Reproduction. 2016 Dec;152(6):673-682.

Macrophages promote the growth and invasion of endometrial stromal cells by downregulating IL-24 in endometriosis.

Shao J¹, Zhang B¹, Yu JJ¹, Wei CY¹, Zhou WJ^1,2, Chang KK^1,3, Yang HL¹, Jin LP⁴, Zhu XY^5,3, Li MQ^5,2,3.

 

Abstract

Macrophages play an important role in the origin and development of endometriosis. Estrogen promoted the growth of decidual stromal cells (DSCs) by downregulating the level of interleukin (IL)-24. The aim of this study was to clarify the role and mechanism of IL-24 and its receptors in the regulation of biological functions of endometrial stromal cells (ESCs) during endometriosis. The level of IL-24 and its receptors in endometrium was measured by immunohistochemistry. In vitro analysis was used to measure the level of IL-24 and receptors and the biological behaviors of ESCs. Here, we found that the expression of IL-24 and its receptors (IL-20R1 and IL-20R2) in control endometrium was significantly higher than that in eutopic and ectopic endometrium of women with endometriosis. Recombinant human IL-24 (rhIL-24) significantly inhibited the viability of ESCs in a dosage-dependent manner. Conversely, blocking IL-24 with anti-IL-24 neutralizing antibody promoted ESCs viability. In addition, rhIL-24 could downregulate the invasiveness of ESCs in vitro After co-culture, macrophages markedly reduced the expression of IL-24 and IL-20R1 in ESCs, but not IL-22R1. Moreover, macrophages significantly restricted the inhibitory effect of IL-24 on the viability, invasion, the proliferation relative gene Ki-67, proliferating cell nuclear antigen (PCNA) and cyclooxygenase2 (COX-2), and the stimulatory effect on the tumor metastasis suppressor gene CD82 in ESCs. These results indicate that the abnormally low level of IL-24 in ESCs possibly induced by macrophages may lead to the enhancement of ESCs’ proliferation and invasiveness and contribute to the development of endometriosis.

 

 

Surg Endosc. 2017 Jul;31(7):2813-2819.

Robotic-assisted colorectal surgery in obese patients: a case-matched series.

Harr JN¹, Luka S¹, Kankaria A², Juo YY¹, Agarwal S¹, Obias V³.

Abstract

BACKGROUND:

Reports demonstrate laparoscopic colorectal surgery in obese patients is associated with higher conversion to laparotomy and complication rates. While several advantages of robotic-assisted surgery have been reported, outcomes in obese patients have not been adequately studied. Therefore, this study compares outcomes of robotic-assisted surgery in non-obese and obese patients.

METHODS:

A retrospective review of 331 consecutive robotic procedures performed at a single institution between 2009 and 2015 was performed. Patients were divided into non-obese (BMI <30 kg/m²) and obese (BMI ≥30 kg/m²) groups, and were clinically matched by gender, age, and procedure performed. Intraoperative and postoperative complications, operative time, estimated blood loss, and length of stay were examined.

RESULTS:

Following matching, each group included 108 patients comprised of 50 men and 58 women. Mean BMI was 24.6 ± 3.15 and 36.2 ± 5.67 kg/m² (p < 0.0001), and the mean age was 59.2 ± 11.28 years for non-obese patients and 57.1 ± 12.44 for obese patients (p = 0.18). Surgeries included low anterior resection, right colectomy, left colectomy, sigmoid colectomy, excision of rectal endometriosis, total proctocolectomy, APR, subtotal colectomy, ileocecectomy, proctectomy, rectopexy, transanal excision of rectal mass, and colostomy site hernia repair. The mean operative time was 272.69 ± 115.43 and 282.42 ± 120.51 min (p = 0.55), estimated blood loss 195.23 ± 230.37 and 289.19 ± 509.27 mL (p = 0.08), conversion to laparotomy 6.48 and 9.26 % (p = 0.45), and length of stay 5.38 ± 4.94 and 4.56 ± 4.04 days (p = 0.18) for the non-obese and obese groups, respectively. Twenty of the non-obese patients had postoperative complications as compared to 27 of the obese patients (p = 0.30). However, the prevalence of wound complications was higher in obese patients (1.9 vs 9.3 %; p = 0.03).

CONCLUSION:

There is no difference in conversion to laparotomy and overall complication rates in non-obese and obese patients undergoing robotic-assisted colorectal surgery. However, obesity is associated with a higher prevalence of wound complications. Robotic-assisted surgery may minimize conversion to laparotomy and complications typically seen in obese patients due to improved visualization, instrumentation, and ergonomics.

 

 

Adv Exp Med Biol. 2016;913:263-285.

Telocytes in Inflammatory Gynaecologic Diseases and Infertility.

Yang XJ¹.

 

Abstract

Women suffered with inflammatory gynecologic diseases, such as endometriosis (EMs) and acute salpingitis (AS) often complained of sub- or infertility, even in those women without obvious macroscopic anatomical pelvic abnormalities also have unexplained infertility. Generally, besides the well-known impairment of classically described oviduct cells caused by inflammatory diseases, such as the ciliated cells, fibroblasts and myofibroblasts, the involvement of the newly identified telocytes (TCs) in disease-affected oviduct tissues and potential pathophysiological roles in fertility problems remain unknown. In this chapter, TCs was investigated in rat model of EMs- and AS-affected oviduct tissues. Results showed inflammation and ischaemia-induced extensive ultrastructural damages of TCs both in cellular body and prolongations, with obvious TCs loss and interstitial fibrotic remodelling. Such in vivo pathological alterations might contribute to structural and functional abnormalities of oviduct tissue and potentially engaged in sub- or infertility. And especially, TCs connected to various activated immunocytes in both normal and diseased tissues, thus might participate in local immunoregulation (either repression or activation) and serve a possible explanation for immune-mediated pregnancy failure. Then, in vitro cell co-culture study showed that uterine TC conditioned media (TCM) can activate mouse peritoneal macrophages and subsequently trigger its cytokine secretion, thus providepreliminary evidence that, TCs are not simply innocent bystanders, but are instead potential functional players in local immunoregulatory and immunosurveillance.

 

 

Nat Genet. 2016 Dec;48(12):1462-1472.

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

Barban N¹, Jansen R², de Vlaming R^3,4,5, Vaez A^6,7, Mandemakers JJ⁸, Tropf FC¹, Shen X^9,10,11, Wilson JF^10,11, Chasman DI¹², Nolte IM⁶, Tragante V¹³, van der Laan SW¹⁴, Perry JR¹⁵, Kong A^16,17; BIOS Consortium, Ahluwalia TS^18,19,20, Albrecht E²¹, Yerges-Armstrong L²², Atzmon G^23,24,25, Auro K^26,27, Ayers K²⁸, Bakshi A²⁹, Ben-Avraham D²⁴, Berger K³⁰, Bergman A³¹, Bertram L^32,33, Bielak LF³⁴, Bjornsdottir G¹⁷, Bonder MJ³⁵, Broer L³⁶, Bui M³⁷, Barbieri C³⁸, Cavadino A^39,40, Chavarro JE^41,42,43, Turman C⁴³, Concas MP⁴⁴, Cordell HJ²⁸, Davies G^45,46, Eibich P⁴⁷, Eriksson N⁴⁸, Esko T^49,50, Eriksson J⁵¹, Falahi F⁶, Felix JF^4,52,53, Fontana MA⁵⁴, Franke L³⁵, Gandin I⁵⁵, Gaskins AJ⁴¹, Gieger C^56,57, Gunderson EP⁵⁸, Guo X⁵⁹, Hayward C¹⁰, He C⁶⁰, Hofer E^61,62, Huang H⁴³, Joshi PK¹¹, Kanoni S⁶³, Karlsson R⁹, Kiechl S⁶⁴, Kifley A⁶⁵, Kluttig A⁶⁶, Kraft P^43,67, Lagou V^68,69,70, Lecoeur C⁷¹, Lahti J^72,73,74, Li-Gao R⁷⁵, Lind PA⁷⁶, Liu T⁷⁷, Makalic E³⁷, Mamasoula C²⁸, Matteson L⁷⁸, Mbarek H^79,80, McArdle PF²², McMahon G⁸¹, Meddens SF^5,82, Mihailov E⁴⁹, Miller M⁸³, Missmer SA^43,84, Monnereau C^4,52,53, van der Most PJ⁶, Myhre R⁸⁵, Nalls MA⁸⁶, Nutile T⁸⁷, Kalafati IP⁸⁸, Porcu E^89,90, Prokopenko I^91,92,93, Rajan KB⁹⁴, Rich-Edwards J^42,43,95, Rietveld CA^3,4,5, Robino A⁹⁶, Rose LM¹², Rueedi R^97,98, Ryan KA²², Saba Y⁹⁹, Schmidt D³⁷, Smith JA³⁴, Stolk L³⁶, Streeten E²², Tönjes A¹⁰⁰, Thorleifsson G¹⁷, Ulivi S⁹⁶, Wedenoja J¹⁰¹, Wellmann J³⁰, Willeit P^64,102,103, Yao J⁵⁹, Yengo L^71,104, Zhao JH¹⁵, Zhao W³⁴, Zhernakova DV³⁵, Amin N⁴, Andrews H¹⁰⁵, Balkau B⁷¹, Barzilai N²³, Bergmann S^97,98, Biino G¹⁰⁶, Bisgaard H²⁰, Bønnelykke K²⁰, Boomsma DI^79,80, Buring JE¹², Campbell H¹¹, Cappellani S⁹⁶, Ciullo M^87,107, Cox SR^45,46, Cucca F^89,90, Toniolo D³⁸, Davey-Smith G¹⁰⁸, Deary IJ^45,46, Dedoussis G⁸⁸, Deloukas P^63,109, van Duijn CM⁴, de Geus EJ^79,80, Eriksson JG^{74,110,111,112,113}, Evans DA⁹⁴, Faul JD¹¹⁴, Sala CF³⁸, Froguel P⁷¹, Gasparini P^55,115, Girotto G^55,115, Grabe HJ¹¹⁶, Greiser KH¹¹⁷, Groenen PJ^5,118, de Haan HG⁷⁵, Haerting J⁶⁶, Harris TB¹¹⁹, Heath AC¹²⁰, Heikkilä K²⁷, Hofman A^4,5,43, Homuth G¹²¹, Holliday EG^122,123, Hopper J³⁷, Hyppönen E^39,124,125, Jacobsson B^85,126, Jaddoe VW^4,52,53, Johannesson M¹²⁷, Jugessur A⁸⁵, Kähönen M¹²⁸, Kajantie E^129,130,131, Kardia SL³⁴, Keavney B^28,132, Kolcic I¹³³, Koponen P¹³⁴, Kovacs P¹³⁵, Kronenberg F¹³⁶, Kutalik Z^98,137, La Bianca M⁹⁶, Lachance G¹³⁸, Iacono WG⁸³, Lai S⁸⁹, Lehtimäki T¹³⁹, Liewald DC⁴⁵; LifeLines Cohort Study, Lindgren CM^{92,93,140,141}, Liu Y¹⁴², Luben R¹⁴¹, Lucht M¹¹⁰, Luoto R¹⁴³, Magnus P⁸⁵, Magnusson PK⁹, Martin NG⁷⁶, McGue M^83,144, McQuillan R¹¹, Medland SE⁷⁶, Meisinger C^57,145, Mellström D⁵¹, Metspalu A^49,146, Traglia M³⁸, Milani L⁴⁹, Mitchell P⁶⁵, Montgomery GW^120,147, Mook-Kanamori D^75,148,149, de Mutsert R⁷⁵, Nohr EA¹⁵⁰, Ohlsson C⁵¹, Olsen J¹⁵¹, Ong KK¹⁵, Paternoster L¹⁰⁸, Pattie A⁴⁶, Penninx BW^2,80, Perola M^26,27,49, Peyser PA³⁴, Pirastu M⁴⁴, Polasek O¹³³, Power C³⁹, Kaprio J^26,27,101, Raffel LJ¹⁵², Räikkönen K⁷², Raitakari O¹⁵³, Ridker PM¹², Ring SM¹⁰⁸, Roll K⁵⁹, Rudan I¹¹, Ruggiero D⁸⁷, Rujescu D¹⁵⁴, Salomaa V²⁶, Schlessinger D¹⁵⁵, Schmidt H⁹⁹, Schmidt R⁶¹, Schupf N¹⁵⁶, Smit J^2,80, Sorice R^87,107, Spector TD¹³⁸, Starr JM^45,157, Stöckl D¹⁵⁶, Strauch K^21,158, Stumvoll M^100,135, Swertz MA³⁵, Thorsteinsdottir U^17,159, Thurik AR^3,5,160, Timpson NJ¹⁰⁸, Tung JY⁴⁸, Uitterlinden AG^3,5,36, Vaccargiu S⁴⁴, Viikari J¹⁶¹, Vitart V¹⁰, Völzke H¹⁶², Vollenweider P¹⁶³, Vuckovic D^55,115, Waage J²⁰, Wagner GG¹⁶⁴, Wang JJ⁶⁵, Wareham NJ¹⁵, Weir DR¹¹⁴, Willemsen G^79,80, Willeit J⁶⁴, Wright AF¹⁰, Zondervan KT^165,166, Stefansson K^17,159, Krueger RF⁸³, Lee JJ⁸³, Benjamin DJ^54,167, Cesarini D^168,169, Koellinger PD^3,5,82, den Hoed M¹⁷⁰, Snieder H⁶, Mills MC¹.

 

Abstract

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

 

 

PLoS One. 2016 Oct 31;11(10):e0165609.

Clinical Significance of Tissue Factor Pathway Inhibitor 2, a Serum Biomarker Candidate for Ovarian Clear Cell Carcinoma.

Arakawa N^1,2, Kobayashi H³, Yonemoto N⁴, Masuishi Y^1,2, Ino Y^1,2, Shigetomi H³, Furukawa N³, Ohtake N⁵, Miyagi Y⁶, Hirahara F⁷, Hirano H^1,2, Miyagi E⁷.

Abstract

BACKGROUND:

There is currently no reliable serum biomarker for ovarian clear cell carcinoma (CCC), a highly lethal histological subtype of epithelial ovarian cancer (EOC). Previously, using a proteome-based approach, we identified tissue factor pathway inhibitor 2 (TFPI2) as a candidate serum biomarker for CCC. In this study, we sought to evaluate the clinical diagnostic performance of TFPI2 in preoperative prediction of CCC.

METHODS:

Serum TFPI2 levels were measured in serum samples from a retrospective training set consisting of patients with benign and borderline ovarian tumors, EOC subtypes, and uterine diseases. Via receiver operating characteristic (ROC) analyses, we compared the diagnostic performance of TFPI2 with that of CA125 in discrimination of patients with ovarian CCC from other patient groups. The observed diagnostic performances were examined in a prospective validation set.

RESULTS:

The 268-patient training set included 29 patients with ovarian CCC. Unlike CA125, which was also elevated in patients with endometriosis and several EOC subtypes, serum TFPI2 levels were specifically elevated only in ovarian CCC patients, consistent with the mRNA expression pattern in tumor tissues. The area under the ROC curve (AUC) of serum TFPI2 was obviously higher than that of CA125 for discrimination of CCC from other ovarian diseases (AUC = 0.891 versus 0.595). Applying a cut-off value of 280 pg/mL, TFPI2 could distinguish early-stage (FIGO I and II) CCC from endometriosis with 72.2% sensitivity, 93.3% specificity, and 88.8% accuracy. Similar results were confirmed in an independent 156-patient prospective validation set.

CONCLUSIONS:

TFPI2 is a useful serum biomarker for preoperative clinical diagnosis of CCC.

 

 

Int J Gynecol Pathol. 2017 Jul;36(4):372-376.

Ovarian Epithelial Inclusions With Mucinous Differentiation: A Clinicopathologic Study of 42 Cases.

Seidman JD¹, Krishnan J.

 

Abstract

Ovarian epithelial inclusions lined by mucinous epithelium are rare and of uncertain origin. Ovaries containing such inclusions were studied in 42 women. The inclusions were divided into 3 groups: serous epithelial lined with typical ciliated morphology but with distinct basophilic cytoplasmic mucin in some or all of the lining cells, those lined by typical mucinous epithelium, and those lined by a combination of typical mucinous epithelium and serous epithelium. The mean patient age was 61.5 years. Pure mucinous inclusions were found in 27 patients, serous-type inclusions with cytoplasmic mucin in 20, and mixed type in 10. All 3 types of inclusions were found in 1 patient. Two types of inclusions were found in 13. Four patients had associated mucinous neoplasms (1 mucinous cystadenoma, 1 atypical proliferative seromucinous tumor, and 2 seromucinous cystadenomas), and 11 patients (26%) had endometriosis. The fallopian tubes in 4 patients (9.5%) also displayed mucinous metaplasia; this was not significantly different from the 3.1% we found in our previously reported series of unselected tubes from the same population. These findings suggest that mucinous inclusions may arise as a direct metaplastic change in serous-type inclusions. Other possible origins of mucinous inclusions in the ovarian cortex include endometriosis and Brenner (transitional cell) nests. Whether such inclusions can be a source of mucinous ovarian neoplasms as are Brenner tumors and mature cystic teratomas is unknown and may warrant further investigation.

 

 

Int J Gynecol Pathol. 2017 Sep;36(5):433-437.

Endometrial Stromal Sarcoma Arising in Colorectal Endometriosis.

Kilzieh R¹, Rakislova N, Torné A, Salvador R, Nadal A, Ordi J, Saco A.

 

Abstract

The malignant transformation of endometriosis is very uncommon. Whereas 75% of tumors arising from endometriosis arise in the ovary, location in extra-genital organs is rare and mesenchymal neoplasms are exceptional. A 47 year-old woman who underwent hysterectomy with bilateral salpingo-ooforectomy due to endometriosis 13 years before presented with abdominal pain. The magnetic resonance imaging (MRI) showed a 9.7×7.5 cm solid-cystic supravesical mass and a recto-vaginal tumor, as well as endometriotic nodules in the sigma, right parametrium and peritoneum that had significantly increased in size over a six months period. The patient underwent surgical resection of the masses. The histological study showed a low-grade endometrial stromal sarcoma (ESS) arising from endometriosis located at recotovaginal septum and affecting colonic wall and multiple peritoneal and pelvic implants. The patient received radiotherapy and aromatase inhibitors and is free of disease after a follow up of 2 years. Only 15 cases of ESS arising in endometriosis of the bowel have been reported. Tumor dissemination at diagnosis is unusual but does not imply a poor prognosis, as only one patient has died due to progression of the tumor. ESS should be included in the differential diagnosis of mesenchymal neoplasms in the intestine.

 

 

Hum Fertil (Camb). 2017 Apr;20(1):48-54.

Follicular fluid lipid peroxidation levels in women with endometriosis during controlled ovarian hyperstimulation.

de Lima CB¹, Cordeiro FB¹, Camargo M¹, Zylbersztejn DS¹, Cedenho AP¹, Bertolla RP¹, Lo Turco EG¹.

 

Abstract

This observational study aimed to establishing a relationship between lipid peroxidation and endometriosis in women undergoing controlled ovarian hyperstimulation. A total of 79 women were divided into two groups: (i) controls (tubal or male factor); and (ii) endometriosis (stages III/IV). The endometriosis diagnosis was confirmed by videolaparoscopy and the controlled ovarian stimulation protocol was similar to all patients. Follicular fluid (FF) lipid peroxidation levels were determined through the quantification of malondialdehyde. Statistical analysis was performed using parametric and non-parametric tests, logistic regression was performed to estimate the chance of achieving a pregnancy in each group and a moving average was calculated for the endometriosis group. Peroxidation levels in the endometriosis group were significantly higher when compared to controls. The moving average showed a decrease of MDA levels in the endometriosis group with increasing female age. Moreover, women with endometriosis who were under 33 years of age were 4.3 times more likely to achieve a pregnancy than women above that age. In conclusion, endometriosis is associated with increased FF oxidative stress (OS) in patients undergoing in vitro fertilization (IVF). Also, increasing age is associated with a decrease in severity of the oxidative status, but a decreased chance of pregnancy.

 

 

Iran J Basic Med Sci. 2016 Sep;19(9):940-945.

Apoptosis induction of human endometriotic epithelial and stromal cells by noscapine.

Khazaei MR¹, Rashidi Z², Chobsaz F¹, Khazaei M¹.

Abstract

OBJECTIVES:

Endometriosis is a complex gynecologic disease with unknown etiology. Noscapine has been introduced as a cancer cell suppressor. Endometriosis was considered as a cancer like disorder, The aim of present study was to investigate noscapine apoptotic effect on human endometriotic epithelial and stromal cells in vitro.

MATERIALS AND METHODS:

In this in vitro study, endometrial biopsies from endometriosis patients (n=9) were prepared and digested by an enzymatic method (collagenase I, 2 mg/ml). Stromal and epithelial cells were separated by sequential filtration through a cell strainer and ficoll layering. The cells of each sample were divided into five groups: control (0), 10, 25, 50 and 100 micromole/liter (µM) concentration of noscapine and were cultured for three different periods of times; 24, 48 and 72 hr. Cell viability was assessed by colorimetric assay. Nitric oxide (NO) concentration was measured by Griess reagent. Cell death was analyzed by Acridine Orange (AO)-Ethidium Bromide (EB) double staining and Terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay. Data were analyzed by one-way ANOVA.

RESULTS:

Viability of endometrial epithelial and stromal cells significantly decreased in 10, 25, 50 and 100 µM noscapine concentration in 24, 48, 72 hr (P<0.05) and apoptotic index increased in 25, 50 and 100 µM noscapine concentrations in 48 hr significantly (P<0.05). Concentrations of NO didn’t show a significant decrease.

CONCLUSION:

Noscapine increased endometriotic epithelial and stromal cell death and can be suggested as a treatment for endometriosis.

 

 

Angiogenesis. 2017 Feb;20(1):85-96.

Tissue factor is an angiogenic-specific receptor for factor VII-targeted immunotherapy and photodynamic therapy.

Hu Z^1,2, Cheng J^3,4, Xu J^3,5, Ruf W⁶, Lockwood CJ⁷.

 

Abstract

Identification of target molecules specific for angiogenic vascular endothelial cells (VEC), the inner layer of pathological neovasculature, is critical for discovery and development of neovascular-targeting therapy for angiogenesis-dependent human diseases, notably cancer, macular degeneration and endometriosis, in which vascular endothelial growth factor (VEGF) plays a central pathophysiological role. Using VEGF-stimulated vascular endothelial cells (VECs) isolated from microvessels, venous and arterial blood vessels as in vitro angiogenic models and unstimulated VECs as a quiescent VEC model, we examined the expression of tissue factor (TF), a membrane-bound receptor on the angiogenic VEC models compared with quiescent VEC controls. We found that TF is specifically expressed on angiogenic VECs in a time-dependent manner in microvessels, venous and arterial vessels. TF-targeted therapeutic agents, including factor VII (fVII)-IgG1 Fc and fVII-conjugated photosensitizer, can selectively bind angiogenic VECs, but not the quiescent VECs. Moreover, fVII-targeted photodynamic therapy can selectively and completely eradicate angiogenic VECs. We conclude that TF is an angiogenic-specific receptor and the target molecule for fVII-targeted therapeutics. This study supports clinical trials of TF-targeted therapeutics for the treatment of angiogenesis-dependent diseases such as cancer, macular degeneration and endometriosis.

 

 

Free Radic Res. 2016 Oct;50(10):1131-1139.

Non-thermal plasma prevents progression of endometriosis in mice.

Ishida C^1,2, Mori M^1,2, Nakamura K², Tanaka H³, Mizuno M³, Hori M⁴, Iwase A², Kikkawa F², Toyokuni S^1,5.

 

Abstract

Endometriosis is observed in ∼10% of reproductive age women. Ovarian endometriosis not only causes dysmenorrhea but also causes infertility and a high risk of adenocarcinoma. Due to its scattered nature, complete surgical resection is difficult. Endometriosis consists of glandular and stromal cells. Previously, we showed that endometrial stromal cells (ESCs) play a role in the protection against pathologic events caused by monthly repeated hemorrhage. Here, we undertook a preclinical study of non-thermal plasma (NTP) as a surgical treatment of endometriosis. Epithelial cells were most sensitive to NTP-activated medium in vitro, whereas ectopic ESCs were most resistant. We then transplanted excised uteruses into BALB/c mice from donors of the same strain with estradiol supplementation. Four weeks after the transplantation, we exposed NTP to each endometriotic lesion after laparotomy. Immunohistochemical analysis revealed that immediately after NTP exposure, epithelial cells exhibited significantly higher levels of nuclear immunostaining for 8-hydroxy-2′-deoxyguanosine than did stromal cells. Four weeks after NTP exposure, the total surface area consisting of endometriotic cysts was significantly smaller with less epithelial proliferative activity than the helium-exposed control, whereas the number of endometriotic lesions had not changed. Therefore, NTP exposure may be useful to prevent the progression and recurrence of endometriosis.

 

 

J Clin Endocrinol Metab. 2016 Nov;101(11):4349-4356.

Role of Versican in the Pathogenesis of Peritoneal Endometriosis.

Tani H¹, Sato Y¹, Ueda M¹, Miyazaki Y¹, Suginami K¹, Horie A¹, Konishi I¹, Shinomura T¹.

Abstract

CONTEXT:

Sampson’s theory cannot explain why only some cycling women develop peritoneal endometriosis. Few studies have focused on the pelvic peritoneum, which receives regurgitated endometrial tissues. We hypothesized that molecular alterations in the peritoneum are involved in the development of peritoneal endometriosis and conducted a microarray analysis to compare macroscopically normal peritoneum sampled from women with peritoneal endometriosis (endometriotic peritoneum) and those without (non-endometriotic peritoneum). Versican, a major proteoglycan component of the extracellular matrix, is one of the molecules up-regulated in endometriotic peritoneum.

OBJECTIVE:

To investigate the role of versican in peritoneal endometriosis. Design, Patients, and Main Outcome Measure: Endometriotic peritoneum and non-endometriotic peritoneum were subjected to RT-PCR, immunostaining, and Western blotting. The versican V1 isoform was stably transfected into Chinese hamster ovary cells (CHO-V1), and the effects of CHO-V1-derived conditioned medium (V1-CM) on primary human endometrial stromal cells were investigated with attachment, invasion, and proliferation assays. The effects of peritoneal fluid collected from endometriotic women (endometriotic PF) or cytokines/growth factors, which were shown to be elevated in endometriotic PF, on versican expression in a human peritoneal cell line (HMrSV5) were also examined.

RESULTS:

Versican V1 expression levels were significantly higher in endometriotic peritoneum. In vitro, V1-CM promoted attachment to the HMrSV5 cell monolayer as well as the Matrigel invasion of endometrial stromal cells. Although versican V1 expression was up-regulated by TGF-β1 in HMrSV5 cells, it remained unchanged in endometriotic PF.

CONCLUSIONS:

Our results suggest the involvement of peritoneal versican in the development of peritoneal endometriosis.

 

 

Biol Reprod. 2016 Nov;95(5):93.

Aberrant Endometrial DNA Methylome and Associated Gene Expression in Women with Endometriosis.

Houshdaran S¹, Nezhat CR², Vo KC¹, Zelenko Z¹, Irwin JC¹, Giudice LC³.

 

Abstract

Endometriosis is an estrogen-dependent, progesterone-resistant disorder largely derived from retrograde transplantation of menstrual tissue/cells into the pelvis, eliciting an inflammatory response, pelvic pain, and infertility. Eutopic endometrium (within the uterus), giving rise to pelvic disease, displays cycle-dependent transcriptomic, proteomic, and signaling abnormalities, and although its DNA methylation profiles dynamically change across the cycle in healthy women, studies in endometriosis are limited. Herein, we investigated the DNA methylome and associated gene expression in three phases of the cycle in eutopic endometrium of women with severe endometriosis versus controls, matched for ethnicity, medications, smoking, and no recent contraceptive steroid use. Genome-wide DNA methylation and gene expression were coassessed in each sample. Cycle phase was determined by histology, serum hormone levels, and unsupervised principal component and hierarchical cluster analyses of microarray data. Altered endometrial DNA methylation in endometriosis was most prominent in the midsecretory phase (peak progesterone), with disruption of the normal pattern of cycle-dependent DNA methylation changes, including a bias toward methylation of CpG islands, suggesting wide-range abnormalities of the chromatin remodeling machinery in endometriosis. DNA methylation changes were associated with altered gene expression relevant to endometrial function/dysfunction, including cell proliferation, inflammation/immune response, angiogenesis, and steroid hormone response. The data provide insight into epigenetic reprogramming and steroid hormone actions in endometrium contributing to the pathogenesis and pathophysiology of endometriosis.

 

 

Mol Hum Reprod. 2016 Nov;22(11):768-777.

TNFα-induced IKKβ complex activation influences epithelial, but not stromal cell survival in endometriosis.

Kocbek V^1,2, Grandi G³, Blank F⁴, Wotzkow C⁴, Bersinger NA^1,2, Mueller MD^1,2, Kyo S⁵, McKinnon BD^6,2.

Abstract

STUDY QUESTION:

Can the activity of the IκB kinase (IKKβ) complex in endometriotic cells contribute to endometriotic lesion survival?

SUMMARY ANSWER:

There is a constitutive activity of the IKKβ catalytic complex in peritoneal and deeply infiltrating lesions that can influence epithelial, but not stromal cell viability.

WHAT IS KNOWN ALREADY:

Endometriotic lesions exist in an inflammatory microenvironment with higher local concentrations of cytokines, such as tumour necrosis factor α (TNFα). TNFα stimulates the activation of the IKKβ complex, an important nodal point in multiple signalling pathways that influence gene transcription, proliferation and apoptosis. However, few data on the regulation of IKKβ in endometriotic tissue are currently available.

STUDY DESIGN, SIZE, DURATION:

A retrospective analysis of endometriotic tissue from peritoneal, ovarian and deeply infiltrating lesions from 37 women.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Basal and activated (phosphorylated) IKKβ concentrations were analysed by western blotting and immunohistochemistry. The relationship between the expression and activation of these proteins and peritoneal fluid (TNFα) concentrations, measured via ELISA, was examined. A subsequent in vitro analysis of TNFα treatment on the activation of IKKβ and the effect on epithelial and stromal cell viability by its inhibition with PS1145 was also performed.

MAIN RESULTS AND ROLE OF CHANCE:

Levels of the phosphorylated IKKβ complex in endometriotic lesions had a significant positive correlation with peritoneal fluid TNFα concentrations. Phosphorylated IKKβ complex was more prevalent in peritoneal and deeply infiltrating endometriosis lesions compared with ovarian lesions. IKKβ was present in both epithelial and stromal cells in all lesions but active IKKβ was limited to epithelial cells. TNFα stimulated an increased expression of phosphorylated IKKβ and the inhibition of this kinase with PS1145 significantly influenced ectopic epithelial cells viability but not eutopic epithelial cells, or endometrial stromal cells.

LIMITATIONS, REASONS FOR CAUTION:

In vitro analysis on epithelial cells was performed with immortalized cell lines and not primary cell cultures and only low sample numbers were available for the study.

WIDER IMPLICATIONS OF THE FINDINGS:

The regulation of aberrant signalling pathways represents a promising yet relatively unexplored area of endometriosis progression. The IKKβ complex is activated by inflammation and is critical nodal point of numerous downstream kinase-signalling pathways, including NFκB (nuclear factor κB), mTOR (mammalian target of rapamycin) and BAD (Bcl2-antagonist of cell death). This study shows a significant relationship between peritoneal fluid TNFα and IKKβ activation in epithelial cells that will have significant consequences for the continued survival of these cells at ectopic locations through the regulation of downstream pathways.

 

 

Gynecol Endocrinol. 2017 Feb;33(2):164-167.

Ovarian endometriosis and vitamin D serum levels.

Ciavattini A¹, Serri M¹, Delli Carpini G¹, Morini S¹, Clemente N¹.

Abstract

AIM:

The aim of this study was to assess the vitamin D serum level in women with ovarian endometriosis; specifically, a possible correlation between the dimensions of ovarian endometriomas and vitamin D serum levels was evaluated.

MATERIALS AND METHODS:

This was an observational study of childbearing-age women diagnosed with singleton ovarian endometrioma from January 2015 to December 2015. Women diagnosed with multiple ovarian endometriomas or extraovarian endometriosis were excluded.

RESULTS:

Forty-nine women constituted the initial study cohort. In these women, the mean (±SD) 25-OH-D3 serum level was 22.0 (±8.9) ng/ml, and 42 of them (85.7%) were diagnosed with hypovitaminosis D. In the “hypovitaminosis D women”, the mean (± SD) diameter of ovarian endometriomas was 40.2 ± 22.6 mm, while in the “normal vitamin D serum level women” it was 26.7 ± 12.1 mm (p = 0.1). However, a significant linear correlation between 25-OH-D3 serum level and the diameter of ovarian endometriomas was found (r = -0.3, p = 0.03).

CONCLUSION:

We found a relatively high rate of women with ovarian endometriosis and hypovitaminosis D. Interestingly, a significant linear correlation between 25-OH-D3 serum levels and the diameter of ovarian endometrioma emerged.

 

 

Reprod Biol Endocrinol. 2016 Nov 3;14(1):73.

Assisted reproductive technology pregnancy complications are significantly associated with endometriosis severity before conception: a retrospective cohort study.

Fujii T¹, Wada-Hiraike O², Nagamatsu T¹, Harada M¹, Hirata T¹, Koga K¹, Fujii T¹, Osuga Y¹.

Abstract

BACKGROUND:

Endometriosis has been shown to be associated with second- to third-trimester pregnancy complications such as preterm birth and placenta previa, but the evidence is inconsistent. We hypothesized that endometriosis severity might affect these inconsistent results. Therefore we aimed to conduct a retrospective cohort study to elucidate whether endometriosis severity is associated with the incidence rates of adverse pregnancy outcomes.

METHODS:

The patients who achieved singleton pregnancy by assisted reproductive technology (ART) in our facility between March 2000 and December 2014 (N = 631) were included in this analysis. Among them, 92 women demonstrated surgically proven endometriosis, and 512 women were shown to not have endometriosis as a complication. Among the 92 cases of endometriosis, 10 were classified as revised American Society for Reproductive Medicine (rASRM) stage I and II, 31 cases were rASRM stage III, and 43 cases were rASRM stage IV; in 8 cases, the rASRM stage was unavailable. Logistic regression analysis was performed to calculate odds ratios (OR) and 95 % confidence interval (CI) for the rates of preterm birth, placenta previa, and small for gestational age. OR were adjusted by age, parity and the number of transferred embryos.

RESULTS:

First we confirmed the frequency of preterm birth and placenta previa were significantly increased in women with endometriosis (preterm birth OR, 2.08; 95 % CI, 1.07-3.89, placenta previa OR, 15.1; 95 % CI, 4.40-61.7), while the frequency of small for gestational age was not. Moreover, we found the frequencies of preterm birth and placenta previa were significantly increased in women with rASRM stage IV endometriosis compared to other two groups: women with rASRM stage I-III endometriosis (preterm birth OR, 7.40; 95 % CI, 1.83-50.3; placenta previa OR, 11.0; 95 % CI, 1.75-216.5) and women without endometriosis (preterm birth adjusted OR, 4.11; 95 % CI, 1.88-8.55; placenta previa adjusted OR, 39.8; 95 % CI, 10.1-189.1). There were no significant difference between women with rASRM I-III endometriosis and women without endometriosis.

CONCLUSIONS:

We found that the frequencies of preterm birth and placenta previa were significantly increased in women with endometriosis, and the severity of endometriosis might have an adverse impact on ART pregnancy.

 

 

Gynecol Obstet Invest. 2017;82(1):96-101.

Abdominal Wall Endometriosis: Myofibroblasts as a Possible Evidence of Metaplasia: A Case Report.

Ibrahim MG¹, Delarue E, Abesadze E, Haas M, Sehouli J, Chiantera V, Mechsner S.

 

Abstract

In this study, we report about a patient with extra-uterine endometriosis (EM) in the abdominal wall muscle with evident metaplasia based on the abundant alpha smooth muscle actin (ASMA)-expressing myofibroblasts. Laparotomy excision of the abdominal wall EM was done following ultrasonographic evidence of a hypodense swelling in the right rectus abdominis, which was confirmed by MRI. Immunohistochemistry staining for ASMA and collagen I was done, with the results confirming that endometriotic stromal cells expressed both. Anterior abdominal wall endometriosis was suspected because of the patient’s history of recurrent EM combined with the cyclic nature of symptoms. MRI is useful in determining the extent of the disease. In case of persisting symptoms even under hormonal treatment, surgical excision is mandatory. The expression of both ASMA and collagen I in and around EM lesions supports the notion of the metaplastic process in the course of disease development.

 

 

 

 

Front Biosci (Landmark Ed). 2017 Jan 1;22:479-492.

Multiplex immunoassays in endometriosis: An array of possibilities.

O DF¹, El Aalamat Y², Waelkens E³, De Moor B², D’Hooghe T¹, Fassbender A⁴.

 

Abstract

Multiplex immunoassays range from small-scaled multiplex sandwich ELISAs in a planar or bead-based format to the more expanded antibody arrays employing direct sample labeling. The plethora of data generated from these arrays could be of great interest to understand a complex disorder such as endometriosis. Multiplex immunoassay analysis may provide information on disease pathology and may lead to improved, timely diagnosis. Until now, the use of multiplex immunoassays has been limited in endometriosis. