J Womens Health (Larchmt). 2017 Jun;26(6):644-654.

Retreatment Rates Among Endometriosis Patients Undergoing Hysterectomy or Laparoscopy.

Soliman AM¹, Du EX², Yang H³, Wu EQ³, Haley JC¹.

 

Abstract

BACKGROUND:

Hysterectomy and laparoscopy are the two most common surgical options used to treat women with endometriosis, yet the disease may still recur. This study aimed to determine the long-term retreatment rates among endometriosis patients in the United States who received either hysterectomy or laparoscopy.

MATERIALS AND METHODS:

Patients aged 18-49 years with endometriosis who underwent hysterectomy or laparoscopy were identified in the Truven Health MarketScan claims database (2004-2013). The retreatment rate up to 8 years after the initial surgery was estimated using Kaplan-Meier survival analysis. The relative risk of retreatment among patients with hysterectomy versus laparoscopy was assessed using a Cox proportional hazard model.

RESULTS:

A total of 24,915 patients with endometriosis who underwent hysterectomy and 37,308 patients with endometriosis who underwent laparoscopy were identified. The estimated retreatment rates were 3.3%, 4.7%, and 5.4% in the 2nd, 5th, and 8th year following hysterectomy, respectively, while the rates following laparoscopy were 15.8%, 27.5%, and 35.2%, respectively. The hazard ratio of retreatment was 0.157 (95% confidence interval [CI]: 0.146-0.169) comparing hysterectomy to laparoscopy. In the sensitivity analysis, which expanded the definition of retreatment by including medical treatments, the retreatment rate increased by a factor of 11-14 for the hysterectomy cohort and by a factor of 2-4 for the laparoscopy cohort, and the hazard ratio of retreatment rate for hysterectomy versus laparoscopy was 0.490 (95% CI: 0.477-0.502).

CONCLUSIONS:

Our study results indicated that the disease retreatment rate after laparoscopy is high among patients with endometriosis; even hysterectomy does not guarantee freedom from retreatment.

 

 

Mol Biosyst. 2017 Jun 1;13(6):1213-1222.

Metabolomic profiling and biochemical evaluation of the follicular fluid of endometriosis patients.

Marianna S¹, Alessia P², Susan C³, Francesca C⁴, Angela S³, Francesca C³, Antonella N⁴, Patrizia I⁵, Nicola C¹, Emilio C².

Abstract

Diseases are complex systems that can be studied through the integration of data derived from different disciplines to obtain a global and reliable picture of the biological phenomenon under investigation. Based on the recent observations that the metabolomics profiling of follicular fluids reflects the ovarian microenvironment of women and that endometriosis represents an example of complex diseases, clearly diagnosed by laparoscopy, we thought that the follicular fluids of endometriosis patients can represent a study model to evaluate the possibility of integrating data obtained by different approaches. Hence, the aim of this work was to analyze and integrate different clinical chemistry parameters with specific reference to the metabolic profile, inflammatory state and cell damage by a ¹H-NMR approach and biochemical analysis in the follicular fluids of women with different stages of endometriosis (I-II and III-IV) subjected to the In Vitro Fertilization (IVF) cycle. Our analysis evidenced that in the follicular fluids of endometriosis patients the levels of phospholipids, lactate, insulin, PTX3, CXCL8, CXCL10, CCL11 and VEGF were higher whereas those of some fatty acids, lysine, choline, glucose, aspartate, alanine, leucine, valine, proline, phosphocholine, total LDH as well its LDH-3 isoform were lower in comparison to the control group. The levels of LDHB, PTX3 and insulin receptor were also confirmed by RT-PCR applied on cumulus cells surrounding oocytes retrieved from the patients. The reduced oocyte quality observed in patients with endometriosis can be certainly correlated to the different levels of these molecules. These data represent how the integration of different experimental approaches may be useful for understanding the underlying mechanisms of a complex disease and can lead to a better clinical management of endometriosis.

 

 

Fertil Steril. 2017 May;107(5):1181-1190.

Incremental direct and indirect cost burden attributed to endometriosissurgeries in the United States.

Soliman AM¹, Taylor H², Bonafede M³, Nelson JK³, Castelli-Haley J⁴.

 

Abstract

OBJECTIVE:

To compare direct and indirect costs between endometriosis patients who underwent endometriosis-related surgery (surgery cohort) and those who have not received surgery (no-surgery cohort).

DESIGN:

Retrospective cohort study.

SETTING:

Not applicable.

PATIENT(S):

Endometriosis patients (aged 18-49 years) with (n = 124,530) or without (n = 37,106) a claim for endometriosis-related surgery were identified from the Truven Health MarketScan Commercial and Health and Productivity Management databases for 2006-2014.

INTERVENTION(S):

Not applicable.

MAIN OUTCOME MEASURE(S):

Primary outcomes were healthcare utilization during 12-month pre- and post-index periods, annual direct (healthcare) and indirect (absenteeism and short- and long-term disability) costs during the 12-month post-index period (in 2014 US dollars). Indirect costs were assessed for patients with available productivity data.

RESULT(S):

Patients in the surgery cohort had significantly higher healthcare resource utilization during the post-index period and had mean annual total adjusted post-index direct costs approximately three times the costs among patients in the no-surgery cohort ($19,203 [SD $7,133] vs. $6,365 [SD $2,364]; average incremental annual direct cost = $12,838). The mean cost of surgery ($7,268 [SD $7,975]) was the single largest contributor to incremental annual direct cost. Mean estimated annual total indirect costs were $8,843 (surgery cohort) vs. $5,603 (no-surgery cohort); average incremental annual indirect cost = $3,240.

CONCLUSION(S):

Endometriosis patients who underwent surgery, compared with endometriosis patients who did not, incurred significantly higher direct costs due to healthcare utilization and indirect costs due to absenteeism or short-term disability. Regardless of the surgery type, the cost of index surgery contributed substantially to the total healthcare expenditure.

 

 

Radiologia. 2017 Jul – Aug;59(4):286-296

Magnetic resonance imaging of pelvic endometriosis.

Méndez Fernández R¹, Barrera Ortega J².

 

Abstract

Endometriosis is common in women of reproductive age; it can cause pelvic pain and infertility. It is important to diagnose endometriosis and to thoroughly evaluate its extension, especially when surgical treatment is being considered. Magnetic resonance imaging (MRI) with careful examination technique and interpretation enables more accurate and complete diagnosis and staging than ultrasonography, especially in cases of deep pelvic endometriosis. Furthermore, MRI can identify implants in sites that can be difficult to access in endoscopic or laparoscopic explorations. In this article, we describe the appropriate MRI protocol for the study of pelvic endometriosis and the MRI signs of pelvic organ involvement. It is necessary to know the subtle findings and to look for them so we can ensure that they are not overlooked. We describe clinical grading systems for endometriosis and review the diagnostic efficacy of MRI in comparison with other imaging techniques and surgery.

 

 

Anticancer Res. 2017 May;37(5):2565-2574.

Clinicopathological Characteristics of Primary Ovarian Adenomyoma: A Single-institutional Experience.

Na K¹, Park SY², Kim HS³.

 

Abstract

Adenomyoma is a benign neoplasm composed of endometrial-type glands, specialized endometrial-type stroma, and well-formed smooth muscle bundles. This tumor typically originates within the uterus, whereas extrauterine adenomyoma is an unusual presentation. The ovary is the most common site of extrauterine adenomyoma. In this study, we describe the clinical and pathological features and immunohistochemical findings of primary ovarian adenomyoma in patients at our Institution. In addition, we provide a thorough review of previously published cases of primary ovarian adenomyoma and clarify their clinicopathological characteristics. The most common clinical presentations of ovarian adenoma were abdominopelvic pain and abnormal menstruation. Imaging features of ovarian adenomyoma varied, showing mixed solid and cystic, solid, or cystic masses. Frequently associated conditions included congenital anomalies of the urinary tract and endometriosis. Although most cases of ovarian adenomyoma exhibit benign histopathological features, we observed one case of endometrioid carcinoma arising in ovarian adenomyoma. Clinical follow-up data indicated that simple excision of the mass is curative for ovarian adenomyoma, but certain patients underwent unnecessary surgical procedures due to lack of awareness of primary ovarian adenomyoma and high index of suspicion for malignancy in patients with solid ovarian masses. Although ovarian adenomyoma is rare, awareness of this tumor type aids pathologists in making correct diagnoses and clinicians in avoiding unwarranted therapeutic procedures.

 

 

Mol Pain. 2017 Jan-Dec;13

Local upregulation of transient receptor potential ankyrin 1 and transient receptor potential vanilloid 1 ion channels in rectosigmoid deep infiltrating endometriosis.

Bohonyi N¹, Pohóczky K^2,3,4, Szalontai B², Perkecz A², Kovács K⁵, Kajtár B⁵, Orbán L⁶, Varga T¹, Szegedi S¹, Bódis J^1,7, Helyes Z^2,3,4,8, Koppán M¹.

