Mol Med Rep. 2018 Mar 29. doi: 10.3892/mmr.2018.8823. [Epub ahead of print] Zearalenone regulates endometrial stromal…
Int J Gynecol Pathol. 2015 Nov;34(6):570-5.
Endometrial Synovial-like Metaplasia Associated With Levonorgestrel-releasing Intrauterine System.
The levonorgestrel-releasing intrauterine system (L-IUS) is widely used in contraception and in the treatment of menorrhagia, dysmenorrhea, adenomyosis, and endometriosis. L-IUS is also increasingly considered in the management of endometrial neoplasia and its precursors. Histologic changes in the endometrium can be due to the effects of high-dose progestogen or may be caused by the local irritant or mechanical effects of an intrauterine foreign body. In the present study, we describe a novel endometrial alteration associated with L-IUS that most closely resembles synovial metaplasia reported at other extra-articular anatomic sites. Eleven cases were identified with a mean age of 49.6 yr. In most patients L-IUS was used for management of menorrhagia or endometrial hyperplasia. Endometrial synovial-like metaplasia was always a focal finding and was associated with areas of surface epithelial erosion. The synovial-like cells showed a distinctive palisaded arrangement with orientation perpendicular to the endometrial surface. Multinucleate cells were present in 2 cases, but granulomas were not identified. The synovial-like cells were vimentin immunoreactive and a variable proportion of cells expressed CD68. Only focal CD10 staining was seen and there was no expression of estrogen receptor, progesterone receptor, or cytokeratin. In summary, L-IUS may be associated with a distinctive synovial-like metaplastic alteration which most likely represents a stromal reaction to an intrauterine foreign body following endometrial surface erosion. The synovial-like cells appear to comprise histiocytes and modified fibroblasts or stromal cells similar to this process in other sites.
Int J Gynecol Cancer. 2015 Nov;25(9):1633-8.
Endometriosis-Associated Abdominal Wall Cancer: A Poor Prognosis?
Endometriosis-associated abdominal wall cancer (EAAWC) is rare, and few reports are available. This article provides a review of reports in the literature on the pathology, diagnosis, management, and outcome of patients with EAAWC.
We performed a review of existing reports in the English language literature on cancer arising from abdominal wall endometriosis. MEDLINE and EMBASE searches were conducted for articles published from September 1986 to August 2014 using combinations of medical subject heading terms.
We identified 26 articles reporting on EAAWC and added 1 patient who was treated at our institution. In all of these patients, EAAWC was described after uterine surgery (mostly cesarean section). The delay between the first surgery and the diagnosis of malignant disease was more than 20 years. Clear cell carcinoma was the most common histology, followed by endometrioid carcinoma. Death was described in 44% of women within a few months of diagnosis.
Endometriosis-associated abdominal wall cancer is rare and aggressive. It seems to be associated with cesarean section, and it shows poor prognosis. The mainstay of treatment remains extensive surgery and chemotherapy.
Reprod Sci. 2016 May;23(5):604-9
Expression Levels of the Oxidative Stress Response Gene ALDH3A2 in Granulosa-Lutein Cells Are Related to Female Age and Infertility Diagnosis.
Oxidative stress (OS) plays an important role in all physiological processes. The effect of OS on cellular processes is modulated by the ability of the cell to express genes implicated in the reversal of lipid, protein, and DNA injury. Aldehyde dehydrogenase 3, member A2 (ALDH3A2) is a ubiquitous enzyme involved in lipid detoxification. The objective of this study was to investigate the expression ofALDH3A2in human granulosa-lutein (GL) cells of women undergoing in vitro fertilization (IVF) and its relationship with age, infertility diagnosis, and IVF outcome variables. Relative expression levels ofALDH3A2were determined by quantitative reverse transcription-polymerase chain reaction. To investigate the effect of age onALDH3A2expression, 72 women between 18 and 44 years of age with no ovarian factor (NOF) were analyzed. To evaluate the effect of infertility diagnosis onALDH3A2expression, the following groups were analyzed: 22 oocyte donors (ODs), 24 women >40 years old (yo) with tubal or male factor and no ovarian pathology, 18 poor responders (PRs), 19 cases with endometriosis(EM), and 18 patients with polycystic ovarian syndrome (PCOS). In NOF,ALDH3A2expression correlated positively with age and with the doses of follicle-stimulating hormone and luteinizing hormone administered and negatively with the number of total and mature oocytes. When different groups were analyzed,ALDH3A2expression levels were higher in patients >40 yo and in PR compared to OD. On the contrary, EM and PCOS levels were lower than expected for age. These data suggest that GL cellALDH3A2expression levels correlate with age, cause of infertility, and ovarian response to stimulation.
Hum Reprod Update. 2016 Jan-Feb;22(1):70-103.
A systematic review on endometriosis during pregnancy: diagnosis, misdiagnosis, complications and outcomes.
Traditionally, pregnancy was considered to have a positive effect on endometriosis and its painful symptoms due not only to blockage of ovulation preventing bleeding of endometriotic tissue but also to different metabolic, hormonal, immune and angiogenesis changes related to pregnancy. However, a growing literature is emerging on the role of endometriosis in affecting the development of pregnancy and its outcomes and also on the impact of pregnancy on endometriosis. The present article aims to underline the difficulty in diagnosing endometriotic lesions during pregnancy and discuss the options for the treatment of decidualized endometriosis in relation to imaging and symptomatology; to describe all the possible acute complications of pregnancy caused by pre-existing endometriosis and evaluate potential treatments of these complications; to assess whether endometriosis affects pregnancy outcome and hypothesize mechanisms to explain the underlying relationships.
This systematic review is based on material searched and obtained via Pubmed and Medline between January 1950 and March 2015. Peer-reviewed, English-language journal articles examining the impact of endometriosis on pregnancy and vice versa were included in this article.
Changes of the endometriotic lesions may occur during pregnancy caused by the modifications of the hormonal milieu, posing a clinical dilemma due to their atypical appearance. The management of these events is actually challenging as only few cases have been described and the review of available literature evidenced a lack of formal estimates of their incidence. Acute complications of endometriosis during pregnancy, such as spontaneous hemoperitoneum, bowel and ovarian complications, represent rare but life-threatening conditions that require, in most of the cases, surgical operations to be managed. Due to the unpredictability of these complications, no specific recommendation for additional interventions to the routinely monitoring of pregnancy of women with known history of endometriosis is advisable. Even if the results of the published studies are controversial, some evidence is suggestive of an association of endometriosis with spontaneous miscarriage, preterm birth and small for gestational age babies. A correlation of endometriosis with placenta previa (odds ratio from 1.67 to 15.1 according to various studies) has been demonstrated, possibly linked to the abnormal frequency and amplitude of uterine contractions observed in women affected. Finally, there is no evidence that prophylactic surgery would prevent the negative impact of endometriosis itself on pregnancy outcome.
Complications of endometriosis during pregnancy are rare and there is no evidence that the disease has a major detrimental effect on pregnancy outcome. Therefore, pregnant women with endometriosiscan be reassured on the course of their pregnancies although the physicians should be aware of the potential increased risk of placenta previa. Current evidence does not support any modification of conventional monitoring of pregnancy in patients with endometriosis.
Biol Res. 2015 Oct 9;48:56.
Differential expression of upstream stimulatory factor (USF) 2 variants in eutopic endometria from women with endometriosis: estradiol regulation.
Endometriosis, pro-inflammatory and invasive benign disease estrogen dependent, abnormally express in endometria the enzyme P450Arom, positively regulated by steroid factor-1 (SF-1). Our objective was to study the nuclear protein contents of upstream stimulating factor 2 (USF2a and USF2b), a positive regulator of SF-1, throughout the menstrual cycle in eutopic endometria from women with and without (control) endometriosisand the involvement of nuclear estrogen receptors (ER) and G-coupled protein estrogen receptor (GPER)-1.
Upstream stimulating factor 2 protein contents were higher in mid (USF2b) and late (USF2a and USF2b) secretory phase in eutopic endometria from endometriosis than control (p < 0.05). In isolated control epithelial cells incubated with E2 and PGE2, to resemble the endometriosis condition, the data showed: (a) significant increase of USF2a and USF2b nuclear protein contents when treated with E2, PPT (specific agonist for ERα) or G1 (specific agonist for GPER1); (b) no increase in USF2 binding to SF-1 E-Box/DNA consensus sequence in E2-treated cells; (c) USF2 variants protein contents were not modified by PGE2; (d) SF-1 nuclear protein content was significantly higher than basal when treated with PGE2, E2 or G1, stimulation unaffected by ICI (nuclear ER antagonist); and (e) increased (p < 0.05) cytosolic protein contents of P450Arom when treated with PGE2, E2, PPT or G1 compared to basal, effect that was additive with E2 + PGE2 together. Nevertheless, in endometriosis cells, the high USF2, SF-1 and P450Arom protein contents in basal condition were unmodified.
These data strongly suggest that USF2 variants and P450Arom are regulated by E2 through ERα and GPER1, whereas SF-1 through GPER1, visualized by the response of the cells obtained from control endometria, being unaffected the endogenously stimulated cells from endometriosis origin. The lack of E2 stimulation on USF2/SF-1 E-Box/DNA-sequence binding and the absence of PGE2 effect on USF2 variants opposite to the strong induction that they exert on SF1 and P450 proteins suggest different mechanisms and indirect regulations. The sustained USF2 variants protein expression during the secretory phase in eutopic endometria from women with endometriosis may participate in the pathophysiology of this disease strongly associated with infertility and its characteristic endometrial invasion to ectopic sites in the pelvic cavity.
J Minim Invasive Gynecol. 2016 Feb 1;23(2):198-205
Laparoscopic En Bloc Right Diaphragmatic Peritonectomy for Diaphragmatic Endometriosis According to the Sugarbaker Technique.
To evaluate the feasibility of a novel laparoscopic procedure for complete eradication of diaphragmatic endometriosis (DE).
A retrospective multicenter study (Canadian Task Force Classification II-2).
University tertiary referral centre.
A consecutive series of 9 women with DE.
Laparoscopic en bloc eradication using Sugarbaker’s peritonectomy technique with or without diaphragmatic resection for DE. All surgical procedures were performed by the same surgeon in 2 tertiary referral centers (Charitè University, Berlin, Germany, and Catholic University of the Sacred Heart, Foundation John Paul II, Campobasso, Italy).
MEASUREMENTS AND MAIN RESULTS:
Rate of conversion to laparotomy, perioperative outcomes, intra- and postoperative complications, and recurrence rate. The procedures were successfully performed in all patients laparoscopically without conversion to laparotomy. All patients also presented with multiple endometriotic lesions in the Morison pouch, and in 3 cases a deep infiltration of the right diaphragm was observed that required partial diaphragmatic resection. In 2 women, pulmonary nodules were also detected, and lung laparoscopic resection was attempted to eradicate the disease. A chest drain was placed in 7 women and was removed after a median time of 6 days (range, 4-10 days). No intra- or postoperative complications were recorded. To complete the diaphragmatic peritonectomy, the median operative time required was 180 minutes (range, 90-240 minutes). The median estimated blood loss was 100 mL (range, 50-300 mL), and the median hospital stay was 10 days (range, 5-17 days). After a median follow-up of 6 months, we observed symptomatic relief for all study patients without major surgery-related morbidity. In 1 woman, laparoscopic adhesiolysis was performed after 18 months from surgery without signs of recurrent endometriosis.
Laparoscopic en bloc eradication of DE with Sugarbaker’s peritonectomy is highly effective in the management of symptomatic DE, with no major intra-/postoperative complications and very favorable perioperative outcomes.
J Minim Invasive Gynecol. 2016 May-Jun;23(4):512-25.
Feasibility and Safety of Laparoscopic-Assisted Bowel Segmental Resection for Deep Infiltrating Endometriosis: A Retrospective Cohort Study With Description of Technique.
To evaluate the feasibility and safety of laparoscopic segmental bowel resection for deep infiltrating endometriosis (DIE).
Retrospective clinical study (Canadian Task Force classification II-3).
Endoscopica Malzoni-Center for Advanced Endoscopic Gynecological Surgery, Avellino, Italy.
A retrospective cohort of 248 patients who underwent laparoscopic segmental bowel resection between January 1, 2011, and December 31, 2014.
Laparoscopic segmental bowel resection for DIE.
MEASUREMENTS AND MAIN RESULTS:
Bowel endometriosis was histologically confirmed in all 248 of the 248 patients (100%). The mean length of the resected specimens was 11.83 ± 4.56 cm. In all cases, margins were free of disease. The muscular layer was infiltrated up to the submucosal layer in all 248 patients (100%), whereas the mucosal layer showed signs of infiltration in only 4 patients (1.6%). Two nodules were found in 36 patients (14.5%), and 3 nodules were found in only 8 patients (3.2%). None of the resected bowel segments had nodules shorter than 3 cm, and the majority of lesions had a longitudinal diameter of 3 to 7 cm. In the majority of cases, resected segments involved the mid to low rectum (distance from the lower margin of resected segment from the anal verge of 4 to 12 cm), whereas in 6% of cases, ultra-low resections (≤4 cm) were performed. No intraoperative complications occurred, and conversion to laparotomy was not required for any patient. Major perioperative and early and late postoperative complications occurred in 20 patients (8.06%). Significantly reduced pain associated with disease was observed up to the 1-year follow-up irrespective of postoperative hormonal treatment. Pelvic relapse was found in up to 50% of patients, especially in patients without hormonal suppression, but only in the form of endometriomas or adherences, with no recurrent deep lesions observed.
This large single-center series demonstrates that laparoscopic bowel resection for DIE is a feasible technique, with low complication rates. In symptomatic patients, treating deep fibrotic endometriosisnodules by laparoscopic segmental resection is very effective in reducing pain and restoring bowel function. This surgical approach is safe but complex, requiring specific skills in laparoscopic urologic and colorectal procedures, and should be performed only in specialized high-volume centers by high-volume surgeons.
J Pathol. 2016 Jan;238(2):185-96.
Models of endometriosis and their utility in studying progression to ovarian clear cell carcinoma.
Endometriosis is a common benign gynaecological condition affecting at least 10% of women of childbearing age and is characterized by pain–frequently debilitating. Although the exact prevalence is unknown, the economic burden is substantial (∼$50 billion a year in the USA alone) and it is associated with considerable morbidity. The development of endometriosis is inextricably linked to the process of menstruation and thus the models that best recapitulate the human disease are in menstruating non-human primates. However, the use of these animals is ethically challenging and very expensive. A variety of models in laboratory animals have been developed and the most recent are based on generating menstrual-like endometrial tissue that can be transferred to a recipient animal. These models are genetically manipulable and facilitate precise mechanistic studies. In addition, these models can be used to study malignant transformation in epithelial ovarian carcinoma. Epidemiological and molecular evidence indicates that endometriosis is the most plausible precursor of both clear cell and endometrioid ovarian cancer (OCCA and OEA, respectively). While this progression is rare, understanding the underlying mechanisms of transformation may offer new strategies for prevention and therapy. Our ability to pursue this is highly dependent on improved animal models but the current transgenic models, which genetically modify the ovarian surface epithelium and oviduct, are poor models of ectopic endometrial tissue. In this review we describe the various models of endometriosis and discuss how they may be applicable to developing our mechanistic understanding of OCCA and OEA.
Fertil Steril. 2016 Jan;105(1):106-10
Chronic endometritis in women with recurrent pregnancy loss and recurrent implantation failure: prevalence and role of office hysteroscopy and immunohistochemistry in diagnosis.
To determine the prevalence of chronic endometritis (CE) in patients with recurrent implantation failure (RIF) after IVF and unexplained recurrent pregnancy loss (RPL).
Prospective observational study between November 2012 and March 2015.
University-affiliated private IVF clinic.
Women with RIF after IVF (group 1) and unexplained RPL (group 2).
Office hysteroscopy followed by an endometrial biopsy was performed as part of the workup for RIF and RPL. The diagnosis of CE was histologically confirmed using immunohistochemistry stains for syndecan-1 (CD138).
MAIN OUTCOME MEASURE(S):
The prevalence of CE in each group and the sensitivity/specificity of office hysteroscopy in the diagnosis of CE.
Ninety-nine patients were included (46 in group 1 and 53 in group 2). The mean age was 36.3 ± 4.9 years in group 1 and 34.5 ± 4.9 years in group 2. Five biopsies were uninterpretable (three in group 1 and two in group 2) because of insufficient specimen. The prevalence of CE was 14% (6/43) in group 1 and 27% (14/51) in group 2. The sensitivity and specificity of office hysteroscopy in the diagnosis of CE were 40% (8/20) and 80% (59/74), respectively.
We found a high prevalence of immunohistochemically confirmed CE in women with RIF and RPL. Office hysteroscopy is a useful diagnostic tool but should be complemented by an endometrial biopsy for the diagnosis of CE.
J Pain. 2016 Jan;17(1):1-13.
Functional Connectivity is Associated With Altered Brain Chemistry in Women With Endometriosis-Associated Chronic Pelvic Pain.
In contrast to women with relatively asymptomatic endometriosis, women with endometriosis-associated chronic pelvic pain (CPP) exhibit nonpelvic hyperalgesia and decreased gray matter volume in key neural pain processing regions. Although these findings suggest central pain amplification in endometriosis-associated CPP, the underlying changes in brain chemistry and function associated with central pain amplification remain unknown. We performed proton spectroscopy and seed-based resting functional connectivity magnetic resonance imaging to determine whether women with endometriosis display differences in insula excitatory neurotransmitter concentrations or intrinsic brain connectivity to other pain-related brain regions. Relative to age-matched pain-free controls, women with endometriosis-associated CPP displayed increased levels of combined glutamine-glutamate (Glx) within the anterior insula and greater anterior insula connectivity to the medial prefrontal cortex (mPFC). Increased connectivity between these regions was positively correlated with anterior insula Glx concentrations (r = .87), as well as clinical anxiety (r = .61, P = .02), depression (r = .60, P = .03), and pain intensity (r = .55, P = .05). There were no significant differences in insula metabolite levels or resting-state connectivity in endometriosis patients without CPP versus controls. We conclude that enhanced anterior insula glutamatergic neurotransmission and connectivity with the mPFC, key regions of the salience and default mode networks, may play a role in the pathophysiology of CPP independent of the presence of endometriosis.
Similar to other chronic pain conditions, endometriosis-associated pelvic pain is associated with altered brain chemistry and function in pain processing regions. These findings support central pain amplification as a mechanism of chronic pelvic pain, and clinicians should consider the use of adjunctive therapies that target central pain dysfunction in these women.
Turk Patoloji Derg. 2015;31(3):226-9.
Müllerianosis with Intestinal Metaplasia: A Case Report.
Müllerianosis or Müllerian choristomas are developmental alterations that consist of an organoid structure with normal Müllerian tissue. We present a 62-year-old patient diagnosed on ultrasound scanning and on CT scan of bilateral ovarian cysts. During surgery, a left ovarian cyst and retroperitoneal tumor (adhered to sigmoid serous surface) were found. On histological examination, the tumor corresponded with a Müllerian choristoma showing endometrial, endosalpingeal and endocervical epithelium, with foci of intestinal metaplasia, a phenomenon not described in the literature.
Case Rep Obstet Gynecol. 2015;2015:123740
Transformation of Abdominal Wall Endometriosis to Clear Cell Carcinoma.
Clear cell carcinoma is the least common of the malignant transformations reported in nonpelvic sites of endometriosis. Two cases with clear cell carcinoma transformation arising from endometriosis in abdominal wall scars are presented. These patients underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy, pelvic washings, and abdominal wall lesion resection. The first case had initial treatment with chemotherapy, while chemotherapy and radiation therapy were given for the second case. A recurrence was noted for the chemotherapy only case for, which she was subsequently given radiation, with further resolution of the lesion.
Int J Oncol. 2015 Dec;47(6):2037-44.
Loss of autophagy-related protein Beclin 1 may define poor prognosis in ovarian clear cell carcinomas.
The aim of the present study was to clarify the role of autophagy in cisplatin (CDDP) sensitivity in OCCCs and the role of Beclin 1 in OCCC progression. Autophagy was measured using: i) western blot analysis of LC3 and p62 and ii) microscopic observation of GFP-LC3 puncta. Autophagy was suppressed using chloroquine and Beclin 1 siRNA. Surgical specimens were examined for Beclin 1 protein expression by immunohistochemistry. The correlations between the loss of Beclin 1 expression and clinicopathological characteristics, prognosis and chemosensitivity were investigated. Inhibition of autophagy by chloroquine or Beclin 1 siRNA did not enhance the sensitivity of the ES2 and TOV-21G OCCC cell lines to CDDP. Loss of Beclin 1 expression was observed in 38.3% (23/60) of the analyzed tumors. There was no significant correlation between loss of Beclin 1 expression and FIGO stage, CA125 levels, patient age, status of endometriosis, Ki-67 labeling index, chemotherapy regimen or status of residual tumor. However, negative expression of Beclin 1 was associated with a shorter progression-free survival in comparison to positive Beclin 1 expression in OCCC who received cytoreductive surgery, followed by a standard platinum-based chemotherapy regimen (P=0.027, log-rank test). Beclin 1-negative tumors were no more resistant to primary adjuvant chemotherapy than were Beclin 1-positive tumors (50.0 vs. 66.7%, P=0.937). Beclin 1 knockdown using siRNA increased cell growth but not cell migration and invasion in ES2 and TOV-21G OCCC cell lines. Autophagy defects caused by loss of Beclin 1 are not related to chemoresistance and metastasis, but may be associated with malignant phenotype and poor prognosis of OCCC.
Iran Biomed J. 2016;20(1):12-7.
in vitro Anti-Proliferative Effect of Adiponectin on Human Endometriotic Stromal Cells through AdipoR1 and AdipoR2 Gene Receptor Expression.
Endometriosis is a complex disorder in reproductive age women which consist of stromal and epithelial cells implantation outside the uterine cavity. Adiponectin is a member of cytokine family with various metabolic roles and proliferation inhibition of many cancer cells. The aim of the present research was to determine adiponectin effect on human endometriotic stromal cells (ESCs) proliferation and their expression of adiponectin receptors.
In this experimental study, endometrial biopsies (n=7) were taken. ESCs isolation was done by enzymatic digestion and cell filtrations. ESCs of each biopsy were divided into four groups: 0 (control), 10, 100, and 200 ng/ml adiponectin concentrations in three different times (24, 48 or 72 h). The effect of adiponectin on ESC viability and expression of mRNA Adipo receptor1 (R1) and Adipo receptor2 (R2) was determined by Trypan blue staining and semi-quantitative RT-PCR, respectively. Data were analyzed by one-way ANOVA and unpaired student’s t-test, and P<0.05 was considered statistically significant.
Adiponectin inhibited human endometriotic stromal cell proliferation in time- and dose-dependent manners significantly (P=0.001). Expression of AdipoR1 and AdipoR2 gene receptors was increased in human ESCs significantly (P<0.05).
Adiponectin can suppress endometriosis by inhibiting ESC proliferation and increased AdipoR1 and AdipoR2 expression.
Eur J Obstet Gynecol Reprod Biol. 2015 Dec;195:7-11.
Simple descriptors and simple rules of the International Ovarian Tumor Analysis (IOTA) Group: a prospective study of combined use for the description of adnexal masses.
External validation of the IOTA group’s three-step diagnostic model (Strategy 1) and comparison with assessment by an expert sonographer (Strategy 2).
Prospective study in patients with persistent adnexal masses, in which an inexperienced sonographer performed transvaginal ultrasound applying simple descriptors (SD) and rules (SR) for classifying as benign or malignant. Any non-classifiable mass was then submitted to an expert examiner for subjective assessment (SA).
Eighty-one patients (mean age, 43; 27.2% postmenopausal) were included in this prospective study. Surgery was performed for 30 (8 malignant and 22 benign) masses; 51 masses were considered as benign and managed expectantly (they were assumed to be benign for statistical purposes). Diagnostic performance for Strategy 1 (SD+SR+SA) was sensitivity (SN): 87.5% (7/8, 95% CI, 47.3-99.7%) and specificity (SP): 100% (73/73, 95% CI, 95.1-100%). For Strategy 2 (SA only) it was SN 87.5% (7/8, 95% CI, 47.3-99.7%), SP 98.6% (72/73, 95% CI, 92.6-100%).
The three-step diagnostic strategy designed by the IOTA group for adnexal masses has a diagnostic performance comparable to that of subjective expert assessment and could be used as a triage method by nonexpert sonographers.
Clin Nucl Med. 2016 Feb;41(2):e120-2.
Unusual Case of Postmenopausal Diffuse Endometriosis Mimicking Metastastic Ovarian Malignancy.
Endometriosis is a common gynecologic condition of the premenopausal years. However, postmenopausal endometriosis is rare (2.2%) and thought to be related to high level of circulating estrogen, especially in hormonal replacement therapy. We present a case of a 69-year-old postmenopausal woman, previously healthy and on no regular medication, with diffuse peritoneal endometriosis and bilateral ovarian endometrioma mimicking metastatic ovarian carcinoma on FDG PET/CT. Both ovarian endometrioma had low-grade activity, but more strikingly, there was diffuse FDG-avid peritoneal dissemination and gross ascites. Endometriosis should not be totally disregarded as a differential diagnosis even at postmenopausal status.
Sao Paulo Med J. 2016 Jan-Feb;134(1):70-3
The role of diagnostic laparoscopy in gynecology.
CONTEXT AND OBJECTIVES:
Laparoscopy is a diagnostic method that is currently becoming consolidated for therapeutic use. It consists of endoscopically viewing the abdominal cavity. The aim here was to evaluate the indications for diagnostic videolaparoscopy and the intraoperative findings in an endoscopic gynecology clinic at a tertiary-level hospital over the last five years.
DESIGN AND SETTING:
Retrospective descriptive study on all diagnostic videolaparoscopy procedures of the last five years carried out in the endoscopic gynecology clinic of a tertiary-level hospital.
The medical records of 618 women who underwent diagnostic laparoscopy between 2008 and 2012 were analyzed. The clinical characteristics of these women, the indications for videolaparoscopy and the intraoperative findings were evaluated.
The women’s mean age was 32 ± 6.4 years. Most of the women had already undergone at least one previous operation (60%), which was most frequently a cesarean. The indications for performing videolaparoscopy were infertility in 57%, chronic pelvic pain in 27% and others (intrauterine device, adnexal tumor, ectopic pregnancy or pelvic inflammatory disease) in 16%. The main laparoscopic findings were tubal alterations in the group with infertility (59.78%) and peritoneal alterations in the group with chronic pelvic pain (43.54%).
The main indications for videolaparoscopy in gynecology were infertility and chronic pelvic pain. However, in most procedures, no abnormalities justifying these complaints were found.
J Obstet Gynaecol. 2016;36(2):153-9.
A current view of the role of epigenetic changes in the aetiopathogenesis of endometriosis.
The purpose of the study was to examine the role of epigenetic changes in the aetiopathogenesis of endometriosis. The analysis and review of the relevant current literature in English language related to the role of epigenetic changes in the aetiopathogenesis of endometriosis. Epigenetic changes are common denominators for hormonal, immunological and inflammatory aberrations which play a key role in the aetiopathogenesis of endometriosis. Many internal and external factors may cause the different running of the epigenetic mechanism. As yet fully unknown genetic factors may increase the sensitivity of the epigenetic mechanism to various internal and external factors. The breakdown of epigenetic regulation is the main factor initiating the pathogenetic mechanisms for endometriosis formation.
J Obstet Gynaecol. 2016 May;36(4):450-4.
Carcinoma of the recto-vaginal septum. Comprehensive literature review.
Carcinoma of the recto-vaginal septum is an extremely rare entity. We performed a MEDLINE-based search on recto-vaginal septum carcinoma, focussing on its management, in order to clarify which are the best treatment options for this disease. In addition an unpublished case report has been added to the review. 34 case reports were included in our review. Surgery and adjuvant chemoradiation therapy seem to be the most common treatment option. However, since primary surgical treatment leads to mutilation by removing a large portion of the vagina and the anal sphincter with a permanent terminal colostomy, primary platinum-based chemoradiation therapy could be considered. In case of extragastrointestinal stromal tumours primary surgical treatment seems to be the best option. Due to the rarity of this entity only limited data is available. Therefore further investigation is necessary.
Hum Reprod. 2015 Dec;30(12):2808-15.
Are endometrial nerve fibres unique to endometriosis? A prospective case-control study of endometrial biopsy as a diagnostic test for endometriosis in women with pelvic pain.
Can the presence of endometrial nerve fibres be used as a diagnostic test for endometriosisin women with pelvic pain?
Endometrial fine nerve fibres were seen in the endometrium of women both with and without endometriosis, making their detection a poor diagnostic tool for endometriosis.
WHAT IS KNOWN ALREADY:
Laparoscopy and biopsy are currently the gold standard for making a diagnosis of endometriosis. It has been reported that small density nerve fibres in the functional layer of the endometrium are unique to women with endometriosis and hence nerve fibre detection could function as a less invasive diagnostic test of endometriosis. However, it may be that other painful conditions of the pelvis are also associated with these nerve fibres. We therefore focused this prospective study on women with pelvic pain to examine the efficacy of endometrial nerve fibre detection as a diagnostic test for endometriosis.
STUDY DESIGN, SIZE, DURATION:
This prospective case-control study conducted between July 2009 and July 2013 included 44 women with pelvic pain undergoing laparoscopic examination for the diagnosis of endometriosis. Immunohistochemical nerve fibre detection in endometrial curettings and biopsies using anti-protein gene product 9.5 was compared with surgical diagnosis.
PARTICIPANTS/MATERIALS, SETTINGS, METHODS:
Paired endometrial biopsies and curettings were taken from patients with (n = 22, study group) and without (n = 22, control group) endometriosis. Tissue was analysed by immunohistochemistry and nerve fibres were counted whenever they were present in the functional layer of the endometrium.
MAIN RESULTS AND THE ROLE OF CHANCE:
Fine nerve fibres were present in the eutopic endometrium of patients both with and without endometriosis. The presence of nerve fibres in curettings was not effective for either diagnosing or excluding endometriosis; sensitivity and specificity were 31.8 and 45.5% respectively, positive predictive value was 36.8% and negative predictive value was 40.0%. Few endometrial biopsy specimens were found to have nerve fibres present; sensitivity and specificity for endometrial biopsy were 13.6 and 68.2% respectively, positive predictive value was 30.0% and negative predictive value was 44.1%.
LIMITATIONS, REASONS FOR CAUTION:
This was a relatively small sample size and studies like this are subject to the heterogeneous nature of the patient population and tissue samples, despite our best efforts to regulate these parameters.
WIDER IMPLICATIONS OF THE FINDINGS:
Our results demonstrate that fine nerve fibres are present in women with and without endometriosis. Future work should focus on the function of endometrial nerves and whether these nerves are involved with the subfertility or pain that endometriosis sufferers experience. Our study does not support the detection of endometrial nerve fibres as a non-invasive diagnostic test of endometriosis in women with pelvic pain.
Mol Hum Reprod. 2015 Dec;21(12):905-16.
Selective modulation of the prostaglandin F2α pathway markedly impacts on endometriosis progression in a xenograft mouse model.
Selective activation or blockade of the prostaglandin (PG) F2α receptor (FP receptor) affects ectopic endometrial tissue growth and endometriosis development.
FP receptor antagonists might represent a promising approach for the treatment of peritoneal endometriosis.
WHAT IS KNOW ALREADY:
Eutopic and ectopic endometrium from women with endometriosis exhibit higher expression of key enzymes involved in the PGF2α biosynthetic pathway. It has also been shown that the PGF2α-FP receptor interaction induces angiogenesis in human endometrial adenocarcinoma.
STUDY DESIGN, SAMPLES/MATERIALS, METHODS:
For this study, a mouse model of endometriosis was developed by inoculating human endometrial biopsies into the peritoneal cavity of nude mouse (n = 15). Mice were treated with AL8810 (FP receptor antagonist), Fluprostenol (FP receptor agonist) or PBS. Endometriosis-like lesions were collected and analysed for set of markers for angiogenesis, tissue remodelling, apoptosis, cell proliferation and capillary formation using qPCR and immunohistochemistry.
MAIN RESULTS AND THE ROLE OF CHANCE:
We found that selective inhibition of the FP receptor with a specific antagonist, AL8810, led to a significant decline in the number (P < 0.01) and size of endometriosis-like lesions (P < 0.001), down-regulated the expression of key mediators of tissue remodelling (MMP9, P < 0.05) and angiogenesis (VEGF, P < 0.01) and up-regulated the pro-apoptotic factor (Bax, P < 0.01) as compared with controls. Immunohistochemical analyses further showed a marked decrease in cell proliferation and capillary formation in endometrial implants from AL8810-treated mice, as determined by proliferating cell nuclear antigen (PCNA) and von Willebrand factor (vWF) immunostaining, respectively. Moreover, Fluprostenol, a selective FP receptor agonist, showed the opposite effects.
LIMITATIONS, REASONS FOR CAUTION:
We carried out this study in nude mice, which have low levels of endogenous estrogens which may affect the lesion growth. Caution is required when interpreting these results to women.
WIDER IMPLICATIONS OF THE FINDINGS:
This study extends the role of PG signalling in endometriosispathogenesis and points towards the possible relevance of selective FP receptor antagonism as a targeted treatment for endometriosis.
LARGE SCALE DATA:
STUDY FUNDING AND COMPETING INTERESTS:
This work was supported by grant MOP-123259 to the late Dr Ali Akoum from the Canadian Institutes for Health Research. The authors have no conflict of interest.
Fertil Steril. 2016 Feb;105(2):423-9.e7.
Bowel occult microscopic endometriosis in resection margins in deep colorectal endometriosis specimens has no impact on short-term postoperative outcomes.
To evaluate the impact of bowel occult microscopic endometriosis (BOME) implants on postoperative outcomes in patients treated with colorectal resection for deep infiltrating digestive endometriosis.
Prospective series of consecutive patients with deep colorectal endometriosis managed by colorectal resection in our department from June 2009 to November 2014 and enrolled in the CIRENDO database (NCT02294825).
University tertiary referral center.
One hundred three patients managed by colorectal resection for deep infiltrating endometriosis.
Histologic examination of colorectal resection specimens.
MAIN OUTCOME MEASURE(S):
Patient characteristics, preoperative and 1-year postoperative symptoms and intraoperative findings were compared between women with and without BOME on specimen resection margins.
In 15 cases, BOME was found in one (nine cases) or both resection limits (six cases). No statistical significance was found between BOME and height of colorectal anastomosis, length of the resected bowel specimen or depth of rectal wall infiltration. One patient with BOME underwent a second colorectal resection 5 years later for rectal recurrence. Comparison between the rates of dyschezia, diarrhea, constipation, bloating and overall values of GIQLI and KESS scores 1 and 3 years postoperatively showed no statistical significance between women with and without BOME.
BOME was found in 14.6% of specimen resection margins. No impact on either pelvic or digestive symptoms was observed after 1-year follow-up postoperatively.
Fertil Steril. 2016 Jan;105(1):35-43.e1-10.
Evidence of a genetic link between endometriosis and ovarian cancer.
To evaluate whether endometriosis-associated genetic variation affects risk of ovarian cancer.
Pooled genetic analysis.
Genetic data from 46,176 participants (15,361 ovarian cancer cases and 30,815 controls) from 41 ovarian cancer studies.
MAIN OUTCOME MEASURE(S):
Endometriosis-associated genetic variation and ovarian cancer.
There was significant evidence of an association between endometriosis-related genetic variation and ovarian cancer risk, especially for the high-grade serous and clear cell histotypes. Overall we observed 15 significant burden statistics, which was three times more than expected.
By focusing on candidate regions from a phenotype associated with ovarian cancer, we have shown a clear genetic link between endometriosis and ovarian cancer that warrants further follow-up. The functional significance of the identified regions and SNPs is presently uncertain, though future fine mapping and histotype-specific functional analyses may shed light on the etiologies of both gynecologic conditions.
Sci Rep. 2015 Oct 19;5:15150
Targeting autocrine HB-EGF signaling with specific ADAM12 inhibition using recombinant ADAM12 prodomain.
Dysregulation of ErbB-family signaling underlies numerous pathologies and has been therapeutically targeted through inhibiting ErbB-receptors themselves or their cognate ligands. For the latter, “decoy” antibodies have been developed to sequester ligands including heparin-binding epidermal growth factor (HB-EGF); however, demonstrating sufficient efficacy has been difficult. Here, we hypothesized that this strategy depends on properties such as ligand-receptor binding affinity, which varies widely across the known ErbB-family ligands. Guided by computational modeling, we found that high-affinity ligands such as HB-EGF are more difficult to target with decoy antibodies compared to low-affinity ligands such as amphiregulin (AREG). To address this issue, we developed an alternative method for inhibiting HB-EGF activity by targeting its cleavage from the cell surface. In a model of the invasive disease endometriosis, we identified A Disintegrin and Metalloproteinase 12 (ADAM12) as a protease implicated in HB-EGF shedding. We designed a specific inhibitor of ADAM12 based on its recombinant prodomain (PA12), which selectively inhibits ADAM12 but not ADAM10 or ADAM17. In endometriotic cells, PA12 significantly reduced HB-EGF shedding and resultant cellular migration. Overall, specific inhibition of ligand shedding represents a possible alternative to decoy antibodies, especially for ligands such as HB-EGF that exhibit high binding affinity and localized signaling.
Gynecol Oncol. 2015 Dec;139(3):520-8.
Fully-sialylated alpha-chain of complement 4-binding protein: Diagnostic utility for ovarian clear cell carcinoma.
While a certain fraction of endometriomas can develop de novo epithelial ovarian cancer (EOC) such as clear cell carcinoma (OCCC), there is currently no useful biomarker available for early detection of OCCC from endometriomas. The aim of this study was to describe the diagnostic utility of a novel biomarker for EOC especially for OCCC to distinguish from endometrioma.
More than 100,000 glycan structures of serum glycoproteins obtained from 134 pretreatment all stage EOC patients (including 45 OCCCs) and 159 non-cancer control women (including 36 endometriomas) were explored for a mass spectrum approach. Diagnostic accuracy of identified biomarker was compared to the one of CA-125 by comparing area under curve (AUC) and positive/negative predictive values (PPV and NPV).
A2160, a fully-sialylated alpha-chain of complement 4-binding protein, was identified as a candidate target marker. A2160 was significantly elevated in all stages of OCCC compared to with endometriomas. Diagnostic accuracy of A2160 (cutoff 1.6U/mL) to distinguish early stage OCCC from endometrioma is significantly higher than that of CA-125 (cutoff 35IU/L): AUC for A2160 versus CA-125, 0.92 versus 0.67; PPV 95% versus 64%; and NPV 85% versus 58%. In addition, fully-sialylated glycans had a higher accuracy for diagnosing EOC as compared to partially-sialylated glycans of alpha-chain of complement 4-binding protein.
Our study suggested that A2160 may be a useful biomarker to distinguish early-stage OCCC from endometrioma. This new biomarker can be potentially applied for the monitoring of endometrioma patients, making possible the early diagnosis of OCCC.
Sci Rep. 2015 Oct 19;5:15286.
Estrogen Secreted by Mesenchymal Stem Cells Necessarily Determines Their Feasibility of Therapeutical Application.
Mesenchymal stem cells are therapeutically applicable and involved in the development of some types of diseases including estrogen (E2)-related ones. Little is known about E2 secretion by mesenchymal stem cells and its potential influence on their therapeutical applications. Our in vitro experiments showed that BMSCs cultured from C57BL/6J mice secreted E2 in a time-dependent manner. In vivo study identified a significantly increased E2 level in serum after a single administration of BMSCs, and a sustained elevation of E2 level upon a repetitive administration. Morris water maze test in the ovariectomised (OVX) mouse model revealed BMSCs transplantation ameliorated OVX-induced memory deficits by secreted E2. On the contrary, in endometriosismodel, BMSCs transplantation aggravated endometriotic lesions because of E2 secretion. Mechanistically, the aromatase cytochrome P450 appeared to be critical for the biosynthesis and exerted effects of estrogen secretion by BMSCs. Our findings suggested that BMSCs transplantation is on the one hand an attractive option for the therapeutic treatment of diseases associated with E2 deficits in part through E2 secretion, on the other hand a detrimental factor for the E2-exasperated diseases largely via E2 production. It is important and necessary to monitor serum E2 level before and after the initiation of BMSCs therapy.
Neurourol Urodyn. 2017 Jan;36(1):57-61
Risk of urinary retention after nerve-sparing surgery for deep infiltrating endometriosis: A systematic review and meta-analysis.
Recently, nerve-sparing (NS) techniques have been incorporated in surgeries for deep infiltrating endometriosis (DIE) to prevent urinary complications. Our aim was to perform a systematic review and meta-analysis to assess the risk of urinary retention after NS surgery for DIE compared with classical (non-NS) techniques.
Following the MOOSE guidelines for systematic reviews of observational studies, data were collected from published research articles that compared NS techniques with non-NS techniques in DIE surgery, with regard to post-operative urinary complications.
randomized clinical trials, intervention or observational (cohort and case-control) studies assessing women who underwent surgery for painful DIE.
cancer surgery and women submitted to bladder or ureteral resections. The respective relative risks (RR) and 95% confidence intervals (CI) were extracted and a forest plot was generated to show individual and combined estimates.
Preliminarily, 1,270 potentially relevant studies were identified from which four studies were selected. A meta-analysis was performed to assess the risk of urinary retention at discharge and 90 days after surgery. We found a common RR of 0.19 [95%CI: 0.03-1.17; (I2 = 50.20%; P = 0.09)] for need of self-catheterization at discharge in the NS group in relation to the conventional technique. Based on two studies, common RR for persistent urinary retention (after 90 days) was 0.16 [95%CI: 0.03-0.84].
Our results suggest significant advantages of the NS technique when considering the RR of persistent urinary retention. Controlled studies evaluating the best approach to manage the urinary tract after complex surgery for DIE are needed. Neurourol. Urodynam. 36:57-61, 2017. © 2015 Wiley Periodicals, Inc.
Reprod Sci. 2016 May;23(5):623-9.
Cathepsin Protease Inhibition Reduces Endometriosis Lesion Establishment.
Endometriosis is a gynecologic disease characterized by the ectopic presence of endometrial tissue on organs within the peritoneal cavity, causing debilitating abdominal pain and infertility. Current treatments alleviate moderate pain symptoms associated with the disorder but exhibit limited ability to prevent new or recurring lesion establishment and growth. Retrograde menstruation has been implicated for introducing endometrial tissue into the peritoneal cavity, but molecular mechanisms underlying attachment and invasion are not fully understood. We hypothesize that cysteine cathepsins, a group of powerful extracellular matrix proteases, facilitate endometrial tissue invasion and endometriosis lesion establishment in the peritoneal wall and inhibiting this activity would decrease endometriosis lesion implantation. To test this, we used an immunocompetent endometriosis mouse model and found that endometriotic lesions exhibited a greater than 5-fold increase in active cathepsins compared to tissue from peritoneal wall or eutopic endometrium, with cathepsins L and K specifically implicated. Human endometriosis lesions also exhibited greater cathepsin activity than adjacent peritoneum tissue, supporting the mouse results. Finally, we tested the hypothesis that inhibiting cathepsin activity could block endometriosis lesion attachment and implantation in vivo. Intraperitoneal injection of the broad cysteine cathepsin inhibitor, E-64, significantly reduced the number of attached endometriosis lesions in our murine model compared to vehicle-treated controls demonstrating that cathepsin proteases contribute to endometriosis lesion establishment, and their inhibition may provide a novel, nonhormonal therapy for endometriosis.
Reprod Sci. 2016 Apr;23(4):531-41.
Hypoxia Promotes Invasion of Endometrial Stromal Cells via Hypoxia-Inducible Factor 1α Upregulation-Mediated β-Catenin Activation in Endometriosis.
Endometriosis is a common benign gynecological disease defined as the presence of endometrial tissue outside the uterine cavity. The aim of this study was to identify the molecular mechanism underlying hypoxia-induced increases in invasive ability of human endometrial stromal cells (HESCs). Herein, we show that the expression levels of hypoxia-inducible factor lα (HIF-1α) and β-catenin were greater in ectopic endometriotic tissue compared with eutopic tissue from controls. Exposure of eutopic endometrial stromal cells under hypoxic conditions or treated with desferrioxamine (DFO, chemical hypoxia) resulted in a time-dependent increase in β-catenin expression and its dephosphorylation. Hypoxia/HIF-1α also activated the β-catenin/T-cell factor (TCF) signaling pathway and the expression of target genes, vascular endothelial growth factor and matrix metalloproteinase 9, and knockdown of HIF-1α or β-catenin abrogated hypoxia-induced increases in HESC invasiveness. These results suggest that HIF-1α interacting with β-catenin/TCF signaling pathway, which is activated by hypoxia, may provide new insights into the etiology of endometriosis.
Eur J Obstet Gynecol Reprod Biol. 2017 Feb;209:100-104.
Ovarian endometriosis during pregnancy: a series of 53 endometriomas.
The sonographic features of endometriomas and their natural history during pregnancy remain poorly known. The objective of our study was to report our experience concerning the diagnosis, spontaneous progression and management of endometriomas during pregnancy.
A retrospective observational study in 46 patients (53 cysts) presenting with an ovarian endometrioma diagnosed during ultrasound examination at the first trimester of pregnancy. Sonographic findings (according to the criteria of the International Ovarian Tumor Analysis (IOTA) group and how they changed for each cyst during pregnancy and postpartum were reviewed, together with cyst management. The median follow-up was 4 years [IQR: 3-6]. Median age at diagnosis was 31 years [IQR: 27-35].
Among the 53 cysts identified as “endometriomas” on the first-trimester ultrasound examination, 49 (92%) were described like “cyst fluid with ground-glass echogenicity”. Fifty-two cysts (98%) had a maximum diameter<100mm, only one cyst (2%) presented papillary projection and 5 cysts (9%) were multiloculated. During the second-trimester ultrasound monitoring of these cysts, of the 33 cysts that we monitored, 8 (24%) increased in size, 11 (34%) decreased in size, 5 (15%) disappeared and 9 (27%) did not change. During the third-trimester ultrasound monitoring of these cysts, of the 13 cysts that we monitored, 5 (39%) increased in size, 5 (39%) decreased in size, 2 (15%) disappeared and 1 (7%) did not change. All children (48 newborns) were born alive at a median gestational age of 39 weeks [IQR=39-40]. Only 10 cysts (19%) required surgical treatment. In all cases, surgery consisted of cystectomy. Two cysts were operated on during pregnancy (between 14 and 17 weeks of gestation) because of symptoms of adnexal torsion, 3 during cesarean section, and 5 postpartum. Four of the 10 (40%) cysts operated on were histopathologically “endometriomas”, and one of them was decidualized. Four cysts were mucinous cystadenomas, one was a serous cystadenoma and one cyst was a dermoid cyst.
This study underscores the difficulty of diagnosing endometriomas during pregnancy and the absolute necessity of surgical removal when ultrasonographic findings are doubtful.
J Pathol. 2016 Jan;238(2):137-40.
Animal and cellular models of human disease.
In this eighteenth (2016) Annual Review Issue of The Journal of Pathology, we present a collection of 19 invited review articles that cover different aspects of cellular and animal models of disease. These include genetically-engineered models, chemically-induced models, naturally-occurring models, and combinations thereof, with the focus on recent methodological and conceptual developments across a wide range of human diseases.
Theriogenology. 2016 Jan 15;85(2):247-53.
Prevalence of cervicitis in dairy cows and its effect on reproduction.
The objective of this study was to determine whether cervicitis in dairy cows is an independent disease or occurs concomitantly with inflammation of the uterus, and to clarify possible effects of cervicitis on reproductive performance. Dairy cows (n = 416) from 33 dairy farms were examined by rectal palpation and vaginoscopy between 42 and 50 days postpartum. Inclusion criteria for this study were absence of abnormal vaginal discharge and abnormalities of the uterus (fluctuation) at rectal palpation. Cervicitis was diagnosed when the second cervical fold was swollen and prolapsed with (C2) or without (C1) reddening. Cytobrush samples from the uterus (n = 370) and the cervix (n = 402) were collected, and the percentage of neutrophils in the uterus (PMNU) and the cervix as indicators of inflammation (threshold: ≥5%) was determined. In addition, endometrial biopsies for histology were collected, 300 of which were suitable for evaluation. Cervicitis (C1/C2) was diagnosed in 253 of 416 (60.8%) of cows. Of these, the prolapsed cervical mucosa was hyperemic (C2) in 29.1% of cases. Of 370 available uterine cytology samples, 221 cows had a clinical cervicitis; however, 170 (76.9%) had PMNU less than 5%. Of 300 uterine histologic examinations, 82 (27.3%) did not reveal any abnormalities; the remaining cows either had uterine inflammation and/or degenerative uterine changes such as endometriosis and angiosclerosis. Furthermore, of 300 biopsied animals, 184 revealed a cervicitis (C1/C2); however, 30.4% of these animals had no histopathologic uterine findings. For further analysis, only animals either without histopathologic findings and normal uterine cytology or with solely endometritis (defined as PMNU ≥ 5% and/or positive histopathology of the uterine tissue) were evaluated (n = 157). Of these, 95 cows had cervicitis. Unexpectedly, 63 of 95 (66.3%) cows had cervicitis without endometritis. With regard to reproductive performance, days to first service were not affected by cervicitis. Number of days open in animals with cervicitis but without endometritis tended to be lower than in cows with cervicitis plus endometritis (P = 0.092). Also, number of days open relative to percentage of neutrophils greater than 5% was lower when the cervical compared to the uterine mucosa was affected (P < 0.05). Total conception and pregnancy rates of animals 200 days into lactation decreased significantly in cows with severe cervical inflammation (C2). In conclusion, the results of this study suggested that cervicitis occurs independent of endometritis, and a higher degree of cervicitis is associated with poorer reproductive performance.
Gynecol Endocrinol. 2015;31(11):899-902
Association of common variations of the E-cadherin with endometriosis.
Endometriosis is a polygenic and multifactorial disease. E-cadherin (CDH1) gene encodes an epithelial cell-cell adhesion glycoprotein that modulates a wide variety of processes, including cell polarization, migration and cancer metastasis. Decreased expression of CDH1 in epithelial cells in peritoneal endometriosis has been reported in advanced stages of endometriotic lesions. We investigated the CDH1 -160C/A and +54C/T variations with susceptibility to endometriosis in an Iranian population. In this case-control study, 149 patients with endometriosis(stages I-IV) and 151 healthy women as controls were included. Genotyping was performed using PCR-RFLP method. A p value of <0.05 was considered statistically significant. The CDH1 + 54TT genotype was significantly lower (p = 0.012; OR = 0.30, 95% CI: 0.12-0.77) in the patients (11.6%) than the control group (26.7%). The CDH1 + 54T allele was significantly lower (p = 0.001; OR = 0.55, 95% CI: 0.38-0.77) in the cases (35.7%) compared with the control group (50.3%). No association was found between CDH1 - 160C/A polymorphism and endometriosis. The CDH1 +54C/T was associated with susceptibility to endometriosis in Iranian population, and +54T allele may have a protective role in progression of endometriosis.
Curr Opin Obstet Gynecol. 2015 Dec;27(6):445-8.
Chronic pelvic pain: how does noninvasive imaging compare with diagnostic laparoscopy?
PURPOSE OF REVIEW:
Chronic pelvic pain (CPP) has an annual prevalence of 38/1000 in the UK, with coexisting pathologies often present. Diagnostic laparoscopy has long been the gold standard diagnostic test, but with up to 40% showing no abnormality, we explore the value of noninvasive imaging, such as pelvic ultrasound and MRI.
A literature review from inception until January 2015 of the following databases: PubMed, MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Excerpta Medica database, and System for Information on Grey Literature in Europe were performed to identify published studies assessing the usefulness of ultrasound, MRI, and laparoscopy in the diagnosis of CPP. Three studies (194 women) addressed their comparative performance in patients with endometriosis, showing the sensitivity of ultrasound ranged between 58 and 88.5%; MRI was 56-91.5% and in the one study using histology as its reference standard, the sensitivity of laparoscopy was 85.7%. Noninvasive imaging has the additional benefit of being well tolerated, safer, and cheaper than surgery.
CPP, by nature of its multifactorial causation, can be difficult to manage and often requires a multidisciplinary team. Ultrasound and MRI may provide information about the presence or lack of abnormality, which would allow general practitioners or office gynaecologists to initiate treatment and think about surgery as a second-line investigative tool.
BMC Cancer. 2015 Oct 21;15:751.
Endometriosis as a risk factor for ovarian or endometrial cancer – results of a hospital-based case-control study.
No screening programs are available for ovarian or endometrial cancer. One reason for this is the low incidence of the conditions, resulting in low positive predictive values for tests, which are not very specific. One way of addressing this problem might be to use risk factors to define subpopulations with a higher incidence. The aim of this study was to investigate the extent to which a medical history of endometriosis can serve as a risk factor for ovarian or endometrial cancer.
In a hospital-based case-control analysis, the cases represented patients with endometrial or ovarian cancer who were participating in studies aimed at assessing the risk for these diseases. The controls were women between the age of 40 and 85 who were invited to take part via a newspaper advertisement. A total of 289 cases and 1016 controls were included. Using logistic regression models, it was tested whether self-reported endometriosis is a predictor of case-control status in addition to age, body mass index (BMI), number of pregnancies and previous oral contraceptive (OC) use.
Endometriosis was reported in 2.1 % of the controls (n = 21) and 4.8 % of the cases (n = 14). Endometriosis was a relevant predictor for case-control status in addition to other predictive factors (OR 2.63; 95 % CI, 1.28 to 5.41).
This case-control study found that self-reported endometriosis may be a risk factor for endometrial or ovarian cancer in women between 40 and 85 years. There have been very few studies addressing this issue, and incorporating it into a clinical prediction model would require a more precise characterization of the risk factor of endometriosis.
Mol Hum Reprod. 2016 Jan;22(1):3-17.
The importance of neuronal growth factors in the ovary.
The neurotrophin family consists of nerve growth factor (NGF), neurotrophin 3 (NT3) and neurotrophin 4/5 (NT4/5), in addition to brain-derived neurotrophic factor (BDNF) and the neuronal growth factors, glial cell line-derived neurotrophic factor (GDNF) and vasointestinal peptide (VIP). Although there are a few literature reviews, mainly of animal studies, on the importance of neurotrophins in the ovary, we aimed to provide a complete review of neurotrophins as well as neuronal growth factors and their important roles in normal and pathological processes in the ovary. Follicular assembly is probably stimulated by complementary effects of NGF, NT4/5 and BDNF and their receptors. The neurotrophins, GDNF and VIP and their receptors have all been identified in preantral and antral follicles of mammalian species, including humans. Transgenic mice with mutations in the genes encoding for Ngf, Nt4/5 and Bdnf and their tropomyosin-related kinase β receptor showed a reduction in preantral follicles and an abnormal ovarian morphology, whereas NGF, NT3, GDNF and VIP increased the in vitro activation of primordial follicles in rats and goats. Additionally, NGF, NT3 and GDNF promoted follicular cell proliferation; NGF, BDNF and VIP were shown to be involved in ovulation; VIP inhibited follicular apoptosis; NT4/5, BDNF and GDNF promoted oocyte maturation and NGF, NT3 and VIP stimulated steroidogenesis. NGF may also exert a stimulatory effect in ovarian cancer and polycystic ovarian syndrome (PCOS). Low levels of NGF and BDNF in follicular fluid may be associated with diminished ovarian reserve and high levels with endometriosis. More knowledge of the roles of neuronal growth factors in the ovary has important implications for the development of new therapeutic drugs (such as anti-NGF agents) for ovarian cancer and PCOS as well as various infertility problems, warranting further research.
Mol Pharmacol. 2016 Jan;89(1):14-26
The Dual Estrogen Receptor α Inhibitory Effects of the Tissue-Selective Estrogen Complex for Endometrial and Breast Safety.
The conjugated estrogen /: bazedoxifene tissue-selective estrogen complex (TSEC) is designed to minimize the undesirable effects of estrogen in the uterus and breast tissues and to allow the beneficial effects of estrogen in other estrogen-target tissues, such as the bone and brain. However, the molecular mechanism underlying endometrial and breast safety during TSEC use is not fully understood. Estrogen receptor α (ERα)-estrogen response element (ERE)-DNA pull-down assays using HeLa nuclear extracts followed by mass spectrometry-immunoblotting analyses revealed that, upon TSEC treatment, ERα interacted with transcriptional repressors rather than coactivators. Therefore, the TSEC-mediated recruitment of transcriptional repressors suppresses ERα-mediated transcription in the breast and uterus. In addition, TSEC treatment also degraded ERα protein in uterine tissue and breast cancer cells, but not in bone cells. Interestingly, ERα-ERE-DNA pull-down assays also revealed that, upon TSEC treatment, ERα interacted with the F-box protein 45 (FBXO45) E3 ubiquitin ligase. The loss-of- and gain-of-FBXO45 function analyses indicated that FBXO45 is involved in TSEC-mediated degradation of the ERα protein in endometrial and breast cells. In preclinical studies, these synergistic effects of TSEC on ERα inhibition also suppressed the estrogen-dependent progression of endometriosis. Therefore, the endometrial and breast safety effects of TSEC are associated with synergy between the selective recruitment of transcriptional repressors to ERα and FBXO45-mediated degradation of the ERα protein.
Gynecol Endocrinol. 2016;32(2):157-60
Evaluation of the correlation between body mass index and endometriosisamong Iranian fertile women.
The investigations have revealed an inverse correlation between body mass index (BMI) and endometriosis. Endometriosis is a common gynecological disease among women of reproductive age, which is defined as the implantation of endometrial glands and stroma outside the uterus. In this respect, we aimed to study the correlation between endometriosis and BMI in Iranian fertile women.
In a case-control design, 46 fertile women with endometriosis and 53 matched controls were recruited. All of the patients had a laparoscopy or laparotomy surgery and histologically confirmed endometriosis. The control group was selected from healthy volunteers who referred to gynecologist for tubal ligation or surgery of benign gynecological diseases. The participants were interviewed based on a structured questionnaire which covered inquiries regarding demographics, reproductive and menstrual history.
Statistical analysis was performed by categorizing the BMI to four main groups: >30, 25-29.9, 18.5-24.9 and <18.5. The results showed a significant inverse correlation between BMI and endometriosis (p = 0.039). BMI over 30 was observed in 26% of healthy controls versus 13% of endometriosis patients. On the other hand, BMI under 18.5 were detected in 3 individuals, all of them belonged to the endometriosis group.
Recent investigations have emphasized the role of BMI in endometriosis. The results of this study suggest that lower BMI is associated with an increased risk of endometriosis. As a parameter easily obtained, BMI may be useful for risk assessment of endometriosis.
Gynecol Endocrinol. 2016;32(4):259-63.
Vitamin D and benign gynaecological diseases: a critical analysis of the current evidence.
Vitamin D is a fat-soluble pro-hormone that plays an important role in bone homeostasis; beside this principal function, vitamin D promotes modulation of cell growth, neuromuscular and immune function, and reduction of inflammation. In addition, several in vitro and in vivo studies have demonstrated that vitamin D deficiency could increase the risk of cancer, autoimmune and cardiovascular diseases. Moreover, vitamin D plays also an important role in female reproduction, because vitamin D receptors are expressed in ovarian tissue, endometrium, fallopian epithelial cells as well as in decidua and placenta. We aimed to review the most updated evidence, which suggests a link between vitamin D metabolism and the development of some gynaecological diseases, such as endometriosis, uterine fibroids and polycystic ovary syndrome.
BMC Womens Health. 2015 Oct 22;15:89.
“You can’t always get what you want”: from doctrine to practicability of study designs for clinical investigation in endometriosis.
Patients, now generally well informed through dedicated websites and support organizations, are beginning to look askance at clinical experimentation. We conducted a survey investigation to verify whether women with endometriosis would still accept to participate in a randomized controlled trial (RCT) on treatment for pelvic pain.
A total of 500 patients consecutively self-referring to an academic outpatient endometriosis clinic, were asked to compile two questionnaires focused on hypothetical comparisons between a new drug and a standard drug, and between medical and surgical treatment, for endometriosis-associated pelvic pain. The main outcome measure was the percentage of patients willing to participate in a theoretical RCT.
A total of 239 (48 %) women would decline participation in a comparative study on a new drug and a standard drug, as 204 (41 %) would prefer the former medication, and 35 (7 %) the latter. Fifty women (10 %) would participate in a RCT, but only 24 (5 %) would accept blinding. The most frequently chosen option was the patient preference trial (211; 42 %). No significant differences were observed in demographic and clinical characteristics between the 50 women who would accept and the 450 who would decline to be enrolled in a RCT. A total of 229 women (46 %) would decline participation in a comparative study on medical versus surgical treatment, as 186 (37 %) would prefer pharmacological therapy and 43 (9 %) a surgical procedure. Only 11 (2 %) women would participate in such a RCT. More than half of the women (260; 52 %) selected the patient preference trial. No significant variations in distributions of answers were observed between women who did or did not undergo a previous surgical procedure.
Only a small minority of the women included in our study sample would accept randomization, and even less so blinding. Patient preference appears to play a central role when planning interventional trials on endometriosis-associated pelvic pain. Adequately designed observational analytic studies could be considered when recruitment in a RCT appears cumbersome.
BMC Res Notes. 2015 Oct 21;8:591.
Endometriosis in a kidney with focal xanthogranulomatous pyelonephritis and a perinephric abscess.
The presence of endometriosis in the kidney is extremely rare. We report a case of endometriosis in renal parenchyma incidentally found in a malfunctioning kidney removed because of xanthogranulomatous pyelonephritis.
A 53-year-old Chinese premenopausal woman presented with intermittent right flank pain for many years. Imaging studies revealed a contracted non-functioning right kidney and a perinephric abscess. The contracted kidney was considered to have resulted from chronic pyelonephritis. The abscess was drained. The patient subsequently underwent a right nephrectomy. Histology revealed endometriosis of renal parenchyma in addition to xanthogranulomatous pyelonephritis and a perinephric abscess. No evidence of endometriosis was identified at the pelvic site. The patient was symptom-free after operation.
Endometriosis is a common benign condition in women of reproductive age that is characterized by the presence of endometrial glands and stroma outside the uterine cavity, which affects either genital or extragenital sites. Involvement of the urinary tract is rare. Among the urinary tract endometriosis, only a few cases involve the kidney. Renal endometriosis is difficult to diagnose; a final diagnosis relies on the pathohistologic findings. Treatment involves hormonal manipulation or a hysterectomy with bilateral salpingo-oophorectomy. Whether a nephrectomy required depends on the level of renal function. Although extremely rare, renal endometriosis should be part of the differential diagnostic spectrum when a contracted, non-functioning kidney is present. Early diagnosis might have prevented an unnecessary nephrectomy in cases of uncomplicated renal endometriosis.
J Ultrasound Med. 2015 Dec;34(12):2133-9.
Contrast-Enhanced Sonographic Features Before and After Interventional Treatment of Ovarian Endometrial Cysts.
The purpose of this study was to assess contrast-enhanced sonography features before and after interventional treatment of ovarian endometrial cysts.
We retrospectively analyzed 53 patients with ovarian endometrial cysts who underwent contrast-enhanced sonography before and after interventional treatment to assess the sonographic features of the cysts at these different times. The sonographic features and quantitative parameters for the cysts were compared before and after treatment.
The wash-in mode showed rapid annular enhancement of the cyst wall and slow wash-out with even and uneven enhancement types. Compared to the internal iliac artery, the enhancement intensity was weaker, and the wash-in and wash-out times were longer in the cyst wall; furthermore, all 5 quantitative parameters differed between the cyst wall and internal iliac artery. The wash-in and wash-out characteristics of the cysts before and after interventional treatment were almost identical. The enhancement was primarily even before treatment and uneven after treatment; the enhancement intensity was low in all cases. Although the wash-in time before and after treatment did not differ, the wash-out time for the cysts before treatment was significantly lower than that observed after treatment. Two quantitative parameters differed before and after treatment.
The contrast-enhanced sonographic features and quantitative parameters for the walls of ovarian endometrial cysts differed before and after ultrasound-guided interventional treatment. These characteristics could be valuable for evaluating the efficacy of interventional treatment of ovarian endometrial cysts.