Biol Reprod. 2017 Nov 1;97(5):660-670.
Interleukin 6 secretion from alternatively activated macrophages promotes the migration of endometriotic epithelial cells.
Accumulating evidence has suggested an interaction between endometriotic cells and macrophages in the endometriotic microenvironment and the potential role of this interaction in the pathogenesis of endometriosis. However, how endometriotic cells communicate with macrophages to influence their function is poorly understood. In the present study, we found that the mRNA expression and production of CC chemokine ligand 2 (CCL2) were much higher in human endometriotic epithelial cells (11Z and 12Z) than those in human endometrial epithelial cells (HES). The inhibition of CCL2 action using neutralizing antibodies substantially suppressed macrophage migration induced by endometriotic epithelial cells. The endometriosis-associated macrophages (EAMs), which are the macrophages that are stimulated by the conditioned medium (CM) of human endometriotic cells, highly expressed the M2 phenotype markers (MRC1 and TREM2). In addition, the CM of EAMs significantly increased cell migration in 12Z cells, but no significant change was observed in cell growth. RT-PCR and antibody array analyses revealed that EAMs highly express and produce interleukin (IL) 6 compared to macrophages stimulated by the CM of HES cells. Moreover, the EAM-CM-induced migration and MMP2/9 expression in endometriotic cells were significantly attenuated by IL6 signaling inhibition. These results suggest a reciprocal activation of macrophages and endometriotic cells via the soluble factors CCL2 and IL6, which may contribute to the development of endometriosis.
J Matern Fetal Neonatal Med. 2017 Oct 29:1-6.
Obstetrical and neonatal outcomes of pregnancies complicated by endometriosis.
Endometriosis is defined as the presence of endometrial-like tissue outside the uterus, associated with pelvic pain and subfertility, affecting 0.6-10% of the general female population. The association between endometriosis and obstetrical outcomes is not well established. We aimed to evaluate whether endometriosis is associated with a higher incidence of obstetrical and neonatal complications.
A retrospective cohort study of all deliveries in a university-affiliated tertiary hospital (2007-2014). Eligibility was limited to women with previously diagnosed endometriosis and singleton pregnancies. Fetuses or neonates diagnosed with structural or chromosomal anomalies were excluded. We compared labor and delivery outcomes and immediate neonatal outcomes among women with endometriosis compared with women without endometriosis.
Overall, 61,535 deliveries were eligible for analysis, of which 135 (0.002%) had endometriosis. Women with in the endometriosis group were characterized by higher maternal age, lower parity and higher nulliparity rate, and an earlier gestational age at delivery. Women with endometriosis had higher rate of failure of induction of labor (aOR 5.2, 95%CI 1.8-14.9), cesarean delivery (aOR 5.0, 95%CI 3.3-7.4), postpartum hemorrhage (aOR 3.7, 95%CI 1.6-8.5), placenta accreta (aOR 6.24, 95%CI 2.20-17.67), postpartum hemoglobin <10 mg/dL (aOR 2.03, 95%CI 1.31-3.14), and packed cell transfusion (aOR 3.66, 95%CI 1.94-6.91). No significant differences in neonatal outcomes were observed.
Endometriosis is associated with higher risk of cesarean delivery and postpartum hemorrhage. Our findings suggest appropriate preparations for delivery, such as uterotonic agents and blood products, should be considered in these women.
J Minim Invasive Gynecol. 2017 Oct 14.
Relationship between Catamenial Pneumothorax or Noncatamenial Pneumothorax and Endometriosis.
To evaluate the clinical characteristics of women presenting with catamenial pneumothorax and compare them with those with noncatamenial pneumothorax.
A case-control study (Canadian Task Force II-2).
A multicenter study.
Forty-two women with pneumothorax: 21 women had catamenial pneumothorax (study group), and 21 were age-matched women with noncatamenial pneumothorax (control group).
All patients underwent video-assisted thoracoscopy and pleural biopsy. We also evaluated the presence and stage of pelvic endometriosis in 16 women with catamenial pneumothorax who had undergone laparoscopic surgery.
MEASUREMENTS AND MAIN RESULTS:
The number of known episodes of catamenial pneumothorax before treatment was between 2 and 8 episodes. Symptoms were mainly chest pain and shortness of breath; 1 patient had hemoptysis. The prevalence of right-sided pneumothorax was 95.2% in the study group and 57.1% in the control group (p = .004). Besides 2 cases with complete collapse of the right lung, most of the cases in the study group had apical pneumothorax. Pelvic endometriosis was found in 15 of 16 women (93.7%), mainly stage 3 or 4, and thoracic endometriosis in 12 of 20 women (60%). None of the patients in the control group had thoracic endometriosis.
Thoracic endometriosis is found in over half of women with catamenial pneumothorax but absent in those with noncatamenial pneumothorax. Right apical pneumothorax is predominant in women with catamenial pneumothorax. Endometriosis plays an important role in the mechanism of catamenial pneumothorax.
Adv Ther. 2017 Nov;34(11):2436-2451.
Treatment Patterns, Complications, and Health Care Utilization Among Endometriosis Patients Undergoing a Laparoscopy or a Hysterectomy: A Retrospective Claims Analysis.
Hysterectomy and laparoscopy are common surgical procedures used for the treatment of endometriosis. This study compares outcomes for women who received either procedure within the first year post initial surgery.
The study used data from the Truven Health MarketScan claims databases from 2004 to 2013 to identify women aged 18-49 years who received an endometriosis-related laparoscopy or hysterectomy. Patients were excluded if they did not have continuous insurance coverage from 1 year before through 1 year after their endometriosis-related procedure, if they were diagnosed with uterine fibroids prior to or on the date of surgery (i.e., index date), or if they had a hysterectomy prior to the index date. The descriptive analyses examined differences between patients with an endometriosis-related laparoscopy or hysterectomy in regard to medications prescribed, complications, and hospitalizations during the immediate year post procedure.
The final sample consisted of 24,915 women who underwent a hysterectomy and 37,308 who underwent a laparoscopy. Results revealed significant differences between the cohorts, with women who received a laparoscopy more likely to be prescribed a GnRH agonist, progestin, danazol, or an opioid analgesic in the immediate year post procedure compared to women who underwent a hysterectomy. In contrast, women who underwent a hysterectomy generally had higher complication rates. Index hospitalization rates and length of stay (LOS) were higher for women who had a hysterectomy, while post-index hospitalization rates and LOS were higher for women who had a laparoscopy. For both cohorts, post-procedure complications were associated with significantly higher hospitalization rates and longer LOS.
This study indicated significantly different 1-year post-surgical outcomes for patients who underwent an endometriosis-related hysterectomy relative to a laparoscopy. Furthermore, the endometriosis patients in this analysis had a considerable risk of surgical complications, subsequent surgeries, and hospital admissions, both during and after their initial therapeutic laparoscopy or hysterectomy.
Hum Reprod. 2017 Nov 1;32(11):2243-2249.
Endometriosis fertility index predicts live births following surgical resection of moderate and severe endometriosis.
Can live birth be accurately predicted following surgical resection of moderate-severe (Stage III-IV) endometriosis?
Live births can accurately be predicted with the endometriosis fertility index (EFI), with adnexal function being the most important factor to predict non-assisted reproductive technology (non-ART) fertility or the requirement for ART (www.endometriosisefi.com).
WHAT IS KNOWN ALREADY:
Fertility prognosis is important to many women with severe endometriosis. Controversy persists regarding optimal post-operative management to achieve pregnancy and the counselling of patients regarding duration of conventional treatments before undergoing ART. The EFI is reported to correlate with expectant management pregnancy rate, although external validation has been performed without specifically addressing fertility in women with moderate and severe endometriosis.
STUDY DESIGN, SIZE, DURATION:
Retrospective cohort study of 279 women from September 2001 to June 2016.
PARTICIPANTS/MATERIALS, SETTINGS, METHODS:
We included women undergoing laparoscopic resection of Stage III-IV endometriosis who attempted pregnancy post-operatively. The EFI was calculated based on detailed operative reports and surgical images. Fertility outcomes were obtained by direct patient contact. Kaplan-Meier model, log rank test and Cox regression were used for analyses.
MAIN RESULTS AND THE ROLE OF CHANCE:
The follow-up rate was 84% with a mean duration of 4.1 years. A total of 147 women (63%) had a live birth following surgery, 94 of them (64%) without ART. The EFI was highly associated with live births (P < 0.001): for women with an EFI of 0-2 the estimated cumulative non-ART live birth rate at five years was 0% and steadily increased up to 91% with an EFI of 9-10, while the proportion of women who attempted ART and had a live birth, steadily increased from 38 to 71% among the same EFI strata (P = 0.1). A low least function score was the most significant predictor of failure (P = 0.003), followed by having had a previous resection (P = 0.019) or incomplete resection (P = 0.028), being older than 40 compared to <35 years of age (P = 0.027), and having leiomyomas (P = 0.037).
LIMITATIONS REASONS FOR CAUTION:
The main limitation of this study is its retrospective design. Imprecision was higher with low EFI due to smaller sample size in this subgroup. Finally, the EFI is somewhat subjective and could be prone to intra- and inter-observer variations.