 

Abstract

Transient Receptor Potential Vanilloid 1 (TRPV1) and Transient Receptor Potential Ankyrin 1 (TRPA1) expressed mainly by primary sensory neurons function as major nociceptive integrators. They are also present on the rat endometrium in an oestrogen-regulated manner. TRPV1 is upregulated in peritoneal and ovarian endometriosispatients, but there is no information about TRPA1 and their pathophysiological significances. In this study, patients undergoing laparoscopic surgery were investigated: severe dysmenorrhoea due to rectosigmoid deep infiltrating endometriosis ( n = 15), uterine fibroid-induced moderate dysmenorrhoea ( n = 7) and tubal infertility with no pain ( n = 6). TRPA1 and TRPV1 mRNA and protein expressions were determined by quantitative polymerase chain reaction and semi-quantitative immunohistochemistry from the endometrium samples taken by curettage. Results were correlated with the clinical characteristics including pain intensity. TRPA1 and TRPV1 receptors were expressed in the healthy human endometrium at mRNA and protein levels. Sparse, scattered cytoplasmic TRPA1 and TRPV1 immunopositivities were found in the stroma and epithelial layers. We detected upregulated mRNA levels in deep infiltrating endometriosis lesions, and TRPV1 gene expression was also elevated in autocontrol endometrium of deep infiltrating endometriosis patients. Histological scoring revealed significant TRPA1 and TRPV1 difference between deep infiltrating endometriosis stroma and epithelium, and in deep infiltrating endometriosis epithelium compared to control samples. Besides, we measured elevated stromal TRPV1 immunopositivity in deep infiltrating endometriosis. Stromal TRPA1 and TRPV1 immunoreactivities strongly correlated with dysmenorrhoea severity, as well TRPV1 expression on ectopic epithelial cells and macrophages with dyspareunia. Epithelial TRPA1 and stromal TRPV1 immunopositivity also positively correlated with dyschezia severity. We provide the first evidence for the presence of non-neuronal TRPA1 receptor in the healthy human endometrium and confirm the expression of TRPV1 channels. Their upregulations in rectosigmoid deep infiltrating endometriosis lesions and correlations with pain intensity suggest potential roles in pathophysiological mechanisms of the disease.

 

 

Georgian Med News. 2017 Mar;(264):90-97.

ANALYSIS OF ONE-CARBON METABOLISM GENES AND EPIDERMAL DIFFERENTIATION COMPLEX IN PATIENTS WITH ICHTHYOSIS VULGARIS.

Fedota O¹, Roshchenyuk L¹, Sadovnychenko I¹, Merenkova I¹, Gontar I¹, Vorontsov V¹.

 

Abstract

The aim of the study was to evaluate the effects of allelic polymorphism of the FLG and MTHFR genes and their associations in gynecological patients with ichthyosis vulgaris. Gynecological disorders are observed in presence of some forms of ichtyosis. From the prospective of improving nation’s healthcare, the greatest attention is drawn to reproductive disorders. Based on this, the research was also tasked with studying of the genetic nature of gynecological diseases, as well as the influence of geographical latitude on the frequencies of mutagenic alleles of the FLG gene and heterogeneous carriers of these mutations. The collection of clinical-gynecological history was carried out by the method of single registration of the proband on the basis of the Regional Clinical Dermatological and Venereological Health Center No. 1 and the Dermatovenerological Health Centers of the Kharkiv Region. The diagnosis and form of dermatosis is established on the basis of the analysis of clinical and gynecological data and the results of laboratory tests in accordance with ICD-10: ichthyosis vulgaris (Q 80.1.0, OMIM 146700). The data on 18 women and 20 men from 3 families, aged 26 to 76 years old, suffering from ichthyosis, were analyzed. As a result of the study, a direct correlation was determined between the latitude and frequencies of mutant alleles of the FLG gene, as well as between the geographical latitude and frequency of heterozygous carriers of these mutations. The frequencies of the T allele and the CT genotype according to polymorphic variant C677T of the MTHFR gene demonstrate feedback with the latitude indicators. The frequency distributions of the 2282del4 allele and the CT genotype, the N/2282del4 and CT genotypes, the 2282del4 and T alleles, the N/2282del4 genotype and the T allele have opposite latitudinal zonation. The established connections made it possible to predict the development of gynecological pathologies in women with ichthyosis vulgaris. The prevalence of endometriosis and endometrial cancer in women with ichthyosis vulgaris in the Kharkiv region was 33.3%, while the average for the female population in the region was 0.29-0.35%. The number of children born to women with ichthyosis vulgaris did not differ from the regional index.

 

 

Hum Reprod. 2017 Jul 1;32(7):1432-1438.

Physical pain and emotion regulation as the main predictive factors of health-related quality of life in women living with endometriosis.

Márki G^1,2, Bokor A³, Rigó J³, Rigó A².

 

Abstract

STUDY QUESTION:

To what extent are pain symptoms, psychological variables (anxiety, depression and distress) and emotion regulation associated with women’s health in endometriosis?

SUMMARY ANSWER:

Physical pain symptoms and emotion regulation difficulties via psychological stress negatively affect the health-related quality of life (HRQoL) of women living with endometriosis.

WHAT IS KNOWN ALREADY:

There are some missing links in the definitive treatment and recovery from endometriosis. Women with chronic pain report a decrease in HRQoL and an increase in the frequency of psychological problems, but little is known about the complex relationship between these variables in the context of endometriosis.

STUDY DESIGN, SIZE, DURATION:

This cross-sectional study was conducted between October 2014 and October 2015 on 193 women living with endometriosis.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

The sample consisted of women with a medically confirmed diagnosis of endometriosis who received treatment at the participating clinic. All participants completed the Short Form Health Survey (SF-36), the Hospital Anxiety and Depression Scale, the Perceived Stress Scale and the Difficulties in Emotion Regulation Scale. Spearman’s rank correlation was used to explore the associations between the measured variables, and structural equation modeling was used to test the proposed mediation models.

MAIN RESULTS AND THE ROLE OF CHANCE:

The response rate was 46%. In this study, 54.79% of the participants presented with anxiety and 20.3% with depressive symptoms. Pain symptoms, psychological variables and difficulties in emotion regulation were negatively associated with HRQoL. Mediation models revealed that physical pain, psychological stress and difficulties in emotion regulation explained 55% of the variance in the overall HRQoL, 41% of the variation in physical and 55% of the variation in mental HRQoL. Accordingly, severe physical pain (β = -0.39, P < 0.001) was directly, and difficulties in emotion regulation (β = -0.38, P < 0.001) was indirectly related to deterioration in overall HRQoL. Physical pain had a higher direct standardized effect (β = -0.51, P < 0.001) on physical HRQoL, and had no significant direct effect on mental HRQoL. Furthermore, both physical pain (β = -0.07, P < 0.001) and difficulties in emotion regulation (β = -0.46, P < 0.001) had a significant indirect effect on mental HRQoL.

LIMITATIONS, REASONS FOR CAUTION:

The data were heterogeneous with regard to the severity of endometriosis. The validity of this cross-sectional study is limited to correlations; therefore, further longitudinal studies using a more representative sample are needed to explore valid causal relationships.

WIDER IMPLICATIONS OF THE FINDINGS:

The results of this study indicate that HRQoL can be improved through pain management and emotion regulation strategies. The authors believe that HRQoL would increase with concomitant application of physical treatment and psychological care.

STUDY FUNDING/COMPETING INTEREST(S):

There were no external funding sources for this study, and the authors have no conflicts of interest to declare.

 

 

Eur J Obstet Gynecol Reprod Biol. 2017 Jun;213:116-122.

Does telomerase activity have an effect on infertility in patients with endometriosis?

Sofiyeva N¹, Ekizoglu S², Gezer A³, Yilmaz H⁴, Kolomuc Gayretli T³, Buyru N², Oral E³.

 

Abstract

OBJECTIVE:

This study aimed to investigate the role of telomerase activity in the development of endometriosis-related infertility by evaluation of the serum telomerase in eutopic and ectopic endometrial tissue.

STUDY DESIGN:

Eutopic endometrium, cystic wall/ovarian cortex, and venous blood were assessed in forty-seven patients. The following groups of patients were identified: females with endometriosis requiring surgical intervention and healthy control females. Patients with histopathologically confirmed endometriosis were further subdivided in the infertile (n=14) and fertile (n=17) groups. Patients who underwent hysterectomy and oophorectomy for benign gynecological conditions were enrolled in the healthy control group (n=16). Telomerase activity was evaluated with three-group, endometriosis-based and fertility-based designs. Analyses were performed regardless the menstrual cycle phase (Phase G), in proliferative (Phase P) (n=22) and secretory phases (Phase S) (n=25). Telomeric Repeat Amplification Protocol PCR was applied for telomerase activity assessment. All statistical analyses were performed with STATA 14.2, GraphPad Prisma 7.01.

RESULTS:

In analyses of the eutopic endometrium, with three-group design, a significant difference was not found in Phase G and P (p=0.58 and p=0.33, respectively). However, a statistical difference was shown in Phase S (p=0.008). A significant difference was not established in Phase G, P and S of endometriosis-based design (p=0.35, p=1.0, p=0.13, respectively). No difference was detected in Phase G and P of fertility-based design (p=0.66 and p=0.14, respectively), whereas in secretory phase difference was approved (p=0,049). Telomerase activity was not established in ectopic endometrium and in serum assessment.

CONCLUSIONS:

Telomerase activity is useless as a biomarker in peripheric blood analysis. The absence of activity in cystic wall approves the high differentiation of endometriosis tissue, what is the possible reason of low malignancy risk. The high rate of telomerase activity in the eutopic endometrium of the infertile group may be considered as a cause of endometriosis-related infertility.

 

 

Eur J Obstet Gynecol Reprod Biol. 2017 Jul;214:65-70.

Dienogest inhibits C-C motif chemokine ligand 20 expression in human endometriotic epithelial cells.

Mita S¹, Nakakuki M², Ichioka M², Shimizu Y³, Hashiba M², Miyazaki H², Kyo S⁴.

 

Abstract

OBJECTIVE:

C-C motif chemokine ligand 20 is thought to contribute to the development of endometriosis by recruiting Th17 lymphocytes into endometriotic foci. The present study investigated the effects of dienogest, a progesterone receptor agonist used to treat endometriosis, on C-C motif chemokine ligand 20 expression by endometriotic cells.

STUDY DESIGN:

Effects of dienogest on mRNA expression and protein secretion of C-C motif chemokine ligand 20 induced by interleukin 1β were assessed in three immortalized endometriotic epithelial cell lines, parental cells (EMosis-CC/TERT1), and stably expressing human progesterone receptor isoform A (EMosis-CC/TERT1/PRA+) or isoform B (EMosis-CC/TERT1/PRA-/PRB+).

RESULTS:

Dienogest markedly inhibited interleukin 1β-stimulated C-C motif chemokine ligand 20 mRNA expression and protein secretion in EMosis-CC/TERT1/PRA-/PRB+, which was abrogated by the progesterone receptor antagonist RU486. In EMosis-CC/TERT1/PRA+, dienogest slightly inhibited C-C motif chemokine ligand 20 mRNA and protein. In EMosis-CC/TERT1, dienogest slightly inhibited C-C motif chemokine ligand 20 mRNA, but had no effect on C-C motif chemokine ligand 20 protein.

CONCLUSION:

Dienogest inhibited interleukin 1β-induced up-regulation of C-C motif chemokine ligand 20 in endometriotic epithelial cells, mainly mediated by progesterone receptor B.

 

 

Cancer Lett. 2017 Aug 10;401:11-19

Down-regulation of ARID1A is sufficient to initiate neoplastic transformation along with epigenetic reprogramming in non-tumorigenic endometriotic cells.

Lakshminarasimhan R¹, Andreu-Vieyra C², Lawrenson K³, Duymich CE¹, Gayther SA⁴, Liang G⁵, Jones PA⁶.

 

Abstract

The chromatin remodeler AT-Rich Interactive Domain 1A (ARID1A) is frequently mutated in ovarian clear cell carcinoma (OCCC) and endometriosis precursor lesions. Here, we show that knocking down ARID1A in an immortalized endometriosis cell line is sufficient to induce phenotypic changes indicative of neoplastic transformation as evidenced by higher efficiency of anchorage-independent growth, increased propensity to adhere to collagen, and greater capacity to invade basement membrane extract in vitro. ARID1A knockdown is associated with expression dysregulation of 99 target genes, and many of these expression changes are also observed in primary OCCC tissues. Further, pathway analysis indicates these genes fall within networks highly relevant to tumorigenesis including integrin and paxillin pathways. We demonstrate that the down-regulation of ARID1A does not markedly alter global chromatin accessibility or DNA methylation but unexpectedly, we find strong increases in the active H3K27ac mark in promoter regions and decreases of H3K27ac at potential enhancers. Taken together, these data provide evidence that ARID1A mutation can be an early stage event in the oncogenic transformation of endometriosis cells giving rise to OCCC.

 

 

Organogenesis. 2017 Jul 3;13(3):95-102.

Endometriosis origin from primordial germ cells.

Makiyan Z¹.

 

Abstract

Endometriosis is defined by the presence of endometrial ectopia. Multiple hypotheses have been postulated to explain the etiology of endometriosis to understand various clinical evidences. The etiology of endometriosis is still unclear.The primary question to understanding the etiology of endometrial ectopia (endometriosis) is determining the origin of eutopic (normally cited) endometrium.According to the new theory, primordial germ cells migrate from hypoblast (yolk sac close to the allantois) to the gonadal ridges. The gonadal ridges which composed of primordial germ cells derive to the: eutopic endometrium, ovary, ovarian ligament and ligamentum teres uteri.There are 2 principal processes in uterine organogenesis: the intersection of gonadal ridges with mesonephral ducts to form the uterine folds with an endometrial cavity and the fusion of the both uterine folds together to form the unicavital (normal) uterus. In the uterine folds there are closer cell-to-cell communications, polypotential germ cells differentiate and grow into myometrium and endometrial layers.Some of the polypotential germ cells fail to reach the ridges and stay in the peritoneal cavity, where they may be transforming into external endometrial heterotopies.The main insight in the etiology of endometriosis is polypotential germ cells origin, which may explain its potency, pathogenesis and expansion.

 

 

Mol Hum Reprod. 2017 Jul 1;23(7):488-499

Dysregulation of the ADAM17/Notch signalling pathways in endometriosis: from oxidative stress to fibrosis.

González-Foruria I^1,2,3, Santulli P^1,2, Chouzenoux S¹, Carmona F⁴, Chapron C^1,2, Batteux F^1,5.

 

Abstract

STUDY QUESTION:

Is oxidative stress associated with the A disintegrin and metalloproteases (ADAM) metallopeptidase domain 17 (ADAM17)/Notch signalling pathway and fibrosis in the development of endometriosis?

SUMMARY ANSWER:

Oxidative stress is correlated with hyperactivation of the ADAM17/Notch signalling pathway and a consequent increase in fibrosis in patients with endometriosis.

WHAT IS KNOWN ALREADY:

It is nowadays accepted that oxidative stress plays an important role in the onset and progression of endometriosis. Oxidative stress is able to induce the synthesis of some members of the ‘ADAM’ family, such as ADAM17. ADAM17/Notch signalling is dysregulated in other profibrotic and inflammatory diseases.

STUDY DESIGN, SIZE, DURATION:

This was a prospective laboratory study conducted in a tertiary-care university hospital between January 2011 and April 2013. We investigated non-pregnant, younger than 42-year-old patients (n = 202) during surgery for a benign gynaecological condition.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

After complete surgical exploration of the abdominopelvic cavity, 121 women with histologically proven endometriosis and 81 endometriosis-free control women were enrolled. Peritoneal fluid (PF) samples were obtained from all the study participants during surgery in order to detect advanced oxidation protein products (AOPPs) and metalloproteinase activity of ADAM17. Stromal cells from endometrial specimens (n = 8) were obtained from endometrium of control patients (Cs), and from eutopic (Es) and ectopic (Ps) endometrium of patients with deep infiltrating endometriosis (DIE) (n = 8). ADAM17, Notch and the fibrosis markers α-smooth muscle actin (α-SMA) and type-I collagen were assessed using immunoblotting in all the endometrial samples obtained. Additionally, fibrosis was assessed after using Notch cleavage inhibitors (DAPT and FLI-06). Notch and fibrosis were also evaluated after stimulation of stromal endometrial cells with ADAM17 purified protein, increasing concentrations of H2O2 and primary cell culture supernatants.

MAIN RESULTS AND THE ROLE OF CHANCE:

Patients with DIE presented higher PF AOPP and ADAM17 protein levels than controls (P < 0.01 and P < 0.05, respectively). In addition, these two markers were positively correlated (r = 0.614; P < 0.001). At the cellular level, ADAM17 activity was increased in Es and Ps compared to Cs (P < 0.001 and P < 0.01, respectively). Furthermore, Ps presented hyperactivation of Notch signalling (P < 0.05) and augmentation of fibrosis markers (P = 0.009 for α-SMA and P = 0.015 for type-I collagen) compared to controls. The use of DAPT and FLI-06 reduced both fibrosis markers in Ps but not in Cs. Stimulation with ADAM17, H2O2 and Ps supernatant culture significantly increased Notch and fibrosis in both Ps and Cs.

LARGE SCALE DATA:

N/A.

LIMITATIONS REASONS FOR CAUTION:

The control group consisted of women who underwent surgery for benign gynaecological conditions, which could lead to biases because some of these conditions may cause alterations in oxidative stress and the ADAM17/Notch pathways. The small sample size of endometrial biopsies used for each group of patients (n = 8) is a limitation of the study, and results should be interpreted with caution.

WIDER IMPLICATIONS OF THE FINDINGS:

We propose a novel pathway in endometriosis pathogenesis that correlates oxidative stress, hyperactivation of ADAM17/Notch signalling and a consequent increase in fibrosis. This study suggests that Notch signalling plays a key role in the fibrotic processes that take place in ectopic lesions of patients with DIE, as already observed in other pro-fibrotic diseases.

STUDY FUNDING AND COMPETING INTEREST(S):

This work was supported by grants from University Paris Descartes, INSERM and Fundación Alfonso Martín Escudero. The authors have no competing interests to declare.

 

 

 

Biotechnol Lett. 2017 Aug;39(8):1263-1268

All-trans retinoic acid enhances in vitro mesenchymal stem cells migration by targeting matrix metalloproteinases 2 and 9.

Pourjafar M^1,2, Saidijam M¹, Etemadi K³, Najafi R^4,5.

 

Abstract

OBJECTIVES:

To investigate the effect of all-trans retinoic acid (ATRA) on caspase 3 activity, matrix metalloproteinase 2 (MMP-2), and MMP-9 expression and activity as well as in vitro rat bone marrow-derived mesenchymal stem cells (MSCs) migration.

RESULTS:

The expression of the MMP-2/-9 was at least five times higher in ATRA-treated MSCs (P < 0.001), and MMP-2/-9 activity was enhanced with increasing doses compared to the control MSCs. The caspase three activity was attenuated by ATRA preconditioning. Scratch test showed that ATRA could promote the migration capacity of the MSCs compared to the untreated MSCs in a dose-dependent manner.

CONCLUSION:

ATRA increases the in vitro migration capacity of the MSCs through stimulating the expression and activity of MMP-2/-9 and inhibiting caspase three enzyme activity.

 

 

N Engl J Med. 2017 May 11;376(19):1835-1848

Cancer-Associated Mutations in Endometriosis without Cancer.

Anglesio MS¹, Papadopoulos N¹, Ayhan A¹, Nazeran TM¹, Noë M¹, Horlings HM¹, Lum A¹, Jones S¹, Senz J¹, Seckin T¹, Ho J¹, Wu RC¹, Lac V¹, Ogawa H¹, Tessier-Cloutier B¹, Alhassan R¹, Wang A¹, Wang Y¹, Cohen JD¹, Wong F¹, Hasanovic A¹, Orr N¹, Zhang M¹, Popoli M¹, McMahon W¹, Wood LD¹, Mattox A¹, Allaire C¹, Segars J¹, Williams C¹, Tomasetti C¹, Boyd N¹, Kinzler KW¹, Gilks CB¹, Diaz L¹, Wang TL¹, Vogelstein B¹, Yong PJ¹, Huntsman DG¹, Shih IM¹.

 

Abstract

BACKGROUND:

Endometriosis, defined as the presence of ectopic endometrial stroma and epithelium, affects approximately 10% of reproductive-age women and can cause pelvic pain and infertility. Endometriotic lesions are considered to be benign inflammatory lesions but have cancerlike features such as local invasion and resistance to apoptosis.

METHODS:

We analyzed deeply infiltrating endometriotic lesions from 27 patients by means of exomewide sequencing (24 patients) or cancer-driver targeted sequencing (3 patients). Mutations were validated with the use of digital genomic methods in microdissected epithelium and stroma. Epithelial and stromal components of lesions from an additional 12 patients were analyzed by means of a droplet digital polymerase-chain-reaction (PCR) assay for recurrent activating KRAS mutations.

RESULTS:

Exome sequencing revealed somatic mutations in 19 of 24 patients (79%). Five patients harbored known cancer driver mutations in ARID1A, PIK3CA, KRAS, or PPP2R1A, which were validated by Safe-Sequencing System or immunohistochemical analysis. The likelihood of driver genes being affected at this rate in the absence of selection was estimated at P=0.001 (binomial test). Targeted sequencing and a droplet digital PCR assay identified KRAS mutations in 2 of 3 patients and 3 of 12 patients, respectively, with mutations in the epithelium but not the stroma. One patient harbored two different KRAS mutations, c.35G→T and c.35G→C, and another carried identical KRAS c.35G→A mutations in three distinct lesions.

CONCLUSIONS:

We found that lesions in deep infiltrating endometriosis, which are associated with virtually no risk of malignant transformation, harbor somatic cancer driver mutations. Ten of 39 deep infiltrating lesions (26%) carried driver mutations; all the tested somatic mutations appeared to be confined to the epithelial compartment of endometriotic lesions.

 

 

Reprod Sci. 2018 Jan;25(1):140-159.

Endometrial Stromal and Epithelial Cells Exhibit Unique Aberrant Molecular Defects in Patients With Endometriosis.

Logan PC¹, Yango P¹, Tran ND¹.

 

Abstract

CONTEXT:

Endometriosis is a chronic inflammatory disease that causes pain and infertility in women of reproductive age.

OBJECTIVE:

To investigate the pathologic pathways in endometrial stromal and epithelial cells that contribute to the manifestation of endometriosis.

DESIGN:

In vitro cellular and molecular analyses of isolated eutopic endometrial stromal and epithelial cells.

METHODS:

Eutopic stromal and epithelial cells from endometriotic and normal patients were isolated by fluorescence-activated cell sorting for paired sibling RNA sequencing and microRNA microarray. Aberrant pathways were identified using ingenuity pathway analysis networks and confirmed with in vitro modulation of the affected pathways in stromal and epithelial cell cultures.

RESULTS:

Both stromal versus epithelial cell types and paired endometriotic versus normal samples exhibited distinct hierarchical clustering. Compared to normal samples, there were 151 and 215 differentially expressed genes in the endometriotic stromal and epithelial populations, respectively, and concomitantly 9 and 16 differentially expressed microRNAs. Overall, endometriotic stromal and epithelial cells revealed distinct defects. In endometriotic stromal cells, key decidualization genes Zinc finger E-box Binding protein 1 (ZEB1), Heart And Neural crest Derivatives expressed 2 (HAND2), WNT4, and Interleukin 15 (IL-15) were found to be downregulated and Periostin (POSTN) and Matrix Metallopeptidase 7 (MMP7) were upregulated. Specifically, ZEB1 was downregulated in stromal cells by aberrant elevation in miR-200b. In contrast, ZEB1 was found to be upregulated in endometriotic epithelial cells through associated upregulation of transforming growth factor β1 (TGFβ1), inducer of the TGFβ1-Bone Morphogenetic Protein 2 (BMP2)-MMP2-Prostaglandin-endoperoxide Synthase 2 (COX2)-ZEB1 pathway, which activates epithelial-mesenchymal transition.

CONCLUSION:

Manifestation of endometriosis involves dysregulation of unique molecular pathways within the diseased endometrial stromal and epithelial cells in the endometrium. Targeting the cell type-specific defects may offer a novel approach to treating endometriosis.

 

 

J Neurosci Res. 2017 Dec;95(12):2448-2455.

Treadmill exercise attenuates 3,4-methylenedioxymethamphetamine-induced memory impairment through a decrease apoptosis in male rat hippocampus.

Gharebaghi A¹, Amiri I², Salehi I³, Shahidi S³, Komaki A³, Mehdizadeh M⁴, Moravej FG⁵, Asl SS^1,5.

 

Abstract

3,4-methylenedioxymethamphetamine (MDMA) leads to apoptosis in the hippocampus with consequent induction of learning and memory impairment. In this study, we have investigated the effects of treadmill exercise on memory in relation to apoptosis and oxidative stress in the hippocampi of MDMA-treated rats. Male Wistar rats received multiple intraperitoneal (IP) injections of MDMA (10 mg/kg) and exercised for one month on a treadmill (simultaneously or asynchronously with MDMA). We assessed memory function with the Morris water maze (MWM) test. Lipid peroxidation (LPO) and expression of caspase 3, Bax, and Bcl-2 were examined by the thiobarbituric acid assay (TBA) and western blot, respectively. Our results showed that asynchronous treadmill exercise could significantly improve MDMA-induced memory impairment in the MWM test. Caspase 3 expression decreased in the exercise group compared to the MDMA group. Although MDMA treatment caused an increase in the Bax/Bcl-2 ratio, the treadmill exercise reduced this ratio. Simultaneous exercise caused a reduction in lipid peroxidation in the hippocampus. This data suggests that treadmill exercise can be a useful strategy for treating memory impairment in persons with neurodegenerative disease and stimulant drug users. © 2017 Wiley Periodicals, Inc.

 

 

 

 

J Clin Nurs. 2018 Jan;27(1-2):205-211

The double-edged experience of healthcare encounters among women with endometriosis: A qualitative study.

Grundström H^1,2, Alehagen S², Kjølhede P^3,4, Berterö C².

 

Abstract

AIMS AND OBJECTIVES:

To identify and describe the experience of healthcare encounters among women with endometriosis.

BACKGROUND:

Endometriosis is a “hidden” chronic gynaecological disease appearing in every 10th woman of fertile age. Different manifestations of pain are the main symptoms, often leading to impaired physical and mental health, and lower quality of life. Previous research on healthcare experiences among women with endometriosishas focused on diagnostic delay and experiences of encountering general practitioners.

DESIGN:

A qualitative, interpretive, phenomenological approach was used.

METHODS:

We interviewed nine women aged 23-55, with a laparoscopy-confirmed diagnosis of endometriosis. The interviews were recorded and transcribed verbatim. The data were analysed following the steps of the interpretive phenomenological approach.

RESULTS:

Two themes were identified in the interview transcripts: being treated with ignorance and being acknowledged. The essence: “the double-edged experience of healthcare encounters” emerged from the themes. The women’s experience was double-edged as it involved contradictory feelings: the encounters were experienced as both destructive or constructive. On the one hand, the destructive side was characterised by ignorance, exposure and disbelief. On the other hand, the constructive side made the women feel acknowledged and confirmed, boosting their self-esteem.

CONCLUSIONS:

The new and important aspects of the findings are that the experience of healthcare encounters is for the first time expressed as double-edged: both destructive and constructive. The experience was of specific importance as it affected the women’s perceptions of themselves and of their bodies.

RELEVANCE TO CLINICAL PRACTICE:

The information about the constructive side of the experience is of clinical valuable for all healthcare professionals (nurses, midwives and doctors) encountering these women, as it provides a new level of understanding of the experiences. The findings demonstrate both psychological and practical aspects that can help professionals to improve the encounters.

 

 

Radiographics. 2017 May-Jun;37(3):797-812.

Soft-Tissue Sarcomas of the Abdomen and Pelvis: Radiologic-Pathologic Features, Part 2-Uncommon Sarcomas.

Levy AD¹, Manning MA¹, Miettinen MM¹.

 

Abstract

Soft-tissue sarcomas occurring in the abdomen and pelvis are an uncommon but important group of malignancies. Recent changes to the World Health Organization classification of soft-tissue tumors include the movement of gastrointestinal stromal tumors (GISTs) into the soft-tissue tumor classification. GIST is the most common intraperitoneal sarcoma. Liposarcoma is the most common retroperitoneal sarcoma, and leiomyosarcoma is the second most common. GIST, liposarcoma, and leiomyosarcoma account for the majority of sarcomas encountered in the abdomen and pelvis and are discussed in part 1 of this article. Undifferentiated pleomorphic sarcoma (previously called malignant fibrous histiocytoma), dermatofibrosarcoma protuberans, solitary fibrous tumor, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, extraskeletal chondro-osseous sarcomas, vascular sarcomas, and sarcomas of uncertain differentiation uncommonly arise in the abdomen and pelvis and the abdominal wall. Although these lesions are rare sarcomas and their imaging features overlap, familiarity with the locations where they occur and their imaging features is important so they can be diagnosed accurately. The anatomic location and clinical history are important factors in the differential diagnosis of these lesions because metastasis, more-common sarcomas, borderline fibroblastic proliferations (such as desmoid tumors), and endometriosis have imaging findings that overlap with those of these uncommon sarcomas. In this article, the clinical, pathologic, and imaging findings of uncommon soft-tissue sarcomas of the abdomen and pelvis and the abdominal wall are reviewed, with an emphasis on their differential diagnosis.

 

 

Int J Surg Case Rep. 2017;36:8-14.

An unexpected diagnosis of primary omental endometrial stromal sarcoma in a patient with acute right abdominal pain: A case report and review of literature.

Buchholz V¹, Kiroff G², Trochsler M², Kanhere H².

 

Abstract

INTRODUCTION:

Extrauterine Endometrial Stromal Sarcoma (EESS) is an extremely rare mesenchymal tumour that simulates other pathologies, and therefore poses a diagnostic challenge. This report outlines a case of EESS arising from the greater omentum mimicking a colonic tumour, with review of literature.

PRESENTATION OF CASE:

A 47-year-old woman, with history of hysterectomy for menorrhagia and hormone replacement therapy (HRT), presented with right sided abdominal pain and localized peritonism. On exploratory laparoscopy an omental tumour, suspected to arise from the transverse colon was identified and biopsied. The histological features suggested an EESS. Colonoscopy ruled out colonic lesion. A laparoscopic tumour resection and bilateral salpingo-oophorectomy (BSO) was performed. Immunohistochemistry confirmed the diagnosis. No additional lesions or associated endometriosis were found. Resection was followed by adjuvant medroxyprogesterone-acetate therapy.

DISCUSSION:

We reviewed 20 cases of EESS originating from extragenital abdominopelvic organs reported since 1990. Acute presentation is rare, as well as upper abdominal occurrence. Isolated omental involvement was previously reported in only one case. Endometriosis is a risk factor for development of EESS and history and/or histological evidence for endometriosis is usually present. HRT is another acknowledged risk factor, mostly on the background of endometriosis. To our knowledge, this is the only report of EESS occurring in a woman on HRT treatment without background of endometriosis.

CONCLUSION:

EESS can occur without endometriosis and HRT may be an aetiological factor. The condition can mimic a chronic or acute abdominal pathology and laparoscopic core biopsy is the best way to achieve a diagnosis and formulate management.

 

 

 

 

Reproduction. 2017 Jul;154(1):93-100.

High-throughput mRNA sequencing of stromal cells from endometriomas and endometrium.

Rekker K^1,2, Saare M^3,2, Eriste E², Tasa T^4,5, Kukuškina V^5,6, Roost AM², Anderson K², Samuel K², Karro H^3,7, Salumets A^3,2,8,9, Peters M^3,2.

 

Abstract

The aetiology of endometriosis is still unclear and to find mechanisms behind the disease development, it is important to study each cell type from endometrium and ectopic lesions independently. The objective of this study was to uncover complete mRNA profiles in uncultured stromal cells from paired samples of endometriomas and eutopic endometrium. High-throughput mRNA sequencing revealed over 1300 dysregulated genes in stromal cells from ectopic lesions, including several novel genes in the context of endometriosis. Functional annotation analysis of differentially expressed genes highlighted pathways related to cell adhesion, extracellular matrix-receptor interaction and complement and coagulation cascade. Most importantly, we found a simultaneous upregulation of complement system components and inhibitors, indicating major imbalances in complement regulation in ectopic stromal cells. We also performed in vitro experiments to evaluate the effect of endometriosispatients’ peritoneal fluid (PF) on complement system gene expression levels, but no significant impact of PF on C3, CD55 and CFH levels was observed. In conclusion, the use of isolated stromal cells enables to determine gene expression levels without the background interference of other cell types. In the future, a new standard design studying all cell types from endometriotic lesions separately should be applied to reveal novel mechanisms behind endometriosis pathogenesis.

 

 

Int J Womens Health. 2017 May 2;9:281-293.

Self-management and psychological-sexological interventions in patients with endometriosis: strategies, outcomes, and integration into clinical care.

Buggio L^1,2, Barbara G³, Facchin F⁴, Frattaruolo MP^1,2, Aimi G², Berlanda N².

 

Abstract

Endometriosis has a multifactorial etiology. The onset and progression of the disease are believed to be related to different pathogenic mechanisms. Among them, the environment and lifestyle may play significant roles. Diet, dietary supplements, physical exercise, osteopathy, massage, acupuncture, transcutaneous electrical nerve stimulation, and Chinese herbal medicine may represent a complementary and feasible approach in the treatment of symptoms related to the disease. In this narrative review, we aimed to examine the most updated evidence on these alternative approaches implicated in the self-management of the disease. In addition, several studies have demonstrated that endometriosis may negatively impact mental health and quality of life, suggesting that affected women may have an increased risk of developing psychological suffering as well as sexual problems due to the presence of pain. In light of these findings, we discuss the importance of integrating psychological interventions (including psychotherapy) and sexual therapy in endometriosis treatment.

 

 

 

 

Hum Reprod. 2017 Jul 1;32(7):1427-1431.

Which is worse? Comparison of ART outcome between women with primary or recurrent endometriomas.

Ata B¹, Mumusoglu S², Aslan K³, Seyhan A⁴, Kasapoglu I², Avci B⁴, Urman B⁴, Bozdag G², Uncu G⁴.

 

Abstract

STUDY QUESTİON:

Are live birth rates (LBR) different after ART cycles between women with primary or recurrent endometrioma?

SUMMARY ANSWER:

Women with recurrent endometrioma have similar LBR as compared to patients with primary endometrioma.

WHAT IS ALREADY KNOWN:

Recurrence rate can be as high as 29% after endometrioma excision. Prior studies on management of endometrioma before ART involve primary endometriomas. There is limited information regarding the prognosis of women with recurrent endometriomas.

STUDY DESIGN, SIZE, DURATION:

A multicenter retrospective cohort study, including 76 women with primary and 82 women with recurrent endometriomas treated at the participating centers over a 6-year period.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Women with endometrioma who underwent ART at three academic ART centers. Couples with another indication for ART were excluded.

MAIN RESULTS AND THE ROLE OF CHANCE:

Female age, median number of prior failed ART cycles, proportion of patients with bilateral endometrioma (28 versus 28.9%), ovarian stimulation protocols, and total gonadotropin consumption were similar between the study groups. Numbers of metaphase two oocytes (5 versus 6), number of embryos transferred, and the proportion of patients undergoing blastocyst transfer were similar across the study groups. Clinical pregnancy rates (36.6 versus 34.2%, absolute difference 2.4%, 95% CI: -12.5 to 17.3%, P = 0.83) and LBR (35.4 versus 30.3%, absolute difference 5.1%, 95% CI: -9.5 to 19.7%, P = 0.51) per started cycle in recurrent and primary endometrioma were similar. Comparable success rates were also confirmed with logistic regression analysis (OR: 1.14, 95% CI: 0.78-0.57, P = 2.3).

LIMITATIONS, REASONS FOR CAUTION:

The retrospective design has inherent limitations. Some women with severely decreased ovarian reserve after primary endometrioma excision may not have pursued further treatment.

WIDER IMPLICATIONS OF THE FINDINGS:

The management of endometrioma prior to ART is controversial but a different management strategy is not required for recurrent endometriomas. Since recurrent endometriomas do not have a worse impact on ART outcome than primary endometriomas, and repeat surgery has a higher risk for complications, conservative management without surgery can be justified.

STUDY FUNDING/COMPETING INTEREST(S):

No funding or competing interests to declare.

 

 

Redox Biol. 2017 Aug;12:956-966.

Redox regulation of microRNAs in endometriosis-associated pain.

Wright KR¹, Mitchell B², Santanam N³.

 

Abstract

Endometriosis is a chronic, painful condition with unknown etiology. A differential expression of microRNAs in the endometriotic tissues from women with endometriosis with pain compared to those without suggested a plausible role for miRNA or epigenetic mechanisms in the etiology of endometriotic pain. The peritoneal milieu is involved in maintenance of endometriotic lesion and nociception. We recently showed the mechanistic role for oxidized-lipoproteins (ox-LDLs) present in peritoneal fluid (PF) in endometriosis and pain. We explored the possibility of ox-LDLs modulating the expression of miRNAs in a manner similar to PF from women with endometriosis. Expression levels of miRNAs and their predicted nociceptive and inflammatory targets were determined in PF and ox-LDL treated human endometrial cell-lines. Samples from IRB-approved and consented patients with and without endometriosis or pain were used. These were compared to endometrial cell-lines treated with various forms of oxidized-lipoproteins. RNA (including miRNAs) were isolated from treated endometrial cells and expression levels were determined using commercial miRNome arrays. Cell lysates were used in immunoblotting for inflammatory proteins using a protein array. Twenty miRNAs including isoforms of miR-29, miR-181 and let-7 were mutually differentially expressed in cells treated with PF from endometriosis patients with pain and those treated with ox-LDL components. The ox-LDLs and endo-PF treatment also produced significant overexpression of microRNA predicted target genes nerve growth factor, interleukin-6 and prostaglandin E synthase and overexpression of their downstream protein targets Mip1α and MCP1. This study showed similarities between miRNA regulation in PF from endometriotic women and ox-LDLs present in abundance in the PF of these women. Key miRNAs responsible for targeting nociceptive and inflammatory molecules were downregulated in the presence of ox-LDLs and endo-PF, thus playing a role in the etiology of endometriotic pain. These redox-sensitive miRNAs can be of potential use as targets in the treatment of endometriosis-associated pain.

 

 

Hormones (Athens). 2017 Jan;16(1):5-21.

Vitamin D and aspects of female fertility.

Voulgaris N¹, Papanastasiou L¹, Piaditis G¹, Angelousi A², Kaltsas G², Mastorakos G³, Kassi E⁴.

 

Abstract

The role of vitamin D in female reproduction has been intensively examined over the last few decades. A large body of evidence suggests that vitamin D might have beneficial effects on metabolic/hormonal parameters of PCOS and endometriosis, while it appears to be associated with IVF outcomes. However, due to the heterogeneity among observational and interventional studies, no cause-effect relationship has yet been established. The aim of this review is to analyze recent in vitro animal and human studies which examined the association of vitamin D with disease entities affecting female fertility potential. Recent research data strongly imply that vitamin D is implicated in female reproduction and might represent a beneficial and inexpensive therapeutic approach, in combination with first-line medical treatments, to female infertility.

 

 

Fertil Steril. 2017 Jun;107(6):1348-1354.

Endometriosis on the uterosacral ligament: a marker of ureteral involvement.

Lima R¹, Abdalla-Ribeiro H², Nicola AL², Eras A², Lobao A², Ribeiro PA².

 

Abstract

OBJECTIVE:

To evaluate the association between ultrasound measurements of endometriosis nodules on the uterosacral ligament (USL) and the risk of ureteral involvement, as well as to assess whether associations with other ultrasound variables increase the sensitivity and specificity of the diagnosis of ureteral endometriosis.

DESIGN:

Cross-sectional, observational study.

SETTING:

University hospital.

PATIENT(S):

Four hundred sixty-three women with deep infiltrating endometriosis (DIE).

INTERVENTION(S):

Patients diagnosed with DIE underwent transvaginal ultrasound endometriosis mapping before laparoscopic surgery for full excision of endometriotic lesions.

MAIN OUTCOME MEASURE(S):

Preoperative ultrasound evaluation, intra- and postoperative assessment, and anatomopathologic confirmation.

RESULT(S):

Of the 463 patients who participated in the study, 111 (23.97%) presented with endometriosisnodules with USL involvement on ultrasound examination conducted by a single radiologist. Receiver operating characteristic curve analysis showed that the size of the USL nodule had a statistically significant association with ipsilateral ureteral involvement. After multivariate logistic regression, the variables reduction in ovarian mobility, ureteral changes on the right side, size of the USL nodule, and presence of endometrioma on the left side were significantly associated with a ureteral endometriosis nodule. However, the combined result for the variables cited was worse than the diagnostic analysis using only the size of the USL nodule.

CONCLUSION(S):

Uterosacral ligament nodules with ultrasound measurements of 1.75 cm and 1.95 cm on the right and left sides, respectively, significantly increase the risk of ureteral involvement. Even with the association of other ultrasound variables, there was no improvement in sensitivity. Therefore, USL nodule size is a key measure for therapeutic planning and consent of the patient.

 

 

J Obstet Gynaecol Res. 2017 Jul;43(7):1227-1231.

Refractory thoracic endometriosis syndrome with bilateral hemothorax.

Lua LL¹, Tran K¹, Desai J¹.

 

Abstract

Thoracic endometriosis syndrome (TES) is a rare disorder presenting with catamenial pneumothorax, hemothorax, hemoptysis or pulmonary nodules. Bilateral involvement is uncommon, and only a very few cases have been reported in the literature. We report a case of bilateral catamenial hemothorax in a patient with recurrent thoracic endometriosis. Despite multiple surgical interventions, the patient continued to develop hemopneumothorax coinciding with menses. Remission was finally achieved with the addition of gonadotropin-releasing hormone agonist, highlighting the effectiveness of postoperative adjuvant hormone therapy and supporting a combined surgical and medical approach in the treatment of TES in patients who desire future fertility.

 

 

J Xray Sci Technol. 2017;25(3):523-532.

MicroRNA expression profiling in endometriosis-associated infertility and its relationship with endometrial receptivity evaluated by ultrasound.

Xu X^1,2, Li Z³, Liu J², Yu S², Wei Z¹.

 

Abstract

OBJECTIVE:

To investigate the microRNA expression profiling in endometriosis-associate infertility, and relationship between the microRNA expression and endometrial receptivity evaluated by ultrasound.

METHODS:

First, miRNA expression profiling difference of ectopic endometrium between 8 endometriosispatients and 6 endometriosis-free patients were compared. Bioinformatics analyses detected 61 differentially expressed (DE) known miRNAs and 57 DE novel miRNAs. Next, other 24 patients were selected for checking the microRNAs in differential expression by RT-PCR. Among them, case and control groups include 14 endometriosisand 10 endometriosis-free infertility patients, respectively. Last, endometrial receptivity of other 20 endometriosispatients was evaluated by ultrasound. In this group of patients, 12 had high endometrial receptivity, in which infertility is caused by fallopian tube occlusion, and 8 had low endometrial receptivity. The study compared endometrial miRNAs expression between two groups, and also evaluated the relationship between the endometrial miRNAs expression and the endometrial receptivity.

RESULTS:

First, study indicated that “proteinaceous extracellular matrix,” “laminin binding” and “extracellular matrix binding” were enriched in 6 up-regulated miRNA targets, while “cell proliferation” was enriched in the 4 down-regulated miRNA targets. Second, 10 miRNAs in different expression (miR-1304- 3p, miR-544b, miR-3684, miR-494-5p, miR-4683, miR-6747-3p; miR-3935, miR-4427, miR-652-5p, miR-205-5p) were detected by RT-PCR, and the results showed statistically significant differences between 2 groups in all 10 miRNAs. Third, the expression levels of miR-1304-3p, miR-494-5p, and miR-4427 were different between the two groups with different endometrial receptivity. But for the miR-544b, there was no statistically significant difference between two groups.

CONCLUSIONS:

The study provided a comprehensive understanding to the current knowledge in the field of miRNAs in endometriosis and the relationship between them and the endometrial receptivity. miRNAs could be used as diagnostic biomarkers and therapeutic agents for this disease. The combination of ultrasound and miRNAs detection could be a better choice for the diagnosis of infertility in the future.

 

 

Ultrasound Obstet Gynecol. 2017 May 15.

The Role of Transvaginal Ultrasound in the Evaluation of Ureteral Involvement in Deep Endometriosis.

Carfagna P¹, De Cicco Nardone C², De Cicco Nardone A¹, Testa AC¹, Scambia G¹, Marana R¹, De Cicco Nardone F¹.

 

Abstract

OBJECTIVE:

To assess whether routine visualization of the pelvic ureter during transvaginal ultrasonography should be performed in all patients with deep endometriosis candidate to surgery, in order to identify a potential silent ureteral involvement by the disease.

METHODS:

This was a prospective study of 200 consecutive patients undergoing surgery for deep endometriosis, evaluated between January 2012 and December 2014 at a tertiary endometriosis center at the Department of Obstetrics and Gynecology, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy. Routine transvaginal ultrasound, abdominal ultrasound, recording of patient history, signs and symptoms, and gynecologic examination were performed. The main outcome of interest was presence of ureteral dilatation or hydronephrosis.

RESULT(S):

13 patients (6.5%) out of the 200 patients with deep endometriosis had associated ureteral dilatation diagnosed at transvaginal ultrasound. Renal ultrasound detected 6 hydronephrosis out of 13 (46%) patients with ureteral dilatation.

CONCLUSION(S):

Our study confirms a relatively high incidence of ureteral involvement in patients with deep endometriosis. Transvaginal ultrasound appears to be a reliable tool for the diagnosis of ureteral involvement; furthermore, it allows to detect both the level and the degree of obstruction. Given the above considerations, these results confirm that transvaginal ultrasound examination is an accurate diagnostic noninvasive tool for the detection of ureteral involvement by endometriosis.

 

 

Hum Reprod. 2017 Jul 1;32(7):1393-1401.

Relationship between the magnetic resonance imaging appearance of adenomyosis and endometriosis phenotypes.

Chapron C^1,2, Tosti C^1,3, Marcellin L^1,2,4, Bourdon M^1,4, Lafay-Pillet MC¹, Millischer AE⁵, Streuli I⁶, Borghese B^1,2, Petraglia F³, Santulli P^1,2,4.

 

Abstract

STUDY QUESTION:

What is the relationship between endometriosis phenotypes superficial peritoneal endometriosis (SUP), ovarian endometrioma (OMA), deep infiltrating endometriosis (DIE) and the adenomyosis appearance by magnetic resonance imaging (MRI)?

SUMMARY ANSWER:

Focal adenomyosis located in the outer myometrium (FAOM) was observed more frequently in women with endometriosis, and was significantly associated with the DIE phenotype.

WHAT IS KNOWN ALREADY:

An association between endometriosis and adenomyosis has been reported previously, although data regarding the association between MRI appearance of adenomyosis and the endometriosis phenotype are currently still lacking.

STUDY DESIGN, SIZE, DURATION:

This was an observational, cross-sectional study using data prospectively collected from non-pregnant patients who were between 18 and 42 years of age, and who underwent surgery for symptomatic benign gynecological conditions between January 2011 and December 2014. For each patient, a standardized questionnaire was completed during a face-to-face interview conducted by the surgeon during the month preceding the surgery. Only women with preoperative standardized uterine MRIs were retained for this study.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Surgery was performed on 292 patients with signed consent and available preoperative MRIs. After a thorough surgical examination of the abdomino-pelvic cavity, 237 women with histologically proven endometriosis were allocated to the endometriosis group and 55 symptomatic women without evidence of endometriosis to the endometriosis free group. The existence of diffuse or FAOM was studied in both groups and according to surgical endometriosis phenotypes (SUP, OMA and DIE).

MAIN RESULTS AND THE ROLE OF CHANCE:

Adenomyosis was observed in 59.9% (n = 175) of the total sample population (n = 292). Based on MRI, the distribution of adenomyosis was as follows: isolated diffuse adenomyosis (53 patients; 18.2%), isolated FAOM (74 patients; 25.3%), associated diffuse and FAOM (48 patients; 16.4%). Diffuse adenomyosis (isolated and associated to FAOM) was observed in one-third of the patients regardless of whether they were endometriotic patients or endometriosis free women taken as controls (34.2% (81 cases) versus 36.4% (20 cases)); P = 0.764. Among endometriotic women, diffuse adenomyosis (isolated and associated to FAOM) failed to reach significant correlation with the endometriosis phenotypes (SUP, 20.0% (8 cases); OMA, 45.2% (14 cases) and DIE, 35.5% (59 cases); P = 0.068). In striking contrast, there was a significant increase in the frequency of FAOM in endometriosis-affected women than in controls (119 cases (50.2%) versus 5.4% (3 cases); P < 0.001). FAOM correlated with the endometriosis phenotypes, significantly with DIE (SUP, 7.5% (3 cases); OMA, 19.3% (6 cases) and DIE, 66.3% (110 cases); P < 0.001).

LIMITATIONS, REASONS FOR CAUTION:

There was a possible selection bias due to the specificity of the study design, as it only included surgical patients in a referral center that specializes in endometriosis surgery. Therefore, women referred to our center may have suffered from particularly severe forms of endometriosis. This could explain the high number of women with DIE (166/237-70%) in our study group. This referral bias for women with severe lesions may have amplified the difference in association of FAOM with the endometriosis-affected patients compared to women without endometriosis. Furthermore, according to inclusion criteria, women in the endometriosis free group were symptomatic women. This may introduce some bias as symptomatic women may be more prone to have associated adenomyosis that in turn could have been overrepresented in the endometriosis free group. Whether this selection could have introduced a bias in the relationship between endometriosis and adenomyosis remains unknown.

WIDER IMPLICATIONS OF THE FINDINGS:

This study opens the door to future epidemiological, clinical and mechanistic studies aimed at better characterizing diffuse and focal adenomyosis. Further studies are necessary to adequately determine if diffuse and focal adenomyosis are two separate entities that differ in terms of pathogenesis.

STUDY FUNDING/COMPETING INTEREST(S):

No funding supported this study. The authors have no conflict of interest to declare.

 

 

Gynecol Obstet Invest. 2017 May 17.

Evaluation of Total, Active, and Specific Myeloperoxidase Levels in Women with and without Endometriosis.

O DF¹, Waelkens E, Peterse DP, Lebovic D, Meuleman C, Tomassetti C, Peeraer K, Alvarez Real A, Bosseloir A, D’Hooghe T, Fassbender A.

 

Abstract

Myeloperoxidase (MPO) is a proinflammatory enzyme and a marker for neutrophil activation and oxidative stress. Since oxidative stress and inflammation are linked to the pathogenesis of endometriosis, we hypothesized that the total, active, and specific (active/total) MPO levels were significantly different in plasma of women with and without endometriosis. Samples were selected from our biobank from women with endometriosis (n = 212) and controls without endometriosis (n = 121) across the menstrual cycle. Total MPO plasma levels were measured by immunoassay and MPO activity by enzymatic assay. Total and active MPO levels did not differ significantly among endometriosis cases and controls, whereas the specific MPO activity was significantly lower in women with endometriosis than that in controls (p = 0.0159). After the subdivision of control patients into women with a normal pelvis and women with other benign gynecological disorders, a significant difference was observed only between women with endometriosis and women with other benign gynecological disorders (p = 0.0266). In conclusion, systemic MPO levels may not be suited as a single biomarker for endometriosis. Our data support the involvement of MPO in other gynecological disorders but do not provide any evidence for an association with endometriosis.

 

 

J Clin Diagn Res. 2017 Mar;11(3)

Primary Ovarian Endometrioid Stromal Sarcoma Presenting with Infertility.

Ilanthodi S¹, Meghashree V², Pai MR³.

 

Abstract

Endometrioid Stromal Sarcoma (ESS) is an uncommon tumour that occurs in women over wide age range of 11 years to 76 years accounting for only 0.2% of all uterine malignancies and for 15%-26% of primary uterine sarcomas. These tumours arising from ovary are extremely rare. Most of them are associated with nulliparous or perimenopausal women. It is commonly associated with endometriosis of the ovary. Here we present this rare case to emphasize on the uniqueness and histomorphology of ovarian ESS in patients with endometriosis.

 

 

J Assist Reprod Genet. 2017 Jul;34(7):921-928.

Factors associated with a poor prognosis for the IVF-ICSI live birth rate in women with rAFS stage III and IV endometriosis.

Roux P¹, Perrin J^2,3, Mancini J^4,5, Agostini A², Boubli L², Courbiere B^2,3.

 

Abstract

PURPOSE:

To assess the factors associated with a poor prognosis for a cumulative IVF live birth rate (LBR) in women with stage III and IV endometriosis according to the revised classification of the American Fertility Society (rAFS).

METHODS:

A retrospective cohort study was conducted between January 1, 2010, and December 31, 2014, in our Reproductive Medicine Center. We analyzed different factors associated with a poor prognosis for a cumulative IVF LBR in women with rAFS stage III and IV endometriosis. A total of 101 patients were included, representing 232 IVF-ICSI cycles and 212 embryo transfers. The primary endpoint was the cumulative LBR per cycle and per patient.

RESULTS:

The cumulative LBR per cycle was 14.7% (n = 34) and that per patient was 31.7% (n = 32). The cumulative LBR was significantly decreased by active smoking [_adjOR = 3.4, 95% CI (1.12-10.60), p = 0.031], poor ovarian response (POR) according to the Bologna criteria [_adjOR = 11.5, 95% CI (1.37-96.83), p = 0.024], and rAFS stage IV [_adjOR = 3.2, 95% CI (1.13-8.95), p = 0.024]. The cumulative LBR per women was 59.4% without factors associated with a poor prognosis and 25.6% in the case of one factor, and it decreased to 7.7% in the case of two or three factors (p < 0.001).

CONCLUSION:

Active smoking, POR according to the Bologna criteria, and rAFS stage IV endometriosis had a negative impact on the IVF-ICSI cumulative LBR for women with rAFS stage III and IV endometriosis. Because smoking dramatically decreases the LBR with endometriosis, stopping smoking before IVF-ICSI should be strongly advised.

 

 

Arch Immunol Ther Exp (Warsz). 2017 Oct;65(5):391-399.

KIR, LILRB and their Ligands’ Genes as Potential Biomarkers in Recurrent Implantation Failure.

Nowak I¹, Wilczyńska K², Wilczyński JR³, Malinowski A⁴, Radwan P^5,6, Radwan M⁵, Kuśnierczyk P².

 

Abstract

Reproductive failure in humans is a very important social and economic problem, because nowadays women decide to conceive later in life and delay motherhood. Unfortunately, with increasing age they have less chance for natural fertilization and maintenance of pregnancy. Many of them need assisted reproductive technology. Approximately 10% of women after in vitro fertilization-embryo transfers experience recurrent implantation failure (RIF). Multiple factors may contribute to RIF, including oocyte and sperm quality, parental chromosomal anomalies, genetic or metabolic abnormalities of the embryo, poor uterine receptivity, immunological disturbances in the implantation site, and some gynecologic pathologies such as endometriosis, uterine fibroids, hydrosalpinx and endometrial polyps. Moreover, the procedure of in vitro fertilization itself could adversely influence the implantation. Nowadays, many studies are focused on the role of natural killer (NK) cells in normal and pathologic pregnancy because NK cells constitute the dominant cell population in the endometrium and they come in close contact with the allogeneic extravillous trophoblast cells in early pregnancy decidua. The majority of these cells are of CD56^bright phenotype. These cells can express killer immunoglobulin-like receptors (KIRs), which, upon recognition of HLA class I molecules (HLA-C and HLA-G) on trophoblasts, may either stimulate or inhibit NK cells to produce soluble factors, and display low cytotoxicity necessary for maintenance of the allogeneic embryo and fetus in the next steps of pregnancy. Moreover, some members of the leukocyte immunoglobulin-like receptor (LILR) family, also named ILT (immunoglobulin-like transcript), are present in the human placenta. LILRB1 (ILT2) was described mainly on stromal cells, while LILRB2 (ILT4), in addition to stromal cells, was also found around vessels in the smooth muscle layer. In this review we focus on the possible role of polymorphism of KIR, LILRB and their ligands (HLA-C, HLA-G) in susceptibility to recurrent implantation failure, which could serve as diagnostic biomarkers of this disease.

 

 

N Engl J Med. 2017 Jul 6;377(1):28-40.

Treatment of Endometriosis-Associated Pain with Elagolix, an Oral GnRH Antagonist.

Taylor HS¹, Giudice LC¹, Lessey BA¹, Abrao MS¹, Kotarski J¹, Archer DF¹, Diamond MP¹, Surrey E¹, Johnson NP¹, Watts NB¹, Gallagher JC¹, Simon JA¹, Carr BR¹, Dmowski WP¹, Leyland N¹, Rowan JP¹, Duan WR¹, Ng J¹, Schwefel B¹, Thomas JW¹, Jain RI¹, Chwalisz K¹.

 

Abstract

BACKGROUND:

Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies.

METHODS:

We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix – 150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group) – as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary.

RESULTS:

A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P=0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings.

CONCLUSIONS:

Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects.

 

 

J Gynecol Obstet Hum Reprod. 2017 Oct;46(8):647-650.

Clinical presentation of endometriosis identified at interval laparoscopic tubal sterilization: Prospective series of 465 cases.

Tissot M¹, Lecointre L², Faller E², Afors K³, Akladios C², Audebert A⁴.

 

Abstract

OBJECTIVES:

Women seeking sterilization are usually parous and have no major complains, such as pelvic pain. This could be a good model to indirectly assess the prevalence of endometriosis in the general population. Prevalence of endometriosis in women undergoing tubal sterilization by laparoscopy has been assessed in 17 published reports. Results indicate a surprising wide variation of prevalence of endometriosis, ranging from 1.4% to 43.3%. This clinical study describes the prevalence and clinical presentations of endometriosis identified at interval laparoscopic tubal sterilization, as a close representation of endometriosis in general population.

MATERIAL AND METHODS:

From July 1989 to February 2009, 465 women undergone interval laparoscopic tubal sterilization and were included in this series. Surgery was realised in a non universitary centre of gynecologic surgery. All patients were operated on by the same surgeon. A complete assessement of pelvic organs was achieved with a particular attention paid for endometriotic lesions. Endometriosis when present was staged according to r-AFS classification. Biopsies were sent for pathological examination to assess endometriosis.

RESULTS:

Mean age of women was 40.7 years (range 15-49 years). 20 women were nulliparous and 12 others had a past history of endometriosis. Endometriosis was visually identified in 55 patients (11.82%), and confirmed by histologic examination in most of cases (50/55: 90.9%). The mean age of women presenting endometriosis at the onset of tubal ligation was 41.27 years. Cases with endometriosis were classified according to the r-AFS. 39,7,8 and 1 cases corresponded to stages I, II, III and IV respectively. In the 20 nulliparous women, the prevalence of endometriosis was 20% (4/20). At the time of laparoscopic sterilization, 91 women presented a painfull condition (dysmenorrhea mainly or dyspareunia). Endometriosis was identified in 16 of them (17.58%). In the group of 360 asymptomatic parous women, the prevalence of endometriosis was 10% (36/360). Nulliparity, associated pelvic pain and retroverted uterus were associated with increased prevalence of endometriosis, without being significant.

CONCLUSION:

In our study, the prevalence of endometriosis identified at interval laparoscopic tubal sterilization was 11.82%. In parous asymptomatic women, the prevalence of endometriosis was 10%. The prevalence of endometriosis was slightly increased in nulliparous women, when pain was associated and in women with a retroverted uterus.

 

 

Curr Top Dev Biol. 2017;125:109-146

Estrogen Hormone Biology.

Hamilton KJ¹, Hewitt SC¹, Arao Y¹, Korach KS².

 

Abstract

The hormone estrogen is involved in both female and male reproduction, as well as numerous other biological systems including the neuroendocrine, vascular, skeletal, and immune systems. Therefore, it is also implicated in many different diseases and conditions such as infertility, obesity, osteoporosis, endometriosis, and a variety of cancers. Estrogen works through its two distinct nuclear receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Various transcriptional regulation mechanisms have been identified as the mode of action for estrogen, mainly the classical mechanism with direct DNA binding but also a nongenomic mode of action and one using tethered or indirect binding. The expression profiles of ERα and ERβ are unique with the primary sites of ERα expression being the uterus and pituitary gland and the main site of ERβ expression being the granulosa cells of the ovary. Mouse models with knockout or mutation of Esr1 and Esr2 have furthered our understanding of the role of each individual receptor plays in physiology. From these studies, it is known that the primary roles for ERα are in the uterus and neuroendocrine system, as female mice lacking ERα are infertile due to impaired ovarian and uterine function, whereas female mice lacking ERβ are subfertile due to ovarian defects. The development of effective therapies for estrogen-related diseases has relied on an understanding of the physiological roles and mechanistic functionalities of ERα and ERβ in human health and disease.

 

 

F1000Res. 2017 Jan 5;6:14.

EPHect – the Endometriosis Phenome (and Biobanking) Harmonisation Project – may be very helpful for clinicians and the women they are treating.

Miller LM¹, Johnson NP².

 

Abstract

This article acts as a summary of the recently published papers by the World Endometriosis Research Foundation aiming to set up the Endometriosis Phenome and Biobanking Harmonisation Project.  The objective of this project is to standardise recording of patient history and characteristics, recording of surgical procedure and extent of disease as well as collection, processing and storage of specimens and consequently create a reliable resource for research into endometriosis.