of biomarkers that could differentiate ovarian endometrioma from other ovarian masses.Urinary biomarkers were evaluated as replacement tests for surgical diagnosis and as triage tests to inform decisions to undertake surgery for endometriosis.

SEARCH METHODS:

The searches were not restricted to particular study design, language or publication dates. We searched the following databases to 20 April – 31 July 2015: CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, Web of Science, LILACS, OAIster, TRIP and ClinicalTrials.gov (trial register). MEDION, DARE, and PubMed were also searched to identify reviews and guidelines as reference sources of potentially relevant studies. Recently published papers not yet indexed in the major databases were also sought. The search strategy incorporated words in the title, abstract, text words across the record and the medical subject headings (MeSH) and was modified for each database.

SELECTION CRITERIA:

Published peer-reviewed, randomised controlled or cross-sectional studies of any size were considered, which included prospectively collected samples from any population of reproductive-aged women suspected of having one or more of the following target conditions: ovarian, peritoneal or deep infiltrating endometriosis (DIE). We included studies comparing the diagnostic test accuracy of one or more urinary biomarkers with surgical visualisation of endometriotic lesions.

DATA COLLECTION AND ANALYSIS:

Two authors independently collected and performed a quality assessment of the data from each study. For each diagnostic test, the data were classified as positive or negative for the surgical detection of endometriosis and sensitivity and specificity estimates were calculated. If two or more tests were evaluated in the same cohort, each was considered as a separate data set. The bivariate model was used to obtain pooled estimates of sensitivity and specificity whenever sufficient data sets were available. The predetermined criteria for a clinically useful urine test to replace diagnostic surgery was one with a sensitivity of 94% and a specificity of 79% to detect endometriosis. The criteria for triage tests were set at sensitivity of equal or greater than 95% and specificity of equal or greater than 50%, which in case of negative result rules out the diagnosis (SnOUT test) or sensitivity of equal or greater than 50% with specificity of equal or greater than 95%, which in case of positive result rules the diagnosis in (SpIN test).

MAIN RESULTS:

We included eight studies involving 646 participants, most of which were of poor methodological quality. The urinary biomarkers were evaluated either in a specific phase of menstrual cycle or irrespective of the cycle phase. Five studies evaluated the diagnostic performance of four urinary biomarkers for endometriosis, including three biomarkers distinguishing women with and without endometriosis (enolase 1 (NNE); vitamin D binding protein (VDBP); and urinary peptide profiling); and one biomarker (cytokeratin 19 (CK 19)) showing no significant difference between the two groups. All of these biomarkers were assessed in small individual studies and could not be statistically evaluated in a meaningful way. None of the biomarkers met the criteria for a replacement test or a triage test. Three studies evaluated three biomarkers that did not differentiate women with endometriosis from disease-free controls.

AUTHORS’ CONCLUSIONS:

There was insufficient evidence to recommend any urinary biomarker for use as a replacement or triage test in clinical practice for the diagnosis of endometriosis. Several urinary biomarkers may have diagnostic potential, but require further evaluation before being introduced into routine clinical practice. Laparoscopy remains the gold standard for the diagnosis of endometriosis, and diagnosis of endometriosis using urinary biomarkers should only be undertaken in a research setting.

 

 

Fertil Steril. 2016 Apr;105(4):968-977

Surgical removal of endometriotic lesions alters local and systemic proinflammatory cytokines in endometriosis patients.

Monsanto SP1Edwards AK1Zhou J2Nagarkatti P2Nagarkatti M2Young SL3Lessey BA4Tayade C5.

 

Abstract

OBJECTIVE:

To determine the impact of endometriotic lesion removal on local and systemic inflammation.

DESIGN:

Multiplex cytokine analysis on samples from endometriosis patients before surgery, 2 weeks after surgery, and 3 months after surgery.

SETTING:

Academic teaching hospital and university.

PATIENT(S):

A total of 43 endometriosis patients before and after excision of lesions by means of laparoscopic surgery, and 25 normal women.

INTERVENTION(S):

None.

MAIN OUTCOME MEASURE(S):

Plasma, eutopic and ectopic tissue, and peritoneal fluid cytokine levels.

RESULT(S):

Compared with presurgery plasma samples, levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL) 2, IL-8, and IL-10 decreased significantly by 2 weeks after surgery in endometriosis patients. Interestingly, levels began to rise at 3 months after surgery in most cases. In tissue, levels of GM-CSF and IL-15 were lower in eutopic tissue, while levels of basic fibroblast growth factor, interferon-inducible protein 10, IL-1 receptor antagonist, granulocyte colony-stimulating factor, macrophage inflammatory protein 1β, IL-7, and IL-5 were higher in eutopic than in ectopic tissue. In peritoneal fluid, levels of IL-5 and IL-12 were higher in early versus advanced stages of endometriosis. Compared with normal women, plasma from endometriosis patients had higher levels of inflammatory cytokines.

CONCLUSION(S):

Endometriotic lesion removal significantly alters the inflammatory profile both locally and systemically in women with endometriosis. Our findings indicate that ectopic lesions are the major drivers of systemic inflammation in endometriosis. The transitory nature of the change may reflect the recurrence of the condition and the influence of systemic factors in its onset.

 

 

Eur J Obstet Gynecol Reprod Biol. 2017 Feb;209:39-43

Symptomatic endometriosis of the posterior cul-de-sac is associated with impaired sleep quality, excessive daytime sleepiness and insomnia: a case-control study.

Leone Roberti Maggiore U1Bizzarri N1Scala C1Tafi E1Siesto G2Alessandri F3Ferrero S4.

 

Abstract

OBJECTIVE:

To assess the impact of endometriosis of the posterior cul-de-sac on quality of sleep, average daytime sleepiness and insomnia.

STUDY DESIGN:

This age-matched case-control study was conducted in a tertiary referral centre for the diagnosis and treatment of endometriosis between May 2012 and December 2013. It included 145 women with endometriosis of the posterior cul-de-sac (cases; group E) and 145 patients referred to our Institution because of routine gynaecologic consultations (controls; group C). This study investigated whether sleep is impaired in patients with endometriosis of the posterior cul-de-sac. Sleep quality, daytime sleepiness and insomnia were assessed using the following self-administered questionnaires: the Pittsburgh Sleep Quality Index, the Epworth sleepiness scale and the Insomnia Severity Index, respectively. The primary objective of the study was to evaluate sleep quality in the two study groups. Secondary outcomes of the study were to assess average daytime sleepiness and insomnia in the two study groups.

RESULTS:

The prevalence of poor sleep quality was significantly higher in group E (64.8%) than in group C (15.1%; p<0.001). The prevalence of excessive daytime sleepiness was significantly higher in group E (23.4%) than in group C (12.9%; p=0.033). Patients of group E experienced subthreshold insomnia (29.0%) and moderate clinical insomnia (16.6%) significantly more frequently than patients in group C (24.4% and 5.0%; p=0.002).

CONCLUSION:

A substantial proportion of women with endometriosis of the posterior cul-de-sac experiences poor sleep quality, excessive daytime sleepiness and insomnia.

 

 

Clin Radiol. 2016 Mar;71(3):179-94

MRI technique for the preoperative evaluation of deep infiltrating endometriosis: current status and protocol recommendation.

Schneider C1Oehmke F2Tinneberg HR2Krombach GA3.

 

Abstract

Endometriosis is a common cause of chronic pelvic pain and infertility. It is defined as the occurrence of endometrial tissue outside the uterine cavity and can manifest as a peritoneal, ovarian or infiltrating form, the latter being referred to as deep infiltrating endometriosis (DIE). Surgery is essential in the treatment of DIE and depending on the severity of the disease, surgery can be difficult and extensive. Beside clinical examination and ultrasound, magnetic resonance imaging (MRI) has proven its value to provide useful information for planning surgery in patients with suspected DIE. To optimise the quality of MRI examinations, radiologists have to be familiar with the capabilities and also the limitations of this technique with respect to the assessment of DIE. MRI yields morphological information by using mainly T1- and T2-weighted sequences, but can also provide functional information by means of intravenous gadolinium, diffusion-weighted imaging or cine-MRI. In this article, these techniques and also adequate measures of patient preparation, which are indispensable for successful MRI imaging for the preoperative evaluation of DIE, are reviewed and a comprehensive protocol recommendation is provided.

Eur J Obstet Gynecol Reprod Biol. 2016 Feb;197:36-40

When sex is not on fire: a prospective multicentre study evaluating the short-term effects of radical resection of endometriosis on quality of sex life and dyspareunia.

Fritzer N1Tammaa A2Haas D3Oppelt P3Renner S4Hornung D5Wölfler M6Ulrich U7Hudelist G8.

 

Abstract

OBJECTIVE:

The aim of the current study was to evaluate the effect of surgical removal of endometriosis on dyspareunia, sexual function, quality of sex life and interpersonal relationships.

STUDY DESIGN:

A questionnaire-based multicentre prospective study was conducted in six tertiary referral centres in Austria and Germany. Ninety-six patients with histologically proven endometriosis and dyspareunia were included. Before surgery and averagely 10 months postoperatively (range 9-12 months), the Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS) were used to screen women’s sexuality. Additionally, we evaluated psychological parameters and pain intensity during/after sexual intercourse via a self-administered questionnaire.

RESULTS:

Pain scores measured via NAS during/after intercourse decreased significantly after surgery. Frequencies of interrupted sexual intercourse, feelings of guilt towards the partner, being afraid of pain before/during sexual intercourse and feelings of being a burden for the relationship also decreased significantly in patients with peritoneal endometriosis and deep infiltrating endometriosis. Interestingly, sexually related personal distress did not improve in women with peritoneal endometriosis/vaginal resection, but improved in cases of deep infiltrating endometriosis (DIE).

CONCLUSION:

Radical laparoscopic excision of endometriosis offers an effective treatment option and offers a significant improvement in dyspareunia and quality of sex life.

 

 

Reprod Sci. 2016 Jul;23(7):871-6.

Molecular Background of Estrogen Receptor Gene Expression in Endometriotic Cells.

Izawa M1Taniguchi F2Harada T2.

 

Abstract

The molecular background of estrogen receptor (ER) expression is important to understand the pathophysiology of the high estrogen environment in endometriosis. However, the molecular details have not been fully understood. The objective of this study is to evaluate the molecular background of ERα and ERβ messenger RNA (mRNA) expression in endometriotic cells. The following summarizes our observations: (1) ERα mRNA expression in endometriotic cells was estimated to be approximately one-tenth of that in endometrial cells. (2) Three mRNAs, which include 3 different 5′-untranslated exons tagged to an open reading frame of wild-type ERα, were detected. (3) Expression of ERβ mRNA depends mostly on 0N promoter and includes 2 open reading frames: one for a wild-type ERβ1 and another for a splice variant ERβ2. (4) Expression of ERβ1 mRNA was approximately 40-fold higher than that in endometrial cells. (5) Expression of ERβ2 mRNA was almost at a comparable level of the ERβ1. 9 (6) ERα and ERβ mRNAs are equivalently expressed in endometriotic cells. These observations show the molecular background of ER mRNA expression in endometriotic cells and provide a clue to further understanding the estrogen-dependent pathophysiology leading to clinical application in endometriosis.

 

 

Reprod Sci. 2016 Jul;23(7):885-91.

Follicle-Stimulating Hormone Receptor Expression in Endometriotic Lesions and the Associated Vasculature: An Immunohistochemical Study.

Robin B1Planeix F1Sastre-Garau X2Pichon C1Olesen TK3Gogusev J4Ghinea N5.

 

Abstract

Follicle-stimulating hormone receptor (FSHR) is present on endothelial cells of blood vessels and endometrial glands of the proliferative and secretory endometrium. So far, the expression of FSHR in endometriosis has not been studied. We evaluated FSHR expression in 194 tissue specimens representing 3 relevant types of endometriosis: rectovaginal endometriotic nodules, ovarian endometriotic cysts, and peritoneal endometriotic implants. Specimens of normal endometrium were used as controls. Archival formalin-fixed and paraffin-embedded material was analyzed immunohistochemically with a highly specific monoclonal antihuman FSHR antibody using the peroxidase method. A robust vascular FSHR expression was found in all 194 patients, irrespective of the endometriosis lesion location. Follicle-stimulating hormone receptor was not detected in normal host tissues located more than 5 mm from the lesions. The endometriotic lymphatic vessels do not express FSHR. The density of FSHR-positive vessels in patients with rectovaginal endometriotic nodules was 46.0 ± 5.7 vessels/mm(2) Similar values were obtained for ovarian endometriotic cysts and peritoneal endometriosis. The density of FSHR-positive vessels associated with the core of rectovaginal endometriotic nodules was 2-fold higher than that of the perilesional, adjacent normal host tissue (64.2 ± 8.2 vs 27.2 ± 3.2 vessels/mm(2), respectively). Expression of FSHR was also detected either in endometriotic glandular epithelial cells, endometriotic stromal cells, or in both cell types (23%, 25%, and 21% of patients, respectively). Normal endometrium expressed FSHR predominately in basalis, in a cellular distribution dependent on hormonal environment. In conclusion, our data suggest novel FSHR expression in endometriotic lesions, qualitatively and quantitatively different from that of normal endometrium.

 

 

Hum Reprod. 2016 Feb;31(2):345-54.

In silico, in vitro and in vivo analysis identifies a potential role for steroid hormone regulation of FOXD3 in endometriosis-associated genes.

Mathew D1Drury JA1Valentijn AJ1Vasieva O2Hapangama DK3.

 

Abstract

STUDY QUESTION:

Can bioinformatics analysis of publically available microarray datasets be utilized in identifying potentially important transcription factors (TF) in the hormonal regulation of the endometrium?

SUMMARY ANSWER:

Systems integration and analysis of existing complex (published) datasets, predicted a role for the novel transcription factor, Forkhead Box D3 (FOXD3) in healthy endometrium and in endometriosis, which was followed by the demonstration of decreased levels of the protein upon decidualisation of normal human endometrial stromal cells in vitro and differential endometrial expression in the stroma in endometriosis.

WHAT IS KNOWN ALREADY:

The reported endometriosis-associated endometrial aberrations are most pronounced in the progesterone-dominant secretory phase and progesterone resistance is a proposed causative factor.

STUDY DESIGN, SIZE, DURATION:

The study was initially an ‘in silico’ study, with confirmatory ‘wet lab’ data from western blotting (WB), qPCR and Immunohistochemistry (IHC) on endometrial biopsies obtained from 142 women undergoing gynaecological surgery.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

The study was conducted at a University Research Institute. Bioinformatic analysis of selected published microarray datasets identified differentially regulated genes for the early and mid-secretory phases relative to the proliferative phase. Diseases and Functions categories were identified with Ingenuity (IPA) ‘core analysis’ software. The key transcription factors controlling secretory phase gene changes were revealed with oPOSSUM software. FOXD3 expression levels were examined in human endometrial samples from women aged 18-55 years by WB, IHC, and qPCR. The progesterone regulation of endometrial FOXD3 levels was examined in vivo and in cultured primary human endometrial stromal cells in vitro.

MAIN RESULTS AND THE ROLE OF CHANCE:

Initial data mining and subsequent bioinformatics analysis of human endometrial microarray datasets identified FOXD3 to be a key regulator of gene expression specific to secretory phase/endometriosis. FOXD3 was dynamically expressed in healthy endometrium and differentially expressed in endometriosis. In vitro decidualisation of primary endometrial stromal cells significantly decreased FOXD3 protein (P = 0.0005) and progestagen (Levonorgestrel) treatment also reduced the high endometrial FOXD3 protein (P = 0.0001) and mRNA levels (P = 0.04) seen in untreated women with endometriosis, with a shift of FOXD3 from the nucleus to the cytoplasm.

LIMITATIONS, REASONS FOR CAUTION:

The quality of Bioinformatics analysis and results depends on the published micro-array data.

WIDER IMPLICATIONS OF THE FINDINGS:

An in depth analysis of FOXD3 function and its relationship with estrogen and progesterone might provide insights into its potential deregulation in proliferative disorders of the endometrium including endometrial cancer where its expression is also deregulated. Further, FOX transcription factors are increasingly seen as novel therapeutic targets in disease.

STUDY FUNDING/COMPETING INTERESTS:

We acknowledge the support by Wellbeing of Women project grant RG1073 (D.K.H., A.J.V.). We also acknowledge the support of Liverpool Women’s Hospital Foundation Trust (J.A.D.), Institute of Translational Medicine (D.M., A.J.V., D.K.H.) and the Institute of Integrative Biology (O.V.), University of Liverpool. All authors declare no conflict of interest.

 

 

Gynecol Obstet Fertil. 2016 Feb;44(2):121-4.

Multiple nodule removal in multifocal colorectal endometriosis instead of “en bloc” large colorectal resection.

Roman H1Darwish B2Bridoux V3Huet E3Coget J3Chati R3Tuech JJ3Abo C2.

 

Abstract

Surgical management of colorectal endometriosis follows the principles of two main philosophies or approaches: radical and conservative. The radical approach has recently been recommended in multifocal colorectal endometriosis, which frequently concerns patients with rectal nodules. However, an alternative conservative management could employ selective retrieval of macroscopic colorectal deep endometriosis nodules by bowel shaving and disc excision, with preservation of the mesorectum. The conservative approach is justified by the evidence that low colorectal resection may lead to postoperative functional digestive symptoms for which management is most challenging. However, there is a lack of data in the literature specifically focusing on patients with multiple excision of deep colorectal endometriosis. No data exist about the minimal length of healthy bowel that should be conserved between two successive transversal bowel sutures, and on consecutive improvement of functional outcomes. Conversely, no evidence exists on presumed reduction of recurrence rate when young patients undergo low large colorectal resection, instead of multiple selective excisions. Further comparative studies would be welcome, among which the ENDORE randomized trial which may play a central role by comparing functional outcomes related to radical and conservative approach in deep endometriosis infiltrating the rectum.

 

 

Eur J Obstet Gynecol Reprod Biol. 2016 Feb;197:59-62.

Are hypertension and diabetes mellitus risk factors for pelvic organ prolapse?

Isık H1Aynıoglu O2Sahbaz A2Selimoglu R3Timur H4Harma M2.

 

Abstract

OBJECTIVES:

Pelvic organ prolapse (POP) is an important problem for women with multifactorial etiology. This study aims to determine the role of hypertension (HT) and diabetes mellitus (DM) in POP.

STUDY DESIGN:

The study included 586 women admitted to Bulent Ecevit University Hospital between September 2013 and April 2015 for hysterectomy, comprising 186 patients with POP and 400 patients without. The demographic characteristics, age, body mass index (BMI), obstetrical history, type of delivery, associated medical diseases, and benign gynecological diseases were recorded. HT, DM, or both together were particularly considered as coexisting medical diseases.

RESULTS:

Median gravida, parity, and live birth numbers were significantly higher in POP patients (4 vs. 3, 3 vs. 2, and 3 vs. 2 respectively, p<0.001). POP patients were more obese than POP-absent patients (p<0.001). Vaginal history of birth increased POP frequency to 25.8% with statistical significance (p<0.001). There was no significant difference between groups regarding coexisting endometritis, endometrial polyp, endometriosis, endometrial hyperplasia (p>0.05). There was a significant difference between groups regarding comorbid diseases (p<0.001). Logistic regression analysis for risk factors of POP revealed age, BMI, vaginal parturition, and co-morbidity with HT+DM together significantly increased POP risk (p<0.05). HT+DM together significantly increased risks with OR of 1.9 (1.1-3.16).

CONCLUSIONS:

In addition to multiple factors increasing POP risk, comorbidities as HT+DM together should be considered as risk factors. Patients with these comorbidities should be encouraged to change their lifestyles to prevent POP.

 

 

Eur J Histochem. 2015 Dec 9;59(4):2570.

High temperature requirement A1, transforming growth factor beta1, phosphoSmad2 and Ki67 in eutopic and ectopic endometrium of women with endometriosis.

Goteri G1Altobelli ETossetta GZizzi AAvellini CLicini CLorenzi TCastellucci MCiavattini AMarzioni D.

 

Abstract

Increasing evidence supports the hypothesis that TGFb1 signalling may be mediated by high temperature requirement A1 (HtrA1) serine protease, acting on important regulatory mechanisms such as cell proliferation and mobility. Evidence is now accumulating to suggest that HtrA1 is involved in the development and progression of several pathologies. The aim of this study was to evaluate: i) if HtrA1 and TGFb1 expressions differ in eutopic and ectopic endometrium in women with endometriosis; ii) if HtrA1 correlates to TGFb1, pSmad and Ki67. This study was carried out including 10 women with ovarian endometriosis (cases) and 10 women with non endometriotic diseases (controls). Endometrial tissue underwent immunohistochemical H-score analysis for HtrA1, TGFb1, pSmad and Ki67 molecules. Data evaluation was performed by a nonparametric Kruskal-Wallis test and Spearman correlation was applied to evaluate the relationship among the molecules investigated in the epithelial and in the stromal compartment. The HtrA1 was significant decreased in ectopic and eutopic endometrium of women with endometriosis when compared with control endometrium in epithelial compartment. TGFb1was significantly increased in eutopic endometrium and decreased in ectopic endometrium in epithelial and stromal compartment. In addition, Ki67 was significant increased and an increase, but not significant, was detected for pSMAd2 in eutopic and ectopic endometrium compared to control one.  In summary, the significant direct correlation between TGFb1 and pSmad2 as well as between HtrA1 and TGFb1 and the very significant increase of Ki67 in stromal compartment of eutopic endometrium suggest a possible involvement of HtrA1 in the pathogenesis of endometriosis.

 

 

 

Front Biosci (Landmark Ed). 2016 Jan 1;21:856-72.

Analysis for Carom complex, signaling and function by database mining.

Liu SXiong XThomas SVXu YCheng XZhao XYang XWang H1.

 

Abstract

Carom is a novel protein that regulates membrane curvature and transmits pathophysiological signaling. The tissue expression of Carom is unclear and its functional role and signaling are unknown. We employed a group of combined database mining strategies and established a working model of Carom signaling. We identified 26 Carom partners and established their expression profiles in human and mouse tissues. We classified three tiers of tissues for Carom/partner expression and found lymph node was the tier 1 tissue expressing Carom and most of its partners. Using GEO database, we discovered that four conditions (hypoxia, endometriosis, PPARgamma deletion and iPSC reprogramming) altered Carom/partner expression in endothelial cells. We identified 26 Carom partner signalings by Ingenuity pathway analysis. Ten of the 26 pathways and three genes (ITSN1, UBC and HSPA5) were reported to be regulated in the above four conditions. Paired induction of Carom/ITSN1 elevation was associated with pathological angiogenesis. Whereas, paired reduction of Carom/HSPA5 or UBC was associated with iPSC generation. These results provide an insight on identifying Carom complex model and predicting its functional implications.

 

 

Reprod Sci. 2016 Jul;23(7):892-901.

Nerve Bundles and Deep Dyspareunia in Endometriosis.

Williams C1Hoang L2Yosef A1Alotaibi F1Allaire C1Brotto L1Fraser IS3Bedaiwy MA1Ng TL2Lee AF2Yong PJ4.

 

Abstract

The etiology of deep dyspareunia in endometriosis is unclear. Our objective was to determine whether nerve bundle density in the cul-de-sac/uterosacrals (zone II) is associated with deep dyspareunia in women with endometriosis. We conducted a blinded retrospective immunohistochemistry study (n = 58) at a tertiary referral center (2011-2013). Patients were stringently phenotyped into a study group and 2 control groups. The study group (tender endometriosis, n = 29) consisted of patients with deep dyspareunia, a tender zone II on examination, and an endometriosis lesion in zone II excised at surgery. Control group 1 (nontender endometriosis, n = 17) consisted of patients without deep dyspareunia, a nontender zone II on examination, and an endometriosis lesion in zone II excised at surgery. Control group 2 (tender nonendometriosis, n = 12) consisted of patients with deep dyspareunia, a tender zone II on examination, and a nonendometriosis lesion (eg, normal histology) in zone II excised at surgery. Protein gene product 9.5 (PGP9.5) immunohistochemistry was performed to identify nerve bundles (nerve fibers surrounded by perineurium) in the excised zone II lesion. PGP9.5 nerve bundle density (bundles/high powered field [HPF]) was then scored by a pathologist blinded to the group. We found a significant difference in PGP9.5 nerve bundle density between the 3 groups (analysis of variance, F2,55 = 6.39, P = .003). Mean PGP9.5 nerve bundle density was significantly higher in the study group (1.16 ± 0.56 bundles/HPF [±standard deviation]) compared to control group 1 (0.65 ± 0.36, Tukey test, P = .005) and control group 2 (0.72 ± 0.56, Tukey test, P = .044). This study provides evidence that neurogenesis in the cul-de-sac/uterosacrals may be an etiological factor for deep dyspareunia in endometriosis.

 

 

World J Gastroenterol. 2015 Dec 21;21(47):13345-51

Colorectal resection in deep pelvic endometriosis: Surgical technique and post-operative complications.

Milone M1Vignali A1Milone F1Pignata G1Elmore U1Musella M1De Placido G1Mollo A1Fernandez LM1Coretti G1Bracale U1Rosati R1.

 

Abstract

AIM:

To investigate the impact of different surgical techniques on post-operative complications after colorectal resection for endometriosis.

METHODS:

A multicenter case-controlled study using the prospectively collected data of 90 women (22 with and 68 without post-operative complications) who underwent laparoscopic colorectal resection for endometriosis was designed to evaluate any risk factors of post-operative complications. The prospectively collected data included: gender, age, body mass index, American Society of Anesthesiologists risk class, endometriosis localization (from anal verge), operative time, conversion, intraoperative complications, and post-operative surgical complications such as anastomotic dehiscence, bleeding, infection, and bowel dysfunction.

RESULTS:

A similar number of complicated cases have been registered for the different surgical techniques evaluated (laparoscopy, single access, flexure mobilization, mesenteric artery ligation, and transvaginal specimen extraction). A multivariate regression analysis showed that, after adjusting for major clinical, demographic, and surgical characteristics, complicated cases were only associated with endometriosis localization from the anal verge (OR = 0.8, 95%CI: 0.74-0.98, P = 0.03). After analyzing the association of post-operative complications and each different surgical technique, we found that only bowel dysfunction after surgery was associated with mesenteric artery ligation (11 out of 44 dysfunctions in the mesenteric artery ligation group vs 2 out of 36 cases in the no mesenteric artery ligation group; P = 0.03).

CONCLUSION:

Although further randomized clinical trials are needed to give a definitive conclusion, laparoscopic colorectal resection for deep infiltrating endometriosis appears to be both feasible and safe. Surgical technique cannot be considered a risk factor of post-operative complications.

 

 

Reprod Sci. 2017 Jun;24(6):818-823.

Medical Therapies for Endometriosis Differentially Inhibit Stem Cell Recruitment.

Ersoy GS1Zolbin MM1Cosar E1Mamillapalli R1Taylor HS1.

 

Abstract

OBJECTIVE:

To determine the effect of the 3 well-known endometriosis treatments on stem cell recruitment to endometriotic lesions.

STUDY DESIGN:

C57BL/6 mice (aged 8 weeks, n = 20) underwent bone marrow transplant following submyeloablation with 5-fluorouracil using 20 × 106 bone marrow stem cells from green fluorescent protein (GFP) mice. Two weeks after transplantation, experimental endometriosis was created in mice by suturing segments of the uterine horn into the peritoneal cavity. Mice were then randomized to receive treatment with medroxyprogesterone acetate (MPA), leuprolide acetate (Gonadotrophin-Releasing Hormone Analogue [GnRHa]), letrozole, or vehicle control (dimethyl sulfoxide). After 3 weeks of treatment, the mice were killed and the endometriosis lesions evaluated.

RESULTS:

All 3 treatments resulted in a significant reduction in lesion volume and weight. Estrogen deprivation using GnRHa or letrozole resulted in greater lesion regression than the progestin MPA. The GFP+/CD45 bone marrow-derived stem cells (BMDSCs) engrafted the lesions of endometriosis. Estrogen deprivation using GnRHa or letrozole significantly reduced BMDSC engraftment in the endometriosis lesions. MPA failed to significantly reduce stem cell number in endometriosis.

CONCLUSION:

The superiority of estrogen deprivation over progestin therapy in depriving the lesions of stem cells may have implications for the long-term treatment of endometriosis. Reduced stem cell engraftment is likely to result in long-term regression of the lesions, whereas progestins may only prevent their growth acutely.

 

J Med Biochem. 2016 Jan;35(1):63-68.

Survivin and VEGF as Novel Biomarkers in Diagnosis of Endometriosis.

Acimovic M1Vidakovic S2Milic N3Jeremic K2Markovic M4Milosevic-Djeric A1Lazovic-Radonjic G2.

 

Abstract

in EnglishSerbian

BACKGROUND:

The aim of this study was to investigate the role of peripheral blood markers as additional diagnostic tools to transvaginal ultrasound (TVU) findings in the diagnosis of endometriosis.

METHODS:

This study included 40 patients undergoing laparoscopy for suspected endometriosis from January to December 2012. Preoperative levels of serum CA125, CA19-9, CEA and mRNA expression levels for survivin and VEGF were obtained. Real-time PCR was used to determine relative gene expression. A new diagnostic score was obtained by deploying the peripheral blood markers to the TVU findings. Statistical methods used were Chi-square, Fisher’s, Student’s t-test or the Mann – Whitney test.

RESULTS:

There was a statistically significant difference in serum CA125, survivin and VEGF levels in patients with endometriosis and those without endometriosis (p<0.001, p=0.025 and p=0.009, respectively). False negative TVU findings were noted in 3/13 patients (23.1%) with peritoneal endometriosis without ovaries involvement. High sensitivity (93.3%), specificity (90.0%), PPV (96.6%), NPV (81.8%) and accuracy (92.5%) were obtained for a diagnostic score based on TVU and significant peripheral blood markers (CA125, survivin and VEGF).

CONCLUSIONS:

Determination of serum CA125, mRNA expression levels for survivin and VEGF along with TVU can contribute to higher accuracy of the noninvasive diagnostic tools for endometriosis.

 

 

Curr Rheumatol Rev. 2016;12(2):140-53.

Psychosocial Vulnerability and Early Life Adversity as Risk Factors for Central Sensitivity Syndromes.

Jones GT1.

 

Abstract

The aim of this narrative review of the epidemiology of central sensitivity syndromes is to provide a summary of the role of early life adversity and psychosocial / psychological factors, in the epidemiology of six main syndromes: (i) fibromyalgia / chronic widespread pain; (ii) headache / migraine; (iii) irritable bowel syndrome; (iv) temporomandibular joint disorder; (v) interstitial cystitis; and (vi) endometriosis / vulvodynia / chronic pelvic pain. The occurrence of each of the above syndromes vary between each other, and between studies. Prevalence ranges from interstitial cystitis, with a prevalence of approximately 14.5 per 100,000, to headache, with some estimates of lifetime prevalence to be around 66%. Precise risk estimates vary between studies, conditions, and exposures, although there is consistent evidence to suggest an association between early life adversity and central sensitivity syndromes (based on the six syndromes under investigation). In further support of this, a number of studies have also demonstrated dose-risk associations. There is also considerable consistency in the literature to suggest a strong association between negative psychological and psychosocial factors, and the occurrence of central sensitivity syndromes and, again, there is some evidence of a dose-risk relationship. The majority of studies in this field are cross-sectional or retrospective in design, and caution is advised when interpreting results. It is possible – indeed there is some evidence – that some findings may be subject to recall bias, and reverse causation is also a potential concern. However, there are also a number of prospective studies which provide more robust evidence.

 

 

PLoS One. 2015 Dec 31;10(12)

Potential Role of Semaphorin 3A and Its Receptors in Regulating Aberrant Sympathetic Innervation in Peritoneal and Deep Infiltrating Endometriosis.

Liang Y1Wang W1Huang J1Tan H1Liu T1Shang C1Liu D1Guo L1Yao S1.

 

Abstract

Previous studies have demonstrated the involvement of nerve repellent factors in regulation of the imbalanced innervation of endometriosis. This prospective study aims to explore the role of Sema 3A in regulating aberrant sympathetic innervation in peritoneal and deep infiltrating endometriosis. Ectopic endometriotic lesion were collected from patients with peritoneal endometriosis (n = 24) and deep infiltrating endometriosis of uterosacral ligament (n = 20) undergoing surgery for endometriosis. Eutopic endometrial samples were collected from patients with endometriosis (n = 22) or without endometriosis (n = 26). Healthy peritoneum (n = 13) from the lateral pelvic wall and healthy uterosacral ligament (n = 13) were obtained from patients who had no surgical and histological proof of endometriosis during hysterectomy for uterine fibroids. Firstly, we studied the immunostaining of Sema 3A, Plexin A1 and NRP-1 in all the tissues described above. Then we studied the nerve fiber density (NFD) of endometriosis-associated (sympathetic) nerve and para-endometriotic (sympathetic) nerve by double immunofluorescence staining. Finally we analyzed the relationship between expression of Sema 3A in stromal cells of endometriotic lesion and the aberrant innervation of endometriosis. Semi-quantitative immunostaining demonstrated that (1) Higher immunostaining of Sema 3A were found in the eutopic endometrial glandular epithelial cells from patients with endometriosis (p = 0.041) than those without endometriosis; (2) Sema 3A immunostaining was higher in glandular epithelial cells of peritoneal endometriosis (P<0.001) and deep infiltrating endometriotic lesions of uterosacral ligament (P = 0.028)compared with glandular epithelial cells of the endometrium from women with endometriosis, while its expression in ectopic stormal cells in both groups were significantly lower than that from eutopic endometrium of women without endometirosis (P<0.001, P<0.001, respectively). NFDs of Anti-TH (+) endometriosis-associated sympathetic nerve of peritoneal endometriosis(p<0.001) and deep endometriosis of uterosacral ligament (p<0.001) were significantly lower than NFDs of para-endometriotic sympathetic nerve. Our results suggest that Sema 3A may contribute to the regulation of aberrant sympathetic innervation in peritoneal and deep infiltrating endometriosis.

 

 

Handb Exp Pharmacol. 2016;232:191-202.

Translational In Vivo Models for Women’s Health: The Nonhuman Primate Endometrium–A Predictive Model for Assessing Steroid Receptor Modulators.

Slayden OD1.

 

Abstract

Macaques and baboons display physiological responses to steroid hormones that are similar to those of women. Herein, we describe various uses of nonhuman primates for preclinical studies on menstruation, endometriosis, and as a model system to evaluate reproductive therapies and contraceptives. Our goal is to outline the strengths of the nonhuman primate model for studies leading to improved therapies for women.

 

 

Int J Clin Exp Pathol. 2015 Oct 1;8(10):13399-404

Correlation between matrix metalloproteinase-9 and endometriosis.

Liu H1Wang J1Wang H1Tang N1Li Y1Zhang Y1Hao T1.

 

Abstract

Endometrial implantation is the major cause of endometriosis (EMS). Matrix metalloproteinase (MMPs) can degrade multiple extracellular matrix and has been postulated to be related with EMC occurrence. This study thus investigated serum and ascites levels of MMP-9 in EMS patients, in an attempt to discuss the correlation between MMP-9 and EMS. A total of 100 EMS patients, including eutopic endometrium and ectopic endometrium, were recruited in this study along with hysteromyoma patients as the control group. Peripheral blood and ascites samples were collected and tested for MMP-9 levels using gelatin zymogram and enzyme-linked immunosorbent assay (ELISA). In EMS patients, MMP-9 levels in serum and ascites were 6.24 ± 0.53 mM and 38.57 ± 4.93 mM, respectively. Both of them were significantly higher than those in control group (P<0.05). Eutopic endometrium group had higher MMP-9 levels compared to those in ectopic endometrium ones (P<0.05). With advancement of disease stage, EMS patients had progressively elevated MMP-9 levels (P<0.05). Patients at proliferative stage had higher MMP-9 secretion (P<0.05). In summary, site of endometrium, clinical stage and proliferative cycle were independent risk factors for EMS. The elevation of serum and ascites MMP-9 existed in EMS patients, of which those had ectopic endometrium, advanced stage and at proliferative stage had higher MMP-9 expression.

 

 

J Steroid Biochem Mol Biol. 2016 Apr;158:117-126.

Effects of steroid hormone on estrogen sulfotransferase and on steroid sulfatase expression in endometriosis tissue and stromal cells.

Piccinato CA1Neme RM2Torres N3Sanches LR4Derogis PB5Brudniewski HF6Rosa e Silva JC7Ferriani RA8.

 

Abstract

Endometriosis is an estrogen-dependent disease that afflicts about 10% of women in their reproductive age, causing severe pain and infertility. The potential roles of female steroid hormones in modulating key estrogen-metabolizing enzymes, steroid sulfatase (STS) and estrogen sulfotransferase (SULT1E1), were investigated. The expression of STS and SULT1E1 mRNA in biopsy samples (n=78) of superficial and deep endometriotic lesions, eutopic endometrium of women with endometriosis and endometrium from control patients were compared according to the menstrual cycle phase. Increased STS gene expression was detected in superficial and deep-infiltrating lesions and a reduced SULT1E1 expression was also observed in the eutopic endometrium relative to the superficial lesions. Additionally, a significantly positive correlation was detected between STS and SULT1E1 mRNA expression levels in biopsy specimens collected from the endometriosis patients, and not in control individuals. The actions of female steroid hormones on SULT1E1 and STS expression were evidenced in endometriosis, revealed by increased expression levels in the luteal phase of the cycle. There was an increased STS expression in primary eutopic and ectopic endometrial stromal cells treated with estradiol and progesterone (representative of the luteal phase, n=3). Although an increased STS mRNA expression was observed in hormone-induced endometrial stromal cells in vitro, no difference could be detected between the hormone treatment groups in estradiol formation from estradiol sulfate measured by LC-MS-MS. Interestingly, a greater expression of STS was observed in stromal cells from eutopic endometrium with an agreement in estradiol formation originated from estradiol sulfate. The differential regulation of STS and SULT1E1 could provide insights for novel studies of the therapeutic use of STS inhibitors.

 

 

J Minim Invasive Gynecol. 2016 May-Jun;23(4):526-34

Laparoscopic Surgery for Severe Rectovaginal Endometriosis Compromising the Bowel: A Prospective Cohort Study.

Kent A1Shakir F2Rockall T3Haines P2Pearson C2Rae-Mitchell W2Jan H4.

 

Abstract

STUDY OBJECTIVE:

Endometriosis can affect 10% of women at reproductive age. Of those, 5.3% to 12% will have endometriosis affecting the bowel. Although outcomes after surgery for severe endometriosis affecting the bowel have previously been studied and have shown improvement in generic quality of life indices and sexual function, few studies have evaluated bowel function or symptoms specific to endometriosis. Our aim was to determine the quality of life after radical excision of rectovagina endometriosis compromising the bowel.

DESIGN:

Single-center prospective cohort study (Canadian Task Force classification II-2).

SETTING:

Specialist referral center for the management of advanced endometriosis.

PATIENTS:

Women with severe rectovaginal endometriosis compromising the bowel.

INTERVENTIONS:

Comparison of preoperative data with a 2-, 6-, and 12-month follow-up was made for consecutive patients who underwent surgery for endometriosis with bowel involvement. The main outcome measures were quality of life using the Endometriosis Health Profile 30 and EuroQol-5 dimension questionnaires. Bowel symptoms were measured using the Gastrointestinal Quality of Life Index. Dysmenorrhea, dyspareunia, dyschezia, and chronic pain were measured using a visual analogue scale. To compare preoperative and postoperative scores, a Freidman test was performed followed by a preoperative and 12-month postoperative Wilcoxon signed-rank test. A Mann-Whitney U test was used to compare the results between those who had pelvic clearance and those who did not.

MEASUREMENTS AND MAIN RESULTS:

In total, 137 patients had surgery, of which 100 completed follow-up to 12 months. The serious perioperative and postoperative complication rate was 7.3%. The results show significant improvement in almost all variables measured (p < .01). At 12 months patients who had a pelvic clearance (hysterectomy with bilateral salpingo-oophorectomy) had significantly less pain with better bowel function. Additionally, they had higher quality of life scores and greater satisfaction with their treatment. There was no significant difference between any postoperative variables tested regardless of the type of bowel surgery.

CONCLUSION:

Severe rectovaginal endometriosis compromising the bowel can be treated surgically with experienced combined gynecologic and colorectal input with a low serious complication rate. Surgery by an experienced multidisciplinary team results in significant improvement in pain, sexual function, and quality of life up to 1 year postoperatively. Pelvic clearance improves outcome and patients should be counseled accordingly. There is no difference in outcome between the types of bowel surgery undertaken as long as all visible/palpable endometriosis is removed.

 

 

Gynecol Obstet Fertil. 2016 Jan;44(1):3-10.

Computed tomography-based virtual colonoscopy in the assessment of bowel endometriosis: The surgeon’s point of view.

Roman H1Carilho J2Da Costa C3De Vecchi C3Suaud O4Monroc M5Hochain P5Vassilieff M2Savoye-Collet C3Saint-Ghislain M2.

 

Abstract

OBJECTIVE:

To discuss the role of computed tomography-based virtual colonoscopy (CTC) in preoperative assessment of bowel endometriosis.

METHODS:

Retrospective study using data prospectively recorded, including 127 patients with colorectal endometriosis, having undergone CTC for bowel endometriosis. The study was conducted in a tertiary referral center during 38 consecutive months. Preoperative assessment included CTC, magnetic resonance imaging (MRI), endorectal ultrasound (ERUS) and clinical examination. Information concerning identification of deep infiltrating endometriosis (DIE) of the bowel, the length and height of colorectal involvement, stenosis of digestive lumen and associated digestive localizations were compared with intraoperative findings.

RESULTS:

Sensitivity and specificity of CTC for DIE of the rectum, the sigmoid colon, associated digestive localizations, and stenosis of the digestive lumen were respectively 97% and 84%, 93% and 88%, 84% and 97%, 96% and 96%. Intraoperative estimation of the length of digestive tract involved by DIE was closer to that provided by CTC than those provided by MRI and ERUS. When CTC revealed stenosis of digestive lumen, higher rates of colorectal resection (63% vs. 9.6%, < 0.001) and disc excision (25.9% vs. 11%, 0.03) were recorded.

DISCUSSION:

For those surgeons using various procedures for management of bowel endometriosis, accurate information on the length and height of bowel involvement, as well as the existence of bowel stenosis enables informed decision regarding the feasibility of conservative techniques versus bowel resection. Preoperative identification of associated localizations above the sigmoid colon is another major advantage related to CTC.

CONCLUSIONS:

CTC provides accurate data on the length and height of colorectal involvement by DIE, stenosis of digestive lumen and associated lesions of digestive tract, which impact on the choice of surgical procedure.

 

 

Free Radic Res. 2016;50(4):414-25.

Lipocalin 2 attenuates iron-related oxidative stress and prolongs the survival of ovarian clear cell carcinoma cells by up-regulating the CD44 variant.

Yamada Y1Miyamoto T1Kashima H1Kobara H1Asaka R1Ando H1Higuchi S1Ida K1Shiozawa T1.

 

Abstract

Ovarian clear cell carcinoma (CCC) arises from ovarian endometriosis. Intra-cystic fluid contains abundant amounts of free iron, which causes persistent oxidative stress, a factor that has been suggested to induce malignant transformation. However, the mechanisms linking oxidative stress and carcinogenesis in CCC currently remain unclear. Lipocalin 2 (LCN2), a multifunctional secretory protein, functions as an iron transporter as well as an antioxidant. Therefore, we herein examined the roles of LCN2 in the regulation of intracellular iron concentrations, oxidative stress, DNA damage, and antioxidative functions using LCN2-overexpressing (ES2), and LCN2-silenced (RMG-1) CCC cell lines. The results of calcein staining indicated that the up-regulated expression of LCN2 correlated with increases in intracellular iron concentrations. However, a DCFH-DA assay and 8OHdG staining revealed that LCN2 reduced intracellular levels of reactive oxygen species and DNA damage. Furthermore, the expression of LCN2 suppressed hydrogen peroxide-induced apoptosis and prolonged cell survival, suggesting an antioxidative role for LCN2. The expression of mRNAs and proteins for various oxidative stress-catalyzing enzymes, such as heme oxygenase (HO), superoxide dismutase (SOD), and glutathione peroxidase, was not affected by LCN2, whereas the intracellular concentration of the potent antioxidant, glutathione (GSH), was increased by LCN2. Furthermore, the expression of xCT, a cystine transporter protein, and CD44 variant 8-10 (CD44v), a stem cell marker, was up-regulated by LCN2. Although LCN2 increased intracellular iron concentrations, LCN2-induced GSH may catalyze and override oxidative stress via CD44v and xCT, and subsequently enhance the survival of CCC cells in oxidative stress-rich endometriosis.

 

 

Indian J Surg. 2015 Dec;77(Suppl 2):682-6

Surgical Treatment of Scar Endometriosis Following Cesarean Section, a Series of 12 Cases.

Uçar MG1Şanlıkan F2Göçmen A2.

 

Abstract

It is difficult to conduct studies with larger series in rarely observed diseases. We report our experience in managing cesarean scar endometriosis (CSE) and emphasize the diagnosis and treatment options. The objective of our study is to review the clinical characteristics of CSE and to evaluate our surgical outcomes. We have collected and documented a case series of 12 patients who underwent surgical wide en bloc excision with surrounding clear margins for CSE. Patients’ demographic features, symptoms, and clinical and operative findings were evaluated. The mean age was 34.6 years. Cyclical pain was documented in seven patients, while three patients presented with noncyclical pain. Menstrually-related enlargement of the nodule was observed in four patients, and only one patient had a complaint of dark brown leakage. The mean operation time was 26 min. The endometriotic lesions ranged from a diameter of 2 to 8 cm in size. Patients recovered completely, and no recurrence was observed. To prevent iatrogenic transplantation, additional attention is needed during surgery that exposes endometrial tissue. Complete wide excision of CSE is both diagnostic and therapeutic. To avoid unnecessary referrals, awareness of its typical clinical manifestations remains the mainstay for intervention. The most important issues to be considered during surgery is nonspreading endometriosis while manipulation.

 

 

 

 

 

Hum Reprod. 2016 Feb;31(2):473-81.

Genetic evidence that lower circulating FSH levels lengthen menstrual cycle, increase age at menopause and impact female reproductive health.

Ruth KS1Beaumont RN1Tyrrell J1Jones SE1Tuke MA1Yaghootkar H1Wood AR1Freathy RM1Weedon MN1Frayling TM1Murray A2.

 

Abstract

STUDY QUESTION:

How does a genetic variant in the FSHB promoter, known to alter FSH levels, impact female reproductive health?

SUMMARY ANSWER:

The T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) results in longer menstrual cycles and later menopause and, while having detrimental effects on fertility, is protective against endometriosis.

WHAT IS KNOWN ALREADY:

The FSHB promoter polymorphism (rs10835638; c.-211G>T) affects levels of FSHB transcription and, as a result, circulating levels of FSH. FSH is required for normal fertility and genetic variants at the FSHB locus are associated with age at menopause and polycystic ovary syndrome (PCOS).

STUDY DESIGN, SIZE, DURATION:

We used cross-sectional data from the UK Biobank to look at associations between the FSHB promoter polymorphism and reproductive traits, and performed a genome-wide association study (GWAS) for length of menstrual cycle.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

We included white British individuals aged 40-69 years in 2006-2010, in the May 2015 release of genetic data from UK Biobank. We tested the FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; c.-211G>T) for associations with 29, mainly female, reproductive phenotypes in up to 63 350 women and 56 608 men. We conducted a GWAS in 9534 individuals to identify genetic variants associated with length of menstrual cycle.

MAIN RESULTS AND THE ROLE OF CHANCE:

The FSH-lowering T allele of the FSHB promoter polymorphism (rs10835638; MAF 0.16) was associated with longer menstrual cycles [0.16 SD (c. 1 day) per minor allele; 95% confidence interval (CI) 0.12-0.20; P = 6 × 10(-16)], later age at menopause (0.13 years per minor allele; 95% CI 0.04-0.22; P = 5.7 × 10(-3)), greater female nulliparity [odds ratio (OR) = 1.06; 95% CI 1.02-1.11; P = 4.8 × 10(-3)] and lower risk of endometriosis (OR = 0.79; 95% CI 0.69-0.90; P = 4.1 × 10(-4)). The FSH-lowering T allele was not associated with other female reproductive illnesses or conditions in our study and we did not replicate associations with male infertility or PCOS. In the GWAS for menstrual cycle length, only variants near the FSHB gene reached genome-wide significance (P < 5 × 10(-9)).

LIMITATIONS, REASONS FOR CAUTION:

The data included might be affected by recall bias. Cycle length was not available for 25% of women still cycling (1% did not answer, 6% did not know and for 18% cycle length was recorded as ‘irregular’). Women with a cycle length recorded were aged over 40 and were approaching menopause; however, we did not find evidence that this affected the results. Many of the groups with illnesses had relatively small sample sizes and so the study may have been under-powered to detect an effect.

WIDER IMPLICATIONS OF THE FINDINGS:

We found a strong novel association between a genetic variant that lowers FSH levels and longer menstrual cycles, at a locus previously robustly associated with age at menopause. The variant was also associated with nulliparity and endometriosis risk. These findings should now be verified in a second independent group of patients. We conclude that lifetime differences in circulating levels of FSH between individuals can influence menstrual cycle length and a range of reproductive outcomes, including menopause timing, infertility, endometriosis and PCOS.

 

 

Reproduction. 2016 Apr;151(4):305-11.

Matrix metalloproteinases 2 and 9 and MMP9/NGAL complex activity in women with PCOS.

Ranjbaran JFarimani M1Tavilani HGhorbani M1Karimi JPoormonsefi F1Khodadadi I.

 

Abstract

It is believed that matrix metalloproteinases (MMPs) play important roles in follicular development and pathogenesis of polycystic ovary syndrome (PCOS). However, conflicting results are available about the alteration of MMP2 and MMP9 concentrations or activities in PCOS. In fact, there is no study entirely investigating both concentration and activity of these MMPs and serum levels of their tissue inhibitors TIMP2 and TIMP1, as well as lipocalin-bound form of MMP9 (MMP9/NGAL). Therefore, the thoroughness of previous studies is questionable. This study was conducted to determine circulatory concentration of MMP2, MMP9, MMP9/NGAL complex, TIMP1 and TIMP2 as well as gelatinase activities of MMP2, MMP9 and MMP9/NGAL complex in women with PCOS and controls. Mean age and BMI as well as serum levels of total cholesterol, triacylglycerol, HDL-C, LDL-C, fasting blood sugar (FBS), insulin, estradiol and sex hormone-binding globulin did not differ between groups, whereas a marked decrease in FSH and significant increases in LH, LH/FSH ratio, testosterone and free androgen index were observed. Women with PCOS and controls showed closed concentrations of MMP2, MMP9, MMP9/NGAL, TIMP1 and TIMP2. Gelatinase activity of MMP9 was found significantly higher in PCOS than in controls (64.53±15.32 vs 44.61±18.95 respectively) while patients and healthy subjects showed similar activities of MMP2 and MMP9/NGAL complex. Additionally, PCOS patients showed a higher MMP9/TIMP1 ratio compared with control women. Direct correlations were also observed between circulatory MMP9 level and the concentration and activity of MMP9/NGAL complex. In conclusion, based on the results of present study, we believe that MMP9 may be involved in the pathogenesis of PCOS.

 

 

Arch Gynecol Obstet. 2016 May;293(5):941-9.

Natural Killer T cell subsets in eutopic and ectopic endometrium: a fresh look to a busy corner.

Laganà AS1Triolo O2Salmeri FM3Granese R2Palmara VI2Ban Frangež H4Vrtčnik Bokal E4Sofo V3.

 

Abstract

PURPOSE:

Invariant Natural Killer T cells (iNKT) are a specialized subset of T cells that use their T cell receptor to recognize self and foreign lipids presented by CD1d as cognate antigens. iNKT have been shown to have either protective or harmful roles in many pathological states, including microbial infection, autoimmune disease, allergic disease and cancer. Accumulating evidence seems to suggest that this unique T cell subset combines both classically innate and adaptive immunologic characteristic. Considering these recent data, the aim of work was to review the current knowledge about iNKT in eutopic and ectopic endometrium.

METHODS:

Narrative overview, synthesizing the findings of literature retrieved from searches of computerized databases.

RESULTS:

Currently, the immune paradigm of reproduction is gradually changing shape: recent data confirmed that cytokine milieu influences the development and plasticity of different subtype of mononuclear cells, and in turn it can be influenced by the cytokine production of the latter. Among the different NKT cell populations, the recently characterized iNKT seems to share actions typical both of innate and adaptive immunity, being capable of secreting Th1 as well as Th2 cytokine pattern. Moreover, several subtypes of iNKT were identified, who partially express the same master transcription factors of the corresponding T cells counterpart.

CONCLUSIONS:

Although the data about iNKT’s actions in eutopic and ectopic endometrium are still scarce, it is possible to hypothesize that future investigation can shed light on this point, thus allowing a better knowledge about the regulation of these two microenvironments.

BMC Cancer. 2016 Jan 6;16:6.

Successful en bloc venous resection with reconstruction and subsequent radiotherapy for 2 consecutive recurrences of intravenous leiomyoma–a case report.

Zhang Y1,2Clark LH3Sheng X4Zhou C5,6.

 

Abstract

BACKGROUND:

Intravenous leiomyomas are a rare variant of uterine leiomyoma. Although histologically benign, these tumors are associated with a poor prognosis due to propensity for metastasis, high recurrence rate, difficulty of obtaining complete resection, and frequent extension into and along major veins.

CASE PRESENTATION:

We describe a 43-year-old patient initially presenting with lower abdominal pain. Clinical examination revealed a large right pelvic mass that was shown by computed tomography (CT) to surround the right external iliac vein, right common iliac vein and distal inferior vena cava. The patient had a history of total abdominal hysterectomy with bilateral ovarian cystectomies for uterine leiomyoma approximately 3 years prior to her presentation. Her past surgical history also included removal of an ovarian endometriosis cyst and right hydrosalpinx. The patient underwent an exploratory laparotomy. Operative findings included complete occlusion of the right iliac vessels and distal vena cava by a large tumor that filled the pelvis and extended to the level of the right kidney. The mass was resected en bloc with the involved veins and synthetic vascular grafts were placed. This highly technical procedure was complicated by hemorrhage requiring a total of 32 units of red blood cells and 2.0 L of plasma. Pathologic examination confirmed intravenous leiomyoma. On Immunohistochemical staining, the tumor cells were positive for CD32, CD34, Vimentin and smooth muscle actin. Eight months after this procedure, the patient again presented with an abdominal mass. She was diagnosed with a pelvic recurrence and noted to have intravascular extension into the left iliac vein and inferior vena cava. For this tumor she underwent radiation treatment with three-dimensional conformal radiation therapy (total dose 4500 cGy). The tumor gradually decreased in size during follow-up and became undetectable by CT.

CONCLUSIONS:

Surgical excision is the mainstay of treatment of intravenous leiomyoma. Radiation therapy may be an effective alternative in patients with unresectable disease or poor surgical candidates.

 

 

 

 

 

Hum Reprod Update. 2016 Apr;22(3).

Kinase signalling pathways in endometriosis: potential targets for non-hormonal therapeutics.

McKinnon BD1Kocbek V2Nirgianakis K2Bersinger NA2Mueller MD2.

 

Abstract

BACKGROUND:

Endometriosis, the growth of endometrial tissue outside the uterine cavity, is associated with chronic pelvic pain, subfertility and an increased risk of ovarian cancer. Current treatments include the surgical removal of the lesions or the induction of a hypoestrogenic state. However, a reappearance of the lesion after surgery is common and a hypoestrogenic state is less than optimal for women of reproductive age. Additional approaches are required. Endometriosis lesions exist in a unique microenvironment characterized by increased concentrations of hormones, inflammation, oxidative stress and iron. This environment influences cell survival through the binding of membrane receptors and a subsequent cascading activation of intracellular kinases that stimulate a cellular response. Many of these kinase signalling pathways are constitutively activated in endometriosis. These pathways are being investigated as therapeutic targets in other diseases and thus may also represent a target for endometriosis treatment.

METHODS:

To identify relevant English language studies published up to 2015 on kinase signalling pathways in endometriosis, we searched the Pubmed database using the following search terms in various combinations; ‘endometriosis’, ‘inflammation’, ‘oxidative stress’, ‘iron’, ‘kinase’, ‘NF kappa’, ‘mTOR’, ‘MAPK’ ‘p38’, ‘JNK’, ‘ERK’ ‘estrogen’ and progesterone’. Further citing references were identified using the Scopus database and finally current clinical trials were searched on the clinicaltrials.gov trial registry.

RESULTS:

The current literature on intracellular kinases activated by the endometriotic environment can be summarized into three main pathways that could be targeted for treatments: the canonical IKKβ/NFκB pathway, the MAPK pathways (ERK1/2, p38 and JNK) and the PI3K/AKT/mTOR pathway. A number of pharmaceutical compounds that target these pathways have been successfully trialled in in vitro and animal models of endometriosis, although they have not yet proceeded to clinical trials. The current generation of kinase inhibitors carry a potential for adverse side effects.

CONCLUSIONS:

Kinase signalling pathways represent viable targets for endometriosis treatment. At present, however, further improvements in clinical efficacy and the profile of adverse effects are required before these compounds can be useful for long-term endometriosis treatment. A better understanding of the molecular activity of these kinases, including the specific extracellular compounds that lead to their activation in endometriotic cells specifically should facilitate their improvement and could potentially lead to new, non-hormonal treatments of endometriosis.

 

 

Gynecol Obstet Invest. 2016;81(4):321-4.

Diagnostic Delay of Endometriosis in the Netherlands.

Staal AH1van der Zanden MNap AW.

 

Abstract

BACKGROUND/AIMS:

Endometriosis has a long diagnostic delay that is influenced by varying socio-economic and healthcare factors. In the Dutch situation, these factors are not yet identified. The aim of this study is to determine the length of the diagnostic delay of endometriosis in the Netherlands and to identify which variables affect this delay.

METHODS:

A retrospective study among 139 patients diagnosed with endometriosis in a secondary care hospital with a specialized multidisciplinary endometriosis team. The diagnostic process was evaluated using a questionnaire-guided telephonic interview.

RESULTS:

The median time interval from the onset of symptoms to diagnosis was 89 months or 7.4 years, divided in 7 months patient delay, 35 months general practitioner (GP) delay and 5 months gynecologist delay. Determinants for a longer diagnostic delay were young age at onset of symptoms, use of oral contraceptives or analgesics prescribed by GP, alternative diagnoses considered by the GP, and cyclic symptoms. Subfertility as presenting symptom resulted in faster diagnosis.

CONCLUSION:

This study shows that the time interval to the diagnosis of endometriosis is long and mainly consists of the period of time the woman consults her first line medical professional.

 

 

Rom J Morphol Embryol. 2015;56(4):1301-7.

The assessment of immunohistochemical profile of endometriosis implants, a practical method to appreciate the aggressiveness and recurrence risk of endometriosis.

Brătilă E1Brătilă CPComandaşu DEBauşic VVlădescu CTMehedinţu CBerceanu CCîrstoiu MMMitroi GStănculescu R.

 

Abstract

Endometriosis represents a chronic female genital tract disease characterized by implants outside the endometrial cavity, leading to alteration of pelvic anatomy and having as result chronic pelvic pain and infertility.

AIM:

From the molecular perspective, the aim of studying endometriosis is identifying a cause and a consequence, that lead to the appearance and perpetual arising of new implants. The description of the immunohistochemical (IHC) profile of ectopic endometrium could represent a new element in the pathogenesis of endometriosis and also a practical method to appreciate the aggressiveness and possibility of recurrence of the disease. The study consisting of histopathological and immunohistochemical (IHC) analysis of the tissues excised included 14 patients, operated from June to December 2014, to which was confirmed the presumptive diagnosis of endometriosis, based on anamnesis, clinical examination and ultrasound appearance. We identified the expression of estrogen and progesterone receptors, whose presence in the ectopic endometrium guides the medical hormone postoperative treatment. We also identified the expression of a cellular proliferation marker – Ki-67, and inhibition marker of cellular apoptosis – Bcl-2, in order to characterize the aggressiveness of endometriosisimplantations and a stromal marker CD10. Although there are plenty of medical and surgical therapeutic methods available, the treatment of endometriosis must be individualized for every patient taking into consideration the IHC analysis. Consolidation of surgical treatment by prescription of a medical long-term treatment is indispensable, because endometriosis is a chronic relapsing disease.

 

 

Rom J Morphol Embryol. 2015;56(4):1357-63.

Different patterns of heterogeneity in ovarian carcinoma.

Stănescu AD1Pleş LEdu AOlaru GOComănescu ACPotecă AGComănescu MV.

 

Abstract

Ovarian cancer is still the leading cause of death from malignant genital tract lesions. Ovarian carcinomas represent about 90% of cancers that arise in the ovaries and are commonly diagnosed around menopausal age. This study examines different aspects of the heterogeneity of ovarian carcinomas and included 50 cases, 10 cases for each subtype. Our data showed that tumor types have distinct morphological and phenotypic patterns: high- and low-grade serous carcinoma, endometrioid, clear cell and mucinous carcinoma. The different subtypes of ovarian carcinomas have different molecular, pathological and clinical characteristics, the histological diversity of epithelial ovarian carcinoma mirroring thus distinct entities not just one disease.

 

 

Acta Neurochir (Wien). 2016 Mar;158(3):507-12

Sequential imaging of intraneural sciatic nerve endometriosis provides insight into symptoms of cyclical sciatica.

Capek S1,2Amrami KK3Howe BM4Collins MS5Sandroni P6Cheville JC7Spinner RJ8.

 

Abstract

Endometriosis of the nerve often remains an elusive diagnosis. We report the first case of intraneural lumbosacral plexus endometriosis with sequential imaging at different phases of the menstrual cycle: during the luteal phase and menstruation. Compared to the first examination, the examination performed during the patient’s period revealed the lumbosacral plexus larger and hyperintense on T2-weighted imaging. The intraneural endometriosiscyst was also larger and showed recent hemorrhage. Additionally, this case represents another example of perineural spread of endometriosis from the uterus to the lumbosacral plexus along the autonomic nerves and then distally to the sciatic nerve and proximally to the spinal nerves.

 

 

Ann Clin Biochem. 2016 Sep;53(Pt 5):599-605.

The plasma and peritoneal fluid concentrations of matrix metalloproteinase-9 are elevated in patients with endometriosis.

Liu H1Wang J1Wang H1Tang N1Li Y1Zhang Y1Hao T2.

 

Abstract

BACKGROUND:

Enzyme matrix metalloproteinase-9 is a member of the matrix metalloproteinase family, which is critical to normal tissue remodelling during embryogenesis and wound healing. In patients with endometriosis, increased expression and activity of matrix metalloproteinase-9 have been observed in ectopic endometrium, but the plasma and peritoneal fluid concentrations of matrix metalloproteinase-9 in patients with endometriosis and their relation to disease severity have not been clear. The aim of the study was to investigate the concentrations of matrix metalloproteinase-9 in plasma and peritoneal fluid of patients with endometriosis.

METHODS:

A prospective case-control study was conducted in Jinan Military General Hospital between January 2010 and December 2013. Fifty patients with proven endometriosis and 26 endometriosis-free controls were enrolled in this study. Patients with endometriosis were evaluated and divided into moderate/severe endometriosisgroup (stage I-II, n = 26) and minimal/mild endometriosis group (stage III-IV, n = 24) according to the revised criteria of the American Society for Reproductive Medicine. Blood samples and peritoneal fluid were obtained from both patients and controls. Matrix metalloproteinase-9 was measured using enzyme-linked immunosorbent assay in plasma and peritoneal fluid. The concentration of matrix metalloproteinase-9 between different groups was compared and its correlation to disease severity was analysed.

RESULTS:

Plasma and peritoneal fluid concentrations of matrix metalloproteinase-9 in patients with endometriosiswere higher than that in controls. In addition, those patients with moderate/severe endometriosis had significantly higher plasma and peritoneal fluid concentrations of matrix metalloproteinase-9 compared to those with minimal/mild endometriosis. Matrix metalloproteinase-9 concentrations in plasma and peritoneal fluid were both positively correlated with severity of endometriosis and plasma matrix metalloproteinase-9 concentrations had a positive correlation with peritoneal fluid matrix metalloproteinase-9 concentrations in patients with endometriosis.

CONCLUSIONS:

Increased concentrations of plasma and peritoneal fluid concentrations of matrix metalloproteinase-9 appear to be associated with disease severity of endometriosis and may serve as an alternative biomarker to determine disease severity of endometriosis.

 

 

Fertil Steril. 2016 Apr;105(4):978-987.

Endometriosis-related infertility: assisted reproductive technology has no adverse impact on pain or quality-of-life scores.

Santulli P1Bourdon M2Presse M2Gayet V2Marcellin L3Prunet C4de Ziegler D2Chapron C5.

 

Abstract

OBJECTIVE:

To evaluate the impact of assisted reproduction technology (ART) on painful symptoms and quality of life (QoL) in women who have endometriosis as compared with disease-free women.

DESIGN:

Prospective controlled, observational cohort study.

SETTING:

University hospital.

PATIENT(S):

Two hundred and sixty-four matched-pairs of endometriosis and disease-free women undergoing ART.

INTERVENTION(S):

Assessment of pain evolution using visual analogue scale (VAS) during ART; QoL assessment with the Fertility Quality of Life (FertiQoL) tool.

MAIN OUTCOME MEASURE(S):

VAS pain intensities relative to dysmenorrhea, dyspareunia, noncyclic chronic pelvic pain (NCCPP), gastrointestinal pain, lower urinary tract pain; trends for VAS change between postretrieval and baseline evaluation; FertiQoL score; and statistical analyses conducted using univariate and adjusted multiple linear regression models.

RESULT(S):

After excluding canceled cycles and patients lost to follow-up observation, 102 women with endometriosis and 104 disease-free women were retained for the study. The trends for VAS change between the postretrieval and baseline evaluations in the women with endometriosis compared with the disease-free women revealed a statistically significant pain decrease for dysmenorrhea (-1.35 ± 3.23 and 0.61 ± 4.00) and dyspareunia (-1.19 ± 2.58 and 0.14 ± 2.06). For NCCPP, gastrointestinal symptoms, and lower urinary tract symptoms, there were no statistically significant differences between the groups. After multiple linear regression, no worsening of pain was observed in the endometriosis group as compared with disease-free group. In addition subgroup analysis according to endometriosis phenotype failed to show any increase of pain. The quality of life in the endometriosis group was comparable to that of the disease-free group.

CONCLUSION(S):

Assisted reproduction technology did not exacerbate the symptoms of endometriosis or negatively impact QoL in women with endometriosis as compared with disease-free women.

 

 

Clin Chim Acta. 2016 Apr 1;455:33-8.

Role of vitamin D in female reproduction.

Shahrokhi SZ1Ghaffari F2Kazerouni F3.

 

Abstract

Vitamin D is a fat-soluble vitamin that belongs to the family of steroid hormones. The biological actions of vitamin D are exerted through a soluble protein, the vitamin D receptor (VDR). VDR is a transcription factor located in the nuclei of target cells that mediates the genomic action of the active form of vitamin D (1,25(OH)2D3). This transcription factor is distributed in various tissues, including the reproductive system. The presence of VDR in female reproductive tissue suggests that vitamin D is involved in female reproduction. The present article reviews the impact of vitamin D on anti-Müllerian hormone (AMH), as an ovarian reserve marker, and ovarian steroidogenesis. This article also discusses the impact of vitamin D as a factor that influences infertility and the outcome of in vitro fertilization (IVF), insulin resistance (IR), hyperandrogenism, endometriosis and polycystic ovary syndrome (PCOS).

 

 

Acta Med Iran. 2015 Dec;53(12):793-5.

Scar Endometriosis: a Case Report with Literature Review.

Gupta P1Gupta S1.

 

Abstract

Endometriosis is defined as the presence of functioning endometrial tissue outside the uterine cavity. Endometriosis can sometimes occur in a previous surgical scar. Scar endometriosis is rare and difficult to diagnose. It mostly follows obstetrical and gynecological surgeries. This condition is often confused with other surgical conditions. We are reporting one case of scar endometriosis involving rectus sheath following cesarean section. The patient required wide surgical excision of the lesion. The pathogenesis, diagnosis, and treatment of this rare condition are being discussed.

 

 

Clin Exp Obstet Gynecol. 2015;42(6):771-5.

Expression and significance of CD133 and ABCG2 in endometriosis.

Liu SZhou JWen J.

 

Abstract

BACKGROUND:

Endometriosis is a common gynecological disease and exact pathogenesis is still unclear. Recently, an increasing interest has been given to the potential role of stem cells in the development of endometriosis. The aim of this study was to test the expression of sterness-related markers CD133 and ABCG2 in endometriosis.

MATERIALS AND METHODS:

CD133 and ABCG2 protein expression in eutopic and ectopic endometrial tissue with endometriosis and endometrium tissue without endometriosis were examined by Western blot.

RESULTS:

Eutopic endometrium showed high level of CD133 and ABCG2 protein when compared with ectopic endometrium (p = 0.042, p = 0.038) and control endometrium (p = 0.000, p = 0.000). The expression of CD133 protein in ectopic endometrium was positively correlated with R-AFS score of endometriosis (p = 0.000, r = 0.793) and no significant relation was noted between ABCG2 and R-AFS score (p = 0.563). Two of three patients with recurrence had much higher expression of ABCG2 protein than the patients without recurrence.

CONCLUSION:

Aberrant expression of CD133 and ABCG2 in eutopic and ectopic endometrial tissue with endometriosis suggests that they are probably associated with the pathogenesis of endometriosis and stem cells play a possible role in its development.

 

 

Clin Exp Obstet Gynecol. 2015;42(6):785-6.

Prevalence of endometriosis at a university hospital in Jeddah, Saudi Arabia.

Rouzi AASahly NKafy SSawan DAbduljabbar H.

 

Abstract

PURPOSE:

To determine the prevalence of endometriosis in women who had gynecologic laparoscopy at a university hospital in Saudi Arabia.

MATERIALS AND METHODS:

The hospital records were reviewed to identify all women who had undergone gynecological laparoscopy between January 2008 and December 2013.

RESULTS:

A total of 190 gynecologic laparoscopies were performed. The indications for laparoscopy were infertility (n = 76; 40%), chronic pelvic pain (n = 34; 17.9%), infertility and chronic pelvic pain (n = 7; 3.7%), ectopic pregnancy (n = 30; 15.8%), pelvic mass (n = 12; 6.3%), removal of a missing intrauterine contraceptive device (n = 6; 3.2%); other indications were documented in 25 cases (13.1%). Endometriosis was diagnosed in 21 women (11.1%). The presenting complaints in women with endometriosis were pelvic pain (n = 7; 33.3%), infertility (n = 5; 23.8%), pelvic pain and infertility (n = 6; 28.6%), and pelvic mass (n = 2; 9.5%); the complaint was unknown in one patient (4.8%).

CONCLUSION:

Endometriosis was uncommon in women who had undergone gynecologic laparoscopy.

 

 

Clin Exp Obstet Gynecol. 2015;42(6):810-1

A novel case of an adenomyosis-related uterine rupture in pregnancy.

Indraccolo UIannicco AMicucci G.

 

Abstract

To date, few cases of uterine rupture related to adenomyosis have been reported. The current case report briefly describes a novel case of an adenomyosis related uterine rupture, while focusing on few symptoms that this kind of uterine rupture may have. Due to increasing rate of adenomyosis in Western countries, practicing obstetricians should carefully take in account silent uterine rupture related to adenomyosis.

 

 

J Ovarian Res. 2016 Jan 12;9:1.

Clear cell carcinoma arising in previous episiotomy scar: a case report and review of the literature.

Han L1Zheng A2Wang H3.

 

Abstract

BACKGROUND:

Malignant transformation of endometriosis associated with episiotomy scar is a rare event, especially histological type of clear cell adenocarcinoma. There are only three clear cell carcinoma in episiotomy scar reported, no standard treatment established.

CASE PRESENTATION:

A 36-year-old woman presented with a two-month history of painless but puritic perineal lump which she noticed was gradually enlarging. She had undergone surgical excision of a mass in the episiotomy scar 9 year ago and resequently histological type of endometriosis. Physical examination revealed a 10 × 5 cm soft, purple scar which is closely related to the apex of the episiotomy.We underwent a local excision of the mass for a biopsy . The second surgery performed after one cycle of paclitaxel and cisplatin (TP) to permit clearance of tumor while preserving normal vaginal function.Pathological result was clear cell adenocarcinoma. Two cycles of TP adjuvant chemotherapy were administrated after surgery.

CONCLUSIONS:

We report a case of primary clear cell carcinoma developing within a previous episiotomy scar in a patient with a history of endometriosis, along with a review of the literature. Accumulation of management data on these rare tumors and Long-term follow-up of such patients is therefore important.

 

 

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