WIDER IMPLICATIONS OF THE FINDINGS:
Women with a high EFI score have excellent fertility prognosis and may be advised to try to become pregnant with timed intercourse compared to women with a low score, for which prompt referral to ART seems more reasonable. Other prognostic factors can be used to guide the management of women with an intermediate EFI score. These data follow women over many years post-resection and represent longitudinal fertility data rarely demonstrated in such a cohort. The location and impact of lesions on the ability of the adnexa to function seems crucial for the fertility prognosis and should be further investigated.
STUDY FUNDING/COMPETING INTEREST(S):
This study was funded by the GRACE Research funds. S.M.-L. is the recipient of a Training Award from the Fonds de Recherche Quebec-Sante. D.A. is the primary author of the Endometriosis Fertility Index. All authors have no conflicts of interest to declare.
Hum Reprod. 2017 Nov 1;32(11):2254-2268.
N-cadherin identifies human endometrial epithelial progenitor cells by in vitro stem cell assays.
Is there a specific surface marker that identifies human endometrial epithelial progenitor cells with adult stem cell activity using in vitro assays?
N-cadherin isolates clonogenic, self-renewing human endometrial epithelial progenitor cells with high proliferative potential that differentiate into cytokeratin+ gland-like structures in vitro and identifies their location in some cells of gland profiles predominantly in basalis endometrium adjacent to the myometrium.
WHAT IS KNOWN ALREADY:
Human endometrium contains a small population of clonogenic, self-renewing epithelial cells with high proliferative potential that differentiate into large gland-like structures, but their identity and location is unknown. Stage-specific embryonic antigen-1 (SSEA-1) distinguishes the epithelium of basalis from functionalis and is a marker of human post-menopausal (Post-M) endometrial epithelium.
STUDY DESIGN, SIZE, DURATION:
Prospective observational study of endometrial epithelial cells obtained from hysterectomy samples taken from 50 pre-menopausal (Pre-M) and 24 Post-M women, of which 4 were from women who had taken daily estradiol valerate 2 mg/day for 8 weeks prior.
PARTICIPANTS/MATERIALS, SETTING, METHODS:
Gene profiling was used to identify differentially expressed surface markers between fresh EpCAM (Epithelial Cell Adhesion Molecule)-magnetic bead-selected basalis-like epithelial cells from Post-M endometrium compared with predominantly functionalis epithelial cells from Pre-M endometrium and validated by qRT-PCR. In vitro clonogenicity and self-renewal assays were used to assess the stem/progenitor cell properties of magnetic bead-sorted N-cadherin+ and N-cadherin- epithelial cells. The cellular identity, location and phenotype of N-cadherin+ cells was assessed by dual colour immunofluorescence and confocal microscopy for cytokeratin, proliferative status (Ki-67), ERα, SSEA-1, SOX9 and epithelial mesenchymal transition (EMT) markers on full thickness human endometrium.
MAIN RESULTS AND THE ROLE OF CHANCE:
CDH2 (N-cadherin gene) was one of 11 surface molecules highly expressed in Post-M compared to Pre-M endometrial epithelial cells. N-cadherin+ cells comprise a median 16.7% (n = 8) and 20.2% (n = 5) of Pre-M endometrial epithelial cells by flow cytometry and magnetic bead sorting, respectively. N-cadherin+ epithelial cells from Pre-M endometrium were more clonogenic than N-cadherin- cells (n = 12, P = 0.003), underwent more population doublings (n = 7), showed greater capacity for serial cloning (n = 7) and differentiated into cytokeratin+ gland-like organoids. N-cadherin immunolocalised to the lateral and apical membrane of epithelial cells in the bases of glands in the basalis of Pre-M endometrium and Post-M gland profiles, co-expressing cytokeratin, ERα but not SSEA-1 or SOX9, which localized on gland profiles proximal to N-cadherin+ cells. N-cadherin+ cells were quiescent (Ki-67-) in the basalis and in Post-M endometrial glands and co-localized with EMT markers vimentin and E-cadherin.
LARGE SCALE DATA:
The raw and processed data files from the gene microarray have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus data set with accession number GSE35221.
LIMITATIONS, REASONS FOR CAUTION:
This is a descriptive study in human endometrium only using in vitro stem cell assays. The differential ability of N-cadherin+ and N-cadherin-cells to generate endometrial glands in vivo was not determined. A small number of uterine tissues analysed contained adenomyosis for which N-cadherin has been implicated in epithelial-EMT.
WIDER IMPLICATIONS OF THE FINDINGS:
A new marker enriching for human endometrial epithelial progenitor cells identifies a different and potentially more primitive cell population than SSEA-1, suggesting a potential hierarchy of epithelial differentiation in the basalis. Using N-cadherin as a marker, the molecular and cellular characteristics of epithelial progenitor cells and their role in endometrial proliferative disorders including endometriosis, adenomyosis and thin dysfunctional endometrium can be investigated.
STUDY FUNDING/COMPETING INTEREST(S):
This research was supported by Cancer Council Victoria grant 491079 (C.E.G.) and Australian National Health and Medical Research Council grants 1021127 (C.E.G.), 1085435 (C.E.G., J.A.D.), 145780 and 288713 (C.N.S.), RD Wright Career Development Award 465121 (C.E.G.), Senior Research Fellowship 1042298 (C.E.G.), the Victorian Government’s Operational Infrastructure Support and an Australian Postgraduate Award (HPTN), and China Council Scholarship (L.X.). The authors have nothing to declare.
J Clin Endocrinol Metab. 2018 Jan 1;103(1):64-74.
Systemic Inflammation Induced by microRNAs: Endometriosis-Derived Alterations in Circulating microRNA 125b-5p and Let-7b-5p Regulate Macrophage Cytokine Production.
Endometriosis is characterized by aberrant inflammation. We previously reported increased levels of microRNA (miRNA) 125b-5p and decreased levels of miRNA Let-7b-5p in serum of patients with endometriosis.
Determine the regulatory function of miRNAs 125b-5p and Let-7b-5p on production of proinflammatory cytokines in endometriosis.
Women with (20) and without (26) endometriosis; human U937 macrophage cell line.
Sera were collected from surgically diagnosed patients and differentiated U937 cells that were transfected with miRNAs 125b-5p and Let-7b-5p mimics and inhibitor.
MAIN OUTCOME MEASURES:
Enzyme-linked immunosorbent assay for tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and IL-1β levels and quantitative real-time polymerase chain reaction for expression of miRNAs 125b-5p and Let-7b-5p in sera of patients with and without endometriosis. Transfected macrophages were evaluated for expression of inflammatory cytokines, intracellular production, and secretion of these cytokines.
We noted substantial elevation of TNF-α, IL-1β, and IL-6, marked upregulation of miRNA 125b, and considerable downregulation of Let-7b in sera of patients with endometriosis vs control. There was a positive correlation between miRNA 125b levels and TNF-α, IL-1β, and IL-6 and a negative correlation between miRNA Let-7b levels and TNF-α in sera of patients with endometriosis. Transfection experiments showed a noteworthy upregulation of TNF-α, IL-1β, IL-6, and IL-8 in macrophages transfected with miRNA 125b mimic or Let-7b inhibitor. The secreted cytokine protein levels and intracellular imaging studies closely correlate with the messenger RNA changes.
Endometriosis-derived miRNAs regulate macrophage cytokine production that contributes to inflammation associated with this condition.
Nat Commun. 2017 Oct 17;8(1):875.
The microbiota continuum along the female reproductive tract and its relation to uterine-related diseases.
Chen C1,2, Song X1,3, Wei W4,5, Zhong H1,2,6, Dai J4,5, Lan Z1, Li F1,2,3, Yu X1,2, Feng Q1,7, Wang Z1, Xie H1, Chen X1, Zeng C1, Wen B1,2, Zeng L4,5, Du H4,5, Tang H4,5, Xu C1,8, Xia Y1,3, Xia H1,2,9, Yang H1,10, Wang J1,10, Wang J1,11, Madsen L1,6,12, Brix S13, Kristiansen K1,6, Xu X1,2, Li J14,15,16,17, Wu R18,19, Jia H20,21,22,23.
Reports on bacteria detected in maternal fluids during pregnancy are typically associated with adverse consequences, and whether the female reproductive tract harbours distinct microbial communities beyond the vagina has been a matter of debate. Here we systematically sample the microbiota within the female reproductive tract in 110 women of reproductive age, and examine the nature of colonisation by 16S rRNA gene amplicon sequencing and cultivation. We find distinct microbial communities in cervical canal, uterus, fallopian tubes and peritoneal fluid, differing from that of the vagina. The results reflect a microbiota continuum along the female reproductive tract, indicative of a non-sterile environment. We also identify microbial taxa and potential functions that correlate with the menstrual cycle or are over-represented in subjects with adenomyosis or infertility due to endometriosis. The study provides insight into the nature of the vagino-uterine microbiome, and suggests that surveying the vaginal or cervical microbiota might be useful for detection of common diseases in the upper reproductive tract.Whether the female reproductive tract harbours distinct microbiomes beyond the vagina has been a matter of debate. Here, the authors show a subject-specific continuity in microbial communities at six sites along the female reproductive tract, indicative of a non-sterile environment.
Int J Fertil Steril. 2018 Jan;11(4):247-252.
Gene Polymorphism of Matrix Metalloproteinase 9 in Asthenozoospermic Male Subjects.
Matrix metalloproteinase (MMPs) play important roles in the structural and functional properties of reproductive organs. The aim of this study is to determine the prevalence of C-1562T MMP-9 (rs3918242) gene polymorphism in fertile and infertile men. In addition, we aim to determine the association between C-1562T MMP-9 and G-1575A MMP-2 gene polymorphisms.
MATERIALS AND METHODS:
A total of 400 subjects, including 200 fertile and 200 infertile men, were recruited for this casecontrol study. The allele frequencies and genotype distributions of single nucleotide polymorphism in the promoter regions of MMP-9 (C-1562T) were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The chi-square (χ2) test was used to assess the distribution of genotype frequencies.
There were no significant differences found in the genotype distributions or allele frequencies between fertile and infertile men for the C-1562T MMP-9 gene polymorphism. The percent of immotile sperm in infertile men with the CC and CT genotypes of C-1562T MMP-9 gene polymorphism significantly differed compared with that of subjects with the TT genotype. The frequency of CC/GA-combined genotypes of C-1562T MMP-9 and G-1575A MMP-2 gene polymorphisms significantly differed in fertile and infertile men (P=0.031).
Our results suggest that genetic polymorphisms in MMP may impact male fertility.
Int J Fertil Steril. 2018 Jan;11(4):318-320.
Pregnancy in Non-Communicating Rudimentary Horn of A Unicornuate Uterus.
Diagnosis and management of pre-rupture stage of the pregnant horn are difficult and usually missed on a routine ultrasound scan. Also most cases are detected after rupture of pregnant horn. We presented a 28-year-oldG2 L1 woman with diagnosis of rudimentary horn pregnancy (RHP) at 14 weeks of gestation. We diagnosed her with a normal intrauterine pregnancy, whereas a pregnancy in a right-sided non-communicating rudimentary horn with massive hemoperitoneum was later discovered on laparotomy. RHP has a high risk of death for mother, so there must be a strong clinical suspicion for the diagnosis of RHP. Although there is a major advancement in field of diagnostic ultrasound and other imaging modalities, prenatal diagnosis has remained elusive and a laparotomy surgery is considered as a definitive diagnosis.
Int J Fertil Steril. 2018 Jan;11(4):321-325. doi: 10.22074/ijfs.2018.5126. Epub 2017 Oct 12.
The Many Guises of Endometriosis: Giant Abdominal Wall EndometriosisMasquerading as An Incisional Hernia.
Endometriosis is defined by the presence of ectopic endometrial tissue outside the uterine cavity. Although it is a leading cause of chronic pelvic pain and infertility, its clinical presentation can vary, resulting in diagnostic and therapeutic challenges. Extrapelvic endometriosis is particularly difficult to diagnose owing to its ability to mimic other conditions. Endometrial tissue in a surgical scar is uncommon and often misdiagnosed as a granuloma, abscess, or malignancy. Cyclical hemorrhagic ascites due to peritoneal endometriosis is exceptionally rare. We report the case of a pre-menopausal, nulliparous 44-year-old woman who presented with ascites and a large abdominal mass that arose from the site of a lower midline laparotomy scar. Five years previously, she had undergone open myomectomy for uterine fibroids. Soon after her initial operation she developed abdominal ascites, which necessitated percutaneous drainage on multiple occasions. We performed a laparotomy with excision of the abdominal wall mass through an inverted T incision. The extra-abdominal mass consisted of mixed cystic and solid components, and weighed 1.52 kg. It communicated with the abdominopelvic cavity through a 2 cm defect in the linea alba. The abdomen contained a large amount of odourless, brown fluid which drained into the mass. There was a large capsule that covered the small and large bowel, liver, gallbladder, and stomach. Final histology reported a 28×19×5 cm mass of endometrial tissue with no evidence of malignant transformation. The patient recovered well post-operatively and has remained asymptomatic. Our case illustrates that, despite being a common disease, endometriosis can masquerade as several other conditions and be missed or diagnosed late. Delay in diagnosis will not only prolong symptoms but can also compromise reproductive lifespan. It is therefore paramount that endometriosis is to be considered early in the management of premenopausal women who present with an irregular pelvic mass or hemorrhagic ascites.
Genes Chromosomes Cancer. 2018 Feb;57(2):51-60.
Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing.
Ovarian clear cell carcinoma (OCCC) is the most refractory subtype of ovarian cancer and more prevalent in Japanese than Caucasians (25% and 5% of all ovarian cancer, respectively). The aim of this study is to discover the genomic alterations that may cause OCCC and effective molecular targets for chemotherapy. Paired genomic DNAs of 48 OCCC tissues and corresponding noncancerous tissues were extracted from formalin-fixed, paraffin embedded specimens collected between 2007 and 2015 at Tohoku University Hospital. All specimens underwent exome sequencing and the somatic genetic alterations were identified. We divided the cases into three clusters based on the mutation spectra. Clinical characteristics such as age of onset and endometriosis are similar among the clusters but one cluster shows mutations related to APOBEC activation, indicating its contribution to subset of OCCC cases. There are three hypermutated cases (showing 12-fold or higher somatic mutations than the other 45 cases) and they have germline and somatic mismatch repair gene alterations. The frequently mutated genes are ARID1A (66.7%), PIK3CA (50%), PPP2R1A (18.8%), and KRAS (16.7%). Somatic mutations important for selection of chemotherapeutic agents, such as BRAF, ERBB2, PDGFRB, PGR, and KRAS are found in 27.1% of OCCC cases, indicating clinical importance of exome analysis for OCCC. Our study suggests that the genetic instability caused by either mismatch repair defect or activation of APOBEC play critical roles in OCCC carcinogenesis.
Curr Med Res Opin. 2017 Nov 10:1-11.
Treatment options and reproductive outcome for adenomyosis-associated infertility.
Adenomyosis is a benign gynecological disease mostly diagnosed in the forth and fifth decades. The recent improvement of the diagnostic tools and a better understanding of the pathology allowed clinicians to postulate a possible relationship between adenomyosis and infertility and to diagnose it in younger asymptomatic women during infertility work-up. Purpose of this article is to review the different theories regarding the possible correlation between adenomyosis and infertility and to discuss the treatment options and the final reproductive outcome after the treatment.
MATERIALS AND METHODS:
We search Pubmed for articles published in the English language with the use of the following MeSH search terms: “adenomyosis” combined with “treatment” and “fertility outcome” with the restriction to the human species. A manual search of review articles and cross-references completed the search. All selected articles were assessed for study design, patients characteristic, diagnosis of adenomyosis, type of treatment, post-treatment rates of conception, full-term pregnancy and completeness of information of the data sets.
Limited data are available concerning the efficacy of the different treatment options of adenomyosis on fertility outcome and the only ones published are retrospective evaluations or small case series.
Adenomyosis represents a common gynecological disorder with a negative impact on fertility. However, it remains challenging to establish if adenomyosis is the only cause of the infertility or not, because patients, in both case and control groups, may be affected by concomitant endometriosis. Further studies are required to determine the reason of implantation failure in women with adenomyosis and the impact of adenomyosis on infertile women with or without endometriosis.
Gynecol Surg. 2017;14(1):19.
Applying a statistical method in transvaginal ultrasound training: lessons from the learning curve cumulative summation test (LC-CUSUM) for endometriosis mapping.
Methods available for assessing the learning curve, such as a predefined number of procedures or direct mentoring are lacking. Our aim was to describe the use of a statistical method to identify the minimal training length of an experienced sonographer, newly trained in deep infiltrating endometriosis (DIE) mapping by evaluating the learning curve of transvaginal ultrasound (TVUS) in the preoperative assessment of endometriosis.
A retrospective study in a tertiary referral center for endometriosis. Reports and stored data from TVUS scans performed by one operator with training in general gynecological ultrasound, but not in endometriosis mapping, were analyzed retrospectively for patients who subsequently underwent laparoscopy, which served as a reference standard. The performance of TVUS was assessed for the following sites: endometriomas, bladder, vagina, pouch of Douglas, bowel and uterosacral ligaments, and correlated with laparoscopic findings. Sensitivity, specificity, PPV, NPV, and accuracy were calculated, and the operator’s diagnostic performance was assessed using the learning curve cumulative summation test (LC-CUSUM).
Data from 94 women were available for analysis. The learning curve using the LC-CUSUM graph showed that the sonographer reached the predefined level of proficiency in detecting endometriosislesions after 20, 26, 32, 31, 38, and 44 examinations for endometriomas, bladder nodules, vaginal nodules, pouch of Douglas obliteration, bowel nodules, and uterosacral ligament nodules, respectively.
LC-CUSUM allows monitoring of individual performance during the learning process of new methodologies. This study shows that a sonographer trained in general gynecologic ultrasonography, who devotes time to learn TVUS for DIE mapping, can achieve proficiency for diagnosing the major types of endometriotic lesions after examining less than 50 patients who subsequently undergo surgery in a training setting.
Interact Cardiovasc Thorac Surg. 2018 Feb 1;26(2):319-322
Hormonal manipulation after surgery for catamenial pneumothorax.
A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether hormonal manipulation with gonadotrophin-releasing hormone analogues reduces the risk of recurrent catamenial pneumothorax after surgery, compared with surgery alone. Altogether 819 papers were found using the reported search, of which 7 represented the best evidence to answer the clinical question. The authors, date, journal, country of publication, study type, level of evidence, patient group studied, relevant outcomes and results of these papers are tabulated. Of the 7 papers selected, 6 demonstrated a reduction in recurrence of catamenial pneumothorax with the use of gonadotrophin-releasing hormone analogues, whereas in the single paper where surgery alone was performed, no evidence of recurrence was demonstrated. We therefore conclude that, based on very small retrospective observational studies, gonadotrophin-releasing hormone analogues used as an adjunct to surgical intervention may reduce the risk of recurrent pneumothorax, when compared with either no hormonal therapy or oestrogen-progesterone therapy, but should be initiated and supervised by gynaecologists who will be familiar with the therapy and the potential side effects.
Biochim Biophys Acta. 2018 Jan;1863(1):71-80.
Long-chain glucosylceramides crosstalk with LYN mediates endometrial cell migration.
Endometriosis is a disease characterized by regurgitated lesions which are invasive and migratory, embedding at ectopic, extra-uterine locations. Extracellular glucosylceramides (GlcCers), bioactive sphingolipids potentiating signals for cell migration, are found in elevated levels in endometriosis; however underlying mechanisms that result in cellular migration are poorly defined. Here, we demonstrated that internalized GlcCer induced migratory activity in immortalized human endometrial stromal cells (HESCs), with highest potency observed in long-chain GlcCer. Long-chain ceramide (Cer) similarly induced cellular migration and mass spectrometry results revealed that the migratory behavior was contributed through glycosylation of ceramides. Cells treated with GlcCer synthase inhibitor, or RNAi-mediated knockdown of glucosylceramide synthase (GCS), the enzyme catalyzing GlcCer production attenuated cell motility. Mechanistic studies showed that GlcCer acts through stromal cell-derived factor-1 alpha and its receptor, CXC chemokine receptor 4 (SDF-1α-CXCR4) signaling axis and is dependent on phosphorylation of LYN kinase at Tyr396, and dephosphorylation of Tyr507. Migration was prominently attenuated in cells exposed to CXCR4 antagonist, AMD3100, yet can be rescued with diprotin A, which prevents the degradation of SDF-1α. Furthermore, blocking of LYN kinase activity in the presence of SDF-1α and GlcCer reduced HESC migration, suggesting that LYN acts downstream of GlcCer-SDF-1α-CXCR4 axis as part of its intracellular signal transduction. Our results reveal a novel role of long-chain GlcCer and the dialog between GlcCer, LYNpTyr396 and SDF-1α-CXCR4 in inducing HESC migration. This finding may improve our understanding how endometriotic lesions invade to their ectopic sites, and the possibility of using GlcCer to modulate the SDF-1α-CXCR4-LYNpTyr396 axis in endometriosis.
Eur J Obstet Gynecol Reprod Biol. 2017 Dec;219:57-65.
Spontaneous hemoperitoneum in pregnancy (SHiP) and endometriosis – A systematic review of the recent literature.
Spontaneous Hemoperitoneum in Pregnancy (SHiP), an unprovoked (nontraumatic) intraperitoneal bleeding in pregnancy (up to 42days postpartum), is associated with serious adverse pregnancy outcomes. To evaluate the clinical consequences of SHiP and its association with endometriosis, a systematic review was conducted according to the PRISMA guidelines. PubMed, Embase.com and Thomson Reuters/Web of Science were searched for articles published since the latest review (August 2008) until September 2016. After assessment for eligibility, forty-four articles were included in this systematic review, describing 59 cases of SHiP. Endometriosis was present in 33/59 cases (55.9%), most often diagnosed prior to pregnancy. An association between the severity of SHiP and the stage of endometriosis could not be found. In the majority of cases, SHiP occurred in the third trimester of pregnancy (30/59 cases (50.8%)); women presented with (sub)acute abdominal pain (56/59 cases (94.9%)), hypovolemic shock (28/59 cases (47.5%)) and/or a decreased level of hemoglobin (37/59 cases (62.7%)). Signs of fetal distress were observed in 24/59 cases (40.7%). Imaging confirmed free peritoneal fluid in (37/59 cases (62.7%)). At time of surgery active bleeding was revealed in 51/56 cases (91,1%), originating from endometriotic implants (11/51 cases (21.6%)), ruptured utero-ovarian vessels (29/51 cases (56.8%)), hemorrhagic nodules of decidualized cells (1/51 cases (2.0%)) or a combination (10/51 cases (19.6%)). Median amount of hemoperitoneum was 1600mL (IQR 1000mL-2500mL). From the 45/59 cases (76.3%) in which surgical interventions was carried out during pregnancy, 7/45 cases (15.6%) reported a successful continuation of pregnancy. 5/59 cases reported recurrence of SHiP (recurrence rate 8.5%). The perinatal mortality rate was 26.9% (18/67 fetus), one maternal death was reported (1/59 cases (1,7%)). In conclusion, SHiP is a very serious complication of pregnancy, highly associated with adverse pregnancy outcomes and particularly relevant to women with endometriosis. Currently preventive measures are lacking, therefore increasing the awareness and recognition of SHiP is crucial to improve pregnancy outcomes.
Ann Thorac Surg. 2017 Dec;104(6):1865-1871.
Thoracic Endometriosis Syndrome Other Than Pneumothorax: Clinical and Pathological Findings.
Thoracic endometriosis syndrome refers to a broad spectrum of clinical manifestations related to the presence of ectopic intrathoracic endometrial tissue. Few studies have reported on manifestations other than pneumothorax.
Clinical, surgical, and pathology records of all consecutive women of reproductive age referred to our institution from September 2001 to August 2016 for clinically suspected thoracic endometriosis syndrome were retrospectively reviewed. After excluding women with pneumothorax, we enrolled 31 patients, divided into three subgroups: catamenial chest pain (n = 20), endometriosis-related diaphragmatic hernia (n = 6), and endometriosis-related pleural effusion (n = 5).
Surgery was performed in 11 patients with catamenial thoracic pain (median age, 30 years; range, 23 to 42). Median pain intensity assessed on the 0 to 10 Visual Analogue Scale was 8 (range, 8 to 9) before surgery. At surgery, 8 patients had diaphragmatic endometriosis implants, which were resected with direct suture of diaphragm. At follow-up, median pain score was 3 (range, 0 to 8). In the group presenting with diaphragmatic hernia (median age, 36 years; range, 29 to 50), diaphragm was repaired by direct suture or placement of prosthesis in 4 and 2 cases, respectively. At follow-up, no sign of recurrent hernia was observed. Finally, among women with endometriosis-related pleural effusion (median age, 30 years; range, 25 to 42), surgical treatment was represented by evacuation of the pleural effusion and biopsy (n = 4) or removal (n = 1) of visible endometrial foci.
Thoracic endometriosis syndrome is a poorly recognized entity responsible for various manifestations other than pneumothorax. In case of catamenial thoracic pain, diaphragmatic hernia and catamenial pleural effusion surgery should be advised in a multidisciplinary setting.
Oxid Med Cell Longev. 2017;2017:7265238.
Oxidative Stress and Endometriosis: A Systematic Review of the Literature.
Endometriosis is one of the most common gynaecologic diseases in women of reproductive age. It is characterized by the presence of endometrial tissue outside the uterine cavity. The women affected suffer from pelvic pain and infertility. The complex etiology is still unclear and it is based on three main theories: retrograde menstruation, coelomic metaplasia, and induction theory. Genetics and epigenetics also play a role in the development of endometriosis. Recent studies have put the attention on the role of oxidative stress, defined as an imbalance between reactive oxygen species (ROS) and antioxidants, which may be implicated in the pathophysiology of endometriosis causing a general inflammatory response in the peritoneal cavity. Reactive oxygen species are intermediaries produced by normal oxygen metabolism and are inflammatory mediators known to modulate cell proliferation and to have deleterious effects. A systematic review was performed in order to clarify the different roles of oxidative stress and its role in the development of endometriosis. Several issues have been investigated: iron metabolism, oxidative stress markers (in the serum, peritoneal fluid, follicular fluid, peritoneal environment, ovarian cortex, and eutopic and ectopic endometrial tissue), genes involved in oxidative stress, endometriosis-associated infertility, and cancer development.
J Pathol. 2018 Feb;244(2):189-202.
Decoy receptor 3 promotes cell adhesion and enhances endometriosisdevelopment.
Endometriosis is a multifactorial inflammatory disease with persistent activation of the nuclear factor-κB (NF-κB) signalling pathway. Aberrant adhesion of endometrium is the essential step in the progression of endometriosis, but the molecular mechanism of ectopic growth of endometrium is still unclear. Decoy receptor 3 (DcR3)/TNFRSF6B, a pleiotropic immunomodulator regulated by oestrogen, is able to activate focal adhesion kinase to promote cell adhesion. We found that DcR3 is upregulated in human ectopic endometrial cells via activation of the Akt-NF-κB signalling pathway, and its expression level correlates positively with that of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and homing cell adhesion molecule (HCAM; CD44). In a multivariate regression model, DcR3 expression level was the most significant parameter associated with endometriosis severity. Knockdown of DcR3 not only downregulated the expression of ICAM-1 and HCAM, but also reduced cell adhesion and migration. In vivo investigation further showed that DcR3 promoted the growth and spread of endometrium, whereas knockdown of DcR3 by lentivirus-delivered short hairpin RNA inhibited ectopic adhesion of endometrium and abrogated endometriosis progression. These observations are in support of DcR3 playing a critical role in the pathogenesis of endometriosis, and the inhibition of DcR3 expression being a promising approach for the treatment of endometriosis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Gynecol Endocrinol. 2017 Oct 23:1-6.
Detrimental effects of endometriosis on oocyte morphology in intracytoplasmic sperm injection cycles: a retrospective cohort study.
While an association can be addressed among endometriosis and subfertility, the causal relationship has not been elucidated yet. Impaired oocyte quality in endometriosis patients has been accused for the unsuccessful outcomes of assisted reproductive techniques. There are limited studies in literature evaluated association between endometriosis and oocyte morphology. We conducted this retrospective study to evaluate whether morphological abnormalities of oocytes are more common in women with endometriosis than women with diagnosis of male factor infertility as a source of healthy oocytes. Totally 1568 oocytes, 775 (49.4%) in endometriosis groups and 793 (50.6%) in control group were evaluated for morphological parameters before ICSI cycles. Abnormal oocyte morphology was detected in 352 (22.4%) of 1568 oocytes. Of the abnormal oocytes, 208 (59.1%) were in endometriosis group and 144 (40.9%) in control group (p < .001). The following dysmorphisms were significantly higher in oocytes retrieved from endometriosis group: dark cytoplasm; dark, large or thin zona pellucida; and flat or fragmented polar body (p < .05 for all). When morphological parameters for oocytes of endometriosis patients evaluated, the oocyte defects has increased significantly in endometriosis patients. These findings are thought to be useful to clarify the subfertility in endometriosis patient, which needs to be confirmed with further studies.
Wideochir Inne Tech Maloinwazyjne. 2017 Sep;12(3):306-310.
Laparoscopic total gastrectomy for a giant gastrointestinal stromal tumor (GIST) with acute massive gastrointestinal bleeding: a case report.
Gastrointestinal stromal tumors (GISTs) include 80% of gastrointestinal mesenchymal tumors that originate from interstitial Cajal cells and include 0.1-3% of GI malignancies, and the stomach is the most commonly involved organ. The only potentially curative treatment is surgical resection with clear margins. Although laparoscopic resection of small GISTs is a standard treatment, there is controversy about laparoscopic surgical resection for large and giant GISTs. A 52-year-old woman, a known case of large GIST of the stomach that was under neoadjuvant imatinib therapy, was admitted to the emergency department due to acute massive gastrointestinal bleeding (GIB). The patient underwent laparoscopic total gastrectomy and received adjuvant imatinib after surgery. Laparoscopic resection is a safe and feasible method in large and giant GISTs with oncologic and long-term outcomes comparable to open surgery, and with better short-term outcomes.
Wideochir Inne Tech Maloinwazyjne. 2017 Sep;12(3):315-319.
Effect of an 8K ultra-high-definition television system in a case of laparoscopic gynecologic surgery.
Various endoscopic devices have been developed for advanced minimally invasive surgery. We recently applied a new 8K ultra-high-definition television system during laparoscopic treatment of endometriosis. The procedure, which is described in detail, stands as the first reported application of an 8K ultra-high-definition system for laparoscopic gynecologic surgery. Comparison is made between depiction of the lesion by the new system and depiction by a full high-definition system. Improved diagnostic accuracy resulted from the increased image resolution, and we believe that this and other advantages will lead to widespread acceptance and further application of 8K ultra-high-definition systems in the field of gynecologic surgery.
Int J Ophthalmol. 2017 Oct 18;10(10):1604-1610.
The impact of combined oral contraceptives on ocular tissues: a review of ocular effects.
The aim of this manuscript is to review the action and adverse effects of combined oral contraceptives (COCs) on ocular tissues. The percentage of unwanted pregnancies and the subsequent abortions make contraception crucial worldwide. Over 100 million women around the world use common contraceptive methods, including intrauterine devices, combined estrogen and progestin oral contraceptives, as well as progestin only preparations (oral contraceptives, implants or injections). COCs are widely used for contraception, but they are also indicated in menorrhagia, endometriosis, acne and hirsutism, fibroid uterus and premenstrual syndrome. However, they have been associated with high rates of cardiovascular events, venous thromboembolic disease, ischemic strokes and breast cancer. The incidence of COCs-related ocular complications is estimated to be 1 in 230 000, including dry eye symptoms, corneal edema, lens opacities and retinal neuro-ophthalmologic or vascular complications. We may infer that the serious ocular complications of COCs can be prevented by eliminating the estrogen dosage and choosing third-generation progestins. In any case, doctors should take into consideration the systemic and ocular history of the patients before selecting any method of contraception.
Minerva Ginecol. 2017 Oct 23.
Pregnancy outcomes in women with endometriosis.
To investigate whether patients with endometriosis who achieved pregnancy have a higher risk for pregnancy complications and adverse perinatal outcomes as compared to patients without endometriosis.
The study compared obstetrical and perinatal outcomes of women with and without endometriosis whodelivered between 1988-2013 at the SorokaUniversity Medical Center. The study population included 504 deliveries divided into the following groups, 1)women with endometriosis (n=35); and 2) without endometriosis (n=467). Endometriosis was diagnosed by laparoscopy or laparotomy. Multiple logistic regression models were used to control for confounders.
No significant increase in obstetrical complications was noted in the endometriosis group, butsignificantly higher rates of rean sections. Perinatal outcomes were comparable between the groups.
In our population, endometriosis was not found as a risk factor for obstetrical complications or adverse perinatal outcomes. Larger population based cohort studies are needed to clarify the relationship between endometriosis and adverse pregnancy outcomes.
Arch Gynecol Obstet. 2018 Jan;297(1):93-99. doi: 10.1007/s00404-017-4549-8. Epub 2017 Oct 24.
Retinoic acid regulates endometriotic stromal cell growth through upregulation of Beclin1.
To elucidate the role of retinoic acid (RA) in autophagy-mediated endometriosis.
The mRNA and protein expressions of autophagy markers were examined in Ishikawa cells and endometriotic stromal cells (ESCs) after RA treatment. Beclin1 expression was specifically analyzed in clinical samples of endometriosis. The effect of Beclin1 knockdown on ESC growth was assessed, and the effect of autophagy inhibition on the sensitivity of endometriotic cells to RA was analyzed.
RA treatment enhanced the autophagy in ESCs, and Beclin1 expression showed a negative correlation with the clinical stage of endometriosis. Beclin1 knockdown enhanced ESC growth, whereas RA treatment reversed this effect. Furthermore, inhibition of autophagy by chloroquine (CQ) and Beclin1 knockdown did not show any positive effect on the sensitivity of endometriotic cells to RA.
RA treatment induces autophagy and Beclin1 may play an important role in endometriosis progression.
J Womens Health (Larchmt). 2017 Oct 24. doi: 10.1089/jwh.2017.6397. [Epub ahead of print]
Quality of Life in Women with Endometriosis: An Integrative Review.
The purpose of this study was to conduct an integrative review of the health-related quality of life (QoL) burden in women with endometriosis.
MATERIALS AND METHODS:
This integrative review was carried out by consulting the BIREME/MEDLINE databases through July 2017. We searched for articles published in the past 12 years using the MeSH terms “quality of life” and “endometriosis” and its representations in Portuguese and English.
Database search yielded 367 records, and eight additional records were identified through other sources. After analyzing articles based on inclusion and exclusion criteria, rigor and methodological evidence, 26 publications constituted the final corpus of our analysis. Generic instruments most commonly used to assess QoL included the Short Form Health Survey (SF-36), World Health Organization Quality of Life Assessment-bref (WHOQOL-bref); the 12-item Short Form Health Survey (SF-12), and the Duke Health Profile, among others. Disease-specific questionnaires were also used, and two studies collected qualitative data. Endometriosis had a negative impact in all domains of QoL, which was more associated to symptoms than to the diagnosis per se. It also negatively affected sleep quality and perceived stress. Impact had age-related differences in most studies, and was not related to endometriosis staging.
Endometriosis negatively affects QoL. A consensus must be reached as to which QoL instrument should be used to make studies comparable.
Surg Endosc. 2017 Oct 24.
Impact of hospital and surgeon case volume on morbidity in colorectal endometriosis management: a plea to define criteria for expert centers.
National and international guidelines recommend referring patients with severe forms of endometriosis to expert centers. However, there is a lack of clear criteria to define an expert center. We examined the roles of surgeon and hospital procedure volumes as determinants of morbidity in deep infiltrating endometriosisof the rectum and sigmoid colon (DIERS).
We conducted a French retrospective multicenter study of hospital facilities performing colorectal surgery for DIERS in 2015. The primary end point was to analyze the relation between case volume and the incidence of complications. We estimated the optimal cut-off (OCO) determined by a minimal p-value approach.
The study included 56 hospital facilities and collected data of 1135 cases of surgical management of colorectal endometriosis. The mean and median number of procedures per year and per surgeon were 9.17 and 5.58, respectively. The overall rate of grade III-V complication was 7.6% (82/1135). One grade V complication occurred. The rates of rectovaginal fistula, anastomotic leakage, pelvic abscess, and ureteral fistula were: 2.7% (31/1135), 0.79% (9/1135), 3.4% (39/1135), and 0.70% (8/1135), respectively. An OCO of 20 procedures per center and per year (p < 0.001) was defined. The OCO per surgeon and per year varied between seven (p = 0.007) and 13 procedures (p = 0.03). In a multivariate analysis, we found that only the volume of activity was independently correlated to complication outcomes (p = 0.0013).
Our results contribute to providing objective morbidity data to determine criteria for defining expert centers for colorectal surgery for endometriosis.
Biol Reprod. 2017 Jan 1;97(6):810-821.
Lesion development is modulated by the natural estrous cycle and mouse strain in a minimally invasive model of endometriosis.
Many rodent models of endometriosis are invasive, involving surgery to implant donor endometrial tissue into recipient animals. Moreover, few studies have compared and contrasted lesions between rodent strains and estrous stages without exogenous hormone manipulation. This is despite extensive data demonstrating that genetic and hormonal factors can influence endometriosis progression. Here, we have refined a minimally invasive model of endometriosis using naturally cycling mice (donor and recipient matched for cycle phase) to investigate lesion development in two different strains (C57BL/6 and BALB/c), induced in estrous stages of high and low estrogen (proestrus or estrus, respectively), and with varying amounts of donor endometrial tissue (7.5-40 mg), injected intraperitoneally. The overall probability of developing endometriosis-like lesions was higher in proestrus than estrus, and increased with greater masses of donor tissue. Similarly, the total number of lesions (0-3) increased from 7.5 to 40 mg, and was significantly greater in proestrus C57BL/6 mice but not BALB/cs. The dominant lesion type also differed between mouse strains; C57BL/6 mice were more likely to develop dense-type lesions, whereas BALB/c mice developed a greater proportion of cystic type. These data further support a role for estrogen in the development of endometriosis, and that genetic variance can influence the degree and characteristics of lesions. Our minimally invasive model would be beneficial for studies with outcome measurements particularly sensitive to incisional injury, such as pain, or alterations to sex hormones, including fertility.
Gynecol Endocrinol. 2017 Oct 26:1-4.
Development of endometrioma after cervical conization.
The association between cervical conization and subsequent development of endometriosis is uncertain. The objective of this study was to estimate the incidence rate of ovarian endometrioma after cervical conization and to determine factors associated with the development of endometrioma. One hundred forty-two patients who underwent cervical conization at the University of Tokyo Hospital between January 2006 and December 2013 were included in the study. Their medical records were retrospectively studied until April 2015. The incidence rate of postconization endometrioma was calculated. Patients’ characteristics (age, parity, preoperative and postoperative diagnosis and observation period) were analyzed. Six patients developed endometrioma after the cervical conization, and the incidence rate of endometrioma among patients who underwent cervical conization was 10.8 per 1000 person-year (95%CI 3.6-20.5). Patients’ age, percent of nulliparous, postoperative diagnosis and observation period were not associated with the development of postconization endometrioma. A preoperative diagnosis with invasive cancer (p < 0.05) was significantly associated with the development of postconization endometrioma. The incidence rate of endometrioma among patients who underwent cervical conization in the current study was higher than that reported population.
Int J Surg Pathol. 2018 Feb;26(1):24-30.
Cecal Endometriosis With Intestinal Metaplasia Misdiagnosed as Neoplasm of the Cecum by Intraoperative Histological Examination.
Appendiceal or cecal endometriosis with intestinal metaplasia is uncommon and may mimic mucinous tumors of the appendix. A 50-year-old woman was found incidentally to have an ileocecal lesion. In the intraoperative histological examination, a diagnosis of neoplasm of the cecum was made predominantly based on mucin extrusion with scattered lining mucinous epithelium. However, postoperative histological diagnosis of the lesion was cecal endometriosis with intestinal metaplasia as determined by thoroughly microscopic inspection and the presence of typical endometrial glands with surrounding endometrial-type stroma. There was no evidence of recurrence and pseudomyxoma peritonei after 1 year of follow-up. Overinterpretation of cytological atypia or mucin extrusion in endometriosis may lead to inappropriate surgical management. Therefore, in any ileocecal or appendiceal lesions with mucinous epithelia and mucin extrusions, removal of sufficient tissue from different portions of the lesion is essential for surgeons and pathologists to make a precise diagnosis in the intraoperative histological examination.
Reproduction. 2018 Jan;155(1):73-83.
Estrogen is an important mediator of mast cell activation in ovarian endometriomas.
Endometriosis is an estrogen-dependent disease. Previous research has shown that abnormal enzymes associated with estrogen (E2) metabolism and an increased number of mast cells (MCs) in endometriomas are implicated in the pathogenesis of endometriosis. However, it remains unclear how MCs mediate the role of E2 in endometriosis. Accordingly, we investigated whether E2 was associated with the number of MCs, and the rate of degranulation, in local ovarian endometriomas, as well as the role of E2 on MCs during the pathogenesis of endometriosis. Using enzyme-linked immunosorbent assay and immunohistochemistry, we found that concentrations of E2, and the number and activity of MCs, were significantly higher in ovarian endometriomas than in controls, and that these parameters were correlated with the severity of endometriosis-associated dysmenorrhea. By measuring the release of hexosaminidase, we found that the rate of RBL2H3 cell degranulation increased after E2 treatment. Furthermore, activation of RBL2H3 cells by E2 was found to trigger the release of biologically active nerve growth factor, which promotes neurite outgrowth in PC12 cells and also sensitizes dorsal root ganglion cells via upregulation of Nav1.8 and transient receptor potential cation channel (subfamily V member 1) expression levels. When treated with E2, endometriotic cells could promote RBL2H3 cell recruitment by upregulating expression levels of stem cell factor, transforming growth factor-β and monocyte chemoattractant protein-1; these observations were not evident with control endometrial cells. Thus, elevated E2 concentrations may be a key factor for degranulation and recruitment of MCs in ovarian endometriomas, which play a key role in endometriosis-associated dysmenorrhea.
PLoS One. 2017 Oct 27;12(10):e0186616.
Effects of acupuncture for the treatment of endometriosis-related pain: A systematic review and meta-analysis.
Endometriosis is a multifactorial, oestrogen-dependent, inflammatory, gynaecological condition that can result in long-lasting visceral pelvic pain and infertility. Acupuncture could be an effective treatment for endometriosis and may relieve pain. Our aim in the present study was to determine the effectiveness of acupuncture as a treatment for endometriosis-related pain.
In December 2016, six databases were searched for randomised controlled trials that determined the effectiveness of acupuncture in the treatment of endometriosis-related pain. Ultimately, 10 studies involving 589 patients were included. The main outcomes assessed were variation in pain level, variation in peripheral blood CA-125 level, and clinical effective rate. All analyses were performed using comprehensive meta-analysis statistical software.
Of the 10 studies included, only one pilot study used a placebo control and assessed blinding; the rest used various controls (medications and herbs), which were impossible to blind. The sample sizes were small in all studies, ranging from 8 to 36 patients per arm. The mean difference (MD) in pain reduction (pre- minus post-interventional pain level-measured on a 0-10-point scale) between the acupuncture and control groups was 1.36 (95% confidence intervals [CI] = 1.01-1.72, P<0.0001). Acupuncture had a positive effect on peripheral blood CA-125 levels, as compared with the control groups (MD = 5.9, 95% CI = 1.56-10.25, P = 0.008). Similarly, the effect of acupuncture on clinical effective rate was positive, as compared with the control groups (odds ratio = 2.07; 95% CI = 1.24-3.44, P = 0.005).
Few randomised, blinded clinical trials have addressed the efficacy of acupuncture in treating endometriosis-related pain. Nonetheless, the current literature suggests that acupuncture reduces pain and serum CA-125 levels, regardless of the control intervention used. To confirm these findings, additional, blinded studies with proper controls and adequate sample sizes are needed.
Fertil Steril. 2017 Nov;108(5):806-814.e2.
Endometriosis, especially mild disease: a risk factor for miscarriages.
To investigate the prevalence of miscarriage in women with endometriosis (WwE) compared with disease-free control women (CW).
Cross-sectional analysis nested in a retrospective observational study (n = 940).
Hospitals and associated private practices.
Previously pregnant women (n = 268) within reproductive age in matched pairs.
Retrospective analysis of surgical reports and self-administered questionnaires.
MAIN OUTCOME MEASURE(S):
Rate of miscarriage, subanalysis for fertility status (≤12 vs. >12 months’ time to conception), endometriosis stages (revised American Society of Reproductive Medicine classification [rASRM] I/II vs. III/IV) and phenotypic localizations (superficial peritoneal, ovarian, and deep infiltrating endometriosis).
The miscarriage rate was higher in WwE (35.8% [95% confidence interval 29.6%-42.0%]) compared with CW (22.0% [16.7%-27.0%]); adjusted incidence risk ratio of 1.97 (95% CI 1.41-2.75). This remained significant in subfertile WwE (50.0% [40.7%-59.4%]) vs. CW (25.8% [8.5%-41.2%]) but not in fertile WwE (24.5% [16.3%-31.6%]) vs. CW (21.5% [15.9%-26.8%]). The miscarriage rate was higher in women with milder forms (rASRM I/II 42.1% [32.6%-51.4%] vs. rASRM III/IV 30.8% [22.6%-38.7%], compared with 22.0% [16.7%-27.0%] in CW), and in women with superficial peritoneal endometriosis(42.0% [32.0%-53.9%]) compared with ovarian endometriosis (28.6% [17.7%-38.7%]) and deep infiltrating endometriosis (33.9% [21.2%-46.0%]) compared with CW (22.0% [16.7%-27.0%]).
Mild endometriosis, as in superficial lesions, is related to a great extent of inflammatory disorder, possibly leading to defective folliculogenesis, fertilization, and/or implantation, presenting as increased risk of miscarriage.
Drug Deliv Transl Res. 2018 Feb;8(1):43-53.
Formulation of 99mTechnetium-labeled leuprolide loaded liposomes and its biodistribution study in New Zealand white female rabbits for assessment of its uterine targeting efficiency.
Leuprolide acetate (LPA), a GnRH analogue, is drug of choice for treatment of uterine fibroids and endometriosis. The current marketed formulations of LPA show severe systemic side effects. This project aims to formulate LPA loaded liposomes to be administered by vaginal route for uterine targeting. Liposomes were prepared by thin film hydration method using 1:1 M ratio of DSPC: Cholesterol and characterized for vesicle size, zeta potential, entrapment efficiency, and loading. Radiolabeling of LPA was performed by direct labeling with reduced technetium-99m. Binding affinity of 99mTc-labeled complexes was assessed by diethylenetriaminepentaacetic acid (DTPA) challenge test. Biodistribution study was done in New Zealand white female rabbits by administering the formulation via vaginal route. Spherical and discrete vesicles of size 189 nm were seen in TEM results with entrapment efficiency and loading of 74.36% and 9.29%w/w, respectively. Liposomes were able to sustain the drug release for 5 days. 99mTc-labeled complexes showed high labeling efficiency and stability both in saline and serum. DTPA challenge test confirmed low transchelation of 99mTc-labeled complexes. Biodistribution study by gamma scintigraphy revealed the preferential uptake of the formulation by uterus when administered vaginally. Compared to plain drug, liposomes concentrated and were retained within the uterus for a longer period of time. Uterine targeting of liposomal LPA indicates its potential to overcome the limitations of presently available formulations. Hence, this seems to be a promising approach for targeting the drugs, whose site of action is uterus.
Acta Obstet Gynecol Scand. 2018 Jan;97(1):47-52..
Risk of bowel obstruction during in vitro fertilization treatment of patients with deep infiltrating endometriosis.
Women with endometriosis often experience pain and infertility. Medical treatment interferes with the possibility of attaining pregnancy. For infertile women with endometriosis, surgery is a possible treatment, but with advanced disease there is an increased risk of serious complications. With only limited pain, women will often be referred for in vitro fertilization treatment instead. The disease is estrogen-dependent and during in vitro fertilization treatment the women could theoretically experience worsening of their symptoms.
MATERIAL AND METHODS:
The study is a retrospective cohort study of 76 women with bowel endometriosis who were treated conservatively and underwent in vitro fertilization treatment.
Nine (11.8%) of the women experienced severe worsening of their bowel-related symptoms, including two patients presenting with colon ileus. One additional woman had no previous diagnosis of endometriosis before she presented with subocclusion of the bowel during in vitro fertilization. In all cases the in vitro fertilization treatment was stopped.
Our study revealed that bowel endometriosis increases the risk of complications during in vitro fertilization treatment. This is in contrast to several publications. However, our study population is different due to the fact that none of these women had previous operations for bowel endometriosis. In all, 88% of the women completed fertility treatment without need for surgery.
Biomed Pharmacother. 2018 Jan;97:91-97.
Curcumin and endometriosis: Review on potential roles and molecular mechanisms.
Endometriosis, an estrogen-dependent inflammatory disease, is one of the most common chronic gynecological disorders affecting women in reproductive age. It is characterized by the presence of endometrial-like tissue outside the uterus. The exact pathophysiology of endometriosis is not still well-known, but the immune system and inflammation have been considered as pivotal factors in disease progression. Turmeric, an important spice all around the world, is obtained from the rhizomes of Curcuma longa, a member of the Zingiberaceae family. It has been used in the prevention and treatment of many diseases since ancient times. Curcumin is the principal polyphenol isolated from turmeric. Several evidences have shown the anti-inflammatory, antioxidant, anti-tumor, anti-angiogenesis, and anti-metastatic activities of curcumin. In this review, relevant articles on the effect of curcumin on endometriosis and possible molecular mechanisms are discussed.
Zhonghua Yi Xue Za Zhi. 2017 Oct 24;97(39):3099-3103.
[Role of oral contraceptives in preventing endometriosis-related pain progression].
Objective: To analyze the effect of oral contraceptives on dysmenorrhea in patients with endometriosis. Methods: We designed dysmenorrhea and chronic pelvic pain questionnaire.From February 2014 to February 2016 in the Gynecological Department of Peking University Third Hospital, patients suffered dysmenorrhea with or without endometriosis or adenomyosis were included.According to their own willingness, patients were divided into the research group and the control group.The research group periodically took oral contraceptives (Diane-35 or Yasmin), while the control group received no treatment.They were followed-up about dysmenorrhea every six months, and the total follow-up time was one and a half year. Results: The dysmenorrhea VAS scores of patients in research group after taking oral contraceptives for six or twelve months were significantly lower than that in baseline (VAS 4 vs 5 vs 7). The dysmenorrhea VAS scores increased after quitting medication, but remained still lower than baseline (VAS 6.5 vs 7). However, the dysmenorrhea VAS scores of patients in control group remained unchanged (VAS 6 vs 6). Patients who took pills for more than one year experienced the same severity of dysmenorrhea after six months’ or one year’s medication (VAS 2 vs 2), and they suffered slowly aggravating recurrent dysmenorrhea, while those who quitted after six months’ medication suffered quickly recurrent dysmenorrhea.The relieving rate of dysmenorrhea in research group was significantly higher than that in control group (79.7% vs 8.2%), and the relieving rate in patients with severe pain was significantly higher than that with mild or moderate pain (87.0% vs 66.6 % vs 77.1%). The relieving rate in patients without lesions was significantly higher than patients with adenomyosis (92.6% vs 59.1%). Conclusions: Endometriosis is a progressing disease. Longterm medication of oral contraceptives can relieve the dysmenorrhea pain.The extent of pain relief was not connected with the length of medication.Dysmenorrhea recurred after quitting medication, and the longer of medication, the slower pain recurred.Patients without lesions experienced higher pain relieving rate than those with adenomyosis.
Tohoku J Exp Med. 2017 Oct;243(2):141-150.
The Expression of Cyclophilin A in Ovarian Endometrioma: Its Correlation with Recurrence and Vascularity.
Endometriosis is defined as the presence of functional endometrial tissues outside of the uterine cavity. Ovarian endometrioma is the most common type of endometriosis. It is an estrogen-dependent inflammatory disease that frequently causes infertility and chronic pelvic pain. Cyclophilin A (CyPA) is secreted from various types of cells in response to inflammatory stimuli. Many previous studies have shown that the increased expression and/or heightened plasma levels of CyPA exacerbates inﬂammation. The aim of this study is to evaluate CyPA immunoreactivity in ovarian endometrioma cyst wall. In this cross-sectional study, CyPA immunoreactivity in endometrial tissue samples obtained from uterine cavity and in endometrioma cyst walls of 44 consecutive women with ovarian endometrioma were compared with control endometrial tissue samples obtained from uterine cavity of 40 women without endometrioma. All endometrioma samples were confirmed via histopathological examination. Finally, the relationship between CyPA immunoreactivity and the clinicopathological findings related to endometrioma were evaluated. The CyPA expression rates in glandular cells, stromal cells, and the capillary endothelium were significantly higher in endometrioma cyst walls of women with ovarian endometrioma than in the control endometrial tissue of women without endometrioma (p = 0.0002, p = 0.0417 and p = 0.0067, respectively). The correlation analysis demonstrated that glandular CyPA expression was correlated with endometrioma recurrence (p = 0.0267). However, stromal and vascular endothelial CyPA expression were correlated with dysmenorrhea recurrence (p = 0.0023 and p = 0.0003, respectively). In conclusion, the increased expression of CyPA in ectopic endometrial tissue is associated with endometrioma recurrences and vascularity.
J Womens Health (Larchmt). 2017 Oct 30.
Dienogest for Treatment of Endometriosis in Chinese Women: A Placebo-Controlled, Randomized, Double-Blind Phase 3 Study.
Dienogest is a progestin with demonstrated efficacy in the treatment of endometriosis in European women. The objective of this study was to evaluate the efficacy and safety of dienogest in Chinese women.
PATIENTS AND METHODS:
This 24-week, randomized, double-blind, placebo-controlled multicenter (n = 23) study evaluated the efficacy and safety of 2 mg dienogest once daily in 255 Chinese women aged 18-45 years with laparoscopically diagnosed endometriosis and an endometriosis-associated pelvic pain (EAPP) score ≥30 mm on a 0-100 mm visual analog scale. The primary efficacy variable was absolute change in EAPP from baseline to week 24. Secondary efficacy variables included proportions of responders and intake of supportive analgesic medication. Safety variables included adverse events (AEs), laboratory parameters, and bleeding patterns. Bone mineral density (BMD) was evaluated in a subset of 140 women.
After 24 weeks of treatment, the difference between treatment arms for mean reduction in EAPP was statistically significant in favor of dienogest (-24.54 mm; 95% CI -29.93 to -19.15; p < 0.0001). Secondary efficacy analyses supported the significant superiority of dienogest over placebo. Dienogest was well tolerated, with few AEs associated with therapy. Dienogest had no effect on BMD levels after 24 weeks of treatment.
Dienogest 2 mg once daily for 24 weeks was superior to placebo in reducing EAPP and was safe and well tolerated in Chinese women with endometriosis. The results are consistent with studies previously conducted in European women.
Indian J Radiol Imaging. 2017 Jul-Sep;27(3):314-317.
Utility of diffusion weighted imaging in diagnosing subdiaphragmatic endometriosis presenting as shoulder pain.
Extrapelvic endometriosis (EPE) is a rare entity which may potentially occur at any site. Symptomatic EPE is now increasingly being managed laparoscopically. Imaging is imperative in diagnosis as well as extent delineation prior to surgery. In addition to increasing the success rate of diagnostic laparoscopy, prior knowledge of EPE at certain sites may modify the standard surgical technique. We present here an unusual case of chronic pain in the right shoulder in a 26-year-old female caused by subdiaphragmatic endometriosis (SDE). It was noticed on conventional magnetic resonance imaging (MRI) sequences; however, due to the lack of the characteristic signal intensity, imaging findings were noncontributory. Diffusion-weighted imaging (DWI) facilitated its characterization and precisely mapped the extent of involvement. SDE should be suspected in young females presenting with cyclical shoulder pain. Due to nonspecific clinical features, it may remain undiagnosed. MRI is the imaging modality of choice in evaluation of EPE. Including DWI sequence in the MR protocol increases the diagnostic precision besides delineating the extent of involvement noninvasively.
Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2017 Oct 28;42(10):1150-1155.
Expression of miR23b and Sp1 in ovarian endometriosisand their clinic significance.
To investigate the expressions of miR23b and Sp1 in ovarian endometriosis and their clinic significance. Methods: qPCR was used to detect the expression of miR23b and Sp1 mRNA in paired ectopic/eutopic and normal endometrium. Immunohistochemistry and Western bolt were used to determine the expression and distribution of Sp1 in paired ectopic/eutopic and normal endometrium. The association of miR23b and Sp1 with the endometriosis was analyzed. Results: MiR23b mRNA expression in paired ectopic/eutopic and normal endometrium was gradually increased (P<0.05). Sp1 protein mainly distributed in the nucleus of endometrial glandular epithelial and stromal cells, with a little or without expression in cytoplasm. Sp1 mRNA and protein expression in paired ectopic/eutopic and normal endometrium was gradually reduced (P<0.05). Pearson correlation analysis showed that miR23b was negatively correlated with Sp1 (r=-0.526, P<0.05). Conclusion: MiR23b and Sp1 are involved in the pathogenesis of ovarian endometriosis, which may facilitate the formation of ectopic lesions.
J Obstet Gynaecol Res. 2017 Nov 2.
Defining probabilities of bowel resection in deep endometriosis of the rectum: Prediction with preoperative magnetic resonance imaging.
Deep endometriosis of the rectum is a highly challenging disease, and a surgical approach is often needed to restore anatomy and function. Two kinds of surgeries may be performed: radical with segmental bowel resection or conservative without resection. Most patients undergo magnetic resonance imaging (MRI) before surgery, but there is currently no method to predict if conservative surgery is feasible or whether bowel resection is required. The aim of this study was to create an algorithm that could predict bowel resection using MRI images, that was easy to apply and could be useful in a clinical setting, in order to adequately discuss informed consent with the patient and plan the an appropriate and efficient surgical session.
We collected medical records from 2010 to 2016 and reviewed the MRI results of 52 patients to detect any parameters that could predict bowel resection. Parameters that were reproducible and with a significant correlation to radical surgery were investigated by statistical regression and combined in an algorithm to give the best prediction of resection.
The calculation of two parameters in MRI, impact angle and lesion size, and their use in a mathematical algorithm permit us to predict bowel resection with a positive predictive value of 87% and a negative predictive value of 83%.
MRI could be of value in predicting the need for bowel resection in deep endometriosisof the rectum. Further research is required to assess the possibility of a wider application of this algorithm outside our single-center stud
Health Care Women Int. 2017 Nov 2:1-19.
Examining subjective wellbeing and health-related quality of life in women with endometriosis.
The purpose of this study was to explore the subjective wellbeing, health-related quality of life and lived experience of women living with endometriosis. In 2015 five hundred participants between the ages of 18-63 (M = 30.5, SD = 7.46) were recruited through Endometriosis Australia and social media, completing an online questionnaire comprising the Personal Wellbeing Index, the Endometriosis Health Profile-30 and various open-ended questions. Results found that women with endometriosis reported low levels of subjective wellbeing (mean PWI total scores of 51.5 ± 2.03), considerably below the normative range of 70-80 for western populations. The mean Endometriosis Health Profile total score indicated a very low health-related quality of life amongst the women in this sample (78.9, ±13.14). There was also a significant relationship between scores on the Endometriosis Health Profile and Personal Wellbeing Index. The findings from the qualitative data suggest that endometriosis impacts negatively on women’s lives in several areas such as; social life, relationships and future plans, this in turn affects women’s overall life quality. The study highlights the strong negative impact that endometriosis can have on women’s subjective wellbeing and health related quality of life, contributing to productivity issues, relationship difficulties and social dissatisfaction and increasing the risk of psychological comorbidities.
Int J Surg Case Rep. 2017;41:226-229.
Endometrioid adenocarcinoma originating simultaneously from endometrium, sites of adenomyosis and ovarian endometriosis: A case report and review of our cancer database.
Although adenomyosis is a common disease, it is a relatively rare site for cancer origin. On the other hand, chocolate cysts have the potential to develop into cancer. We report a case of endometrioid adenocarcinoma occurred at three sites simultaneously; uterine endometrium, adenomyosis and ovarian endometriosis.
PRESENTATION OF CASE:
A 51-year-old woman underwent total hysterectomy and bilateral salpingo-oophorectomy after a diagnosis of corpus cancer (endometrioid adenocarcinoma, G1) stage IA. However, cancer was also found independently at the site of adenomyosis and in endometrioid cysts after a detailed postoperative histological investigation. There has been no sign of recurrence at 12 months after six cycles of chemotherapy with paclitaxel and carboplatin.
We reviewed cases of corpus cancer between January 2011 and December 2015 from our cancer database. Two hundred thirty-three patients with corpus cancer were identified. Ovarian malignancies were found in nine cases and six cases of them were histologically the same with the corpus cancer, but ovarian endometriosis was found in only two cases. On the other hand, adenomyosis was found histologically in 30 of these cases, but the case presented here was the only one diagnosed with cancer at a site of adenomyosis.
The mechanism by which malignancy develops in the normal endometrial tissue is not clear, but if endometrial cancer is found in the uterus, it could also be present in ectopic endometrial tissues such as sites of adenomyosis or chocolate cysts.
Comput Biol Chem. 2017 Dec;71:136-143.
Systematic identification of the druggable interactions between human protein kinases and naturally occurring compounds in endometriosis.
Diverse kinase signaling pathways have been involved in the pathogenesis of endometriosis (EM), which can be modulated either by directly targeting the hub kinases or by indirectly regulating marginal members in the pathways. Here, a systematic kinase-inhibitor interaction profile was created for 8 naturally occurring compounds against 20 human protein kinases. The compounds are all non-sterid that have been reported as pharmacologically active molecular entities potential for EM therapeutics, while the kinases were curated via gene ontology terms enriched from the gene co-citation network with EM. The resulting profile was analyzed at structural, energetic and dynamic levels to identify druggable kinase-compound interactions. The compounds Gossypol, Curcumin and EGCG showed a similar interaction profile across these kinases; they can bind tightly to the top-listed kinases in gene ontology, while the compounds Marrubiin, Apigenin and DIM were predicted to exhibit generally weak affinity for the 20 curated kinases. The JNK kinase, a MAPK family member, was identified as a putative candidate of druggable target for EM therapeutics; the inhibitory activity of eight naturally occurring compounds as well as a sophisticated kinase inhibitor SP600125 against the JNK was tested using enzymatic activity analysis. As might be expected, the Gossypol and EGCG were determined to have high inhibitory activity at namomolar level (IC50=55 and 94nM, respectively), which are comparable with or better than the positive control SP600125 (IC50=76nM), while other tested compounds exhibited weak inhibition (IC50>100nM) or bad potency (IC50=n.d.) against the kinase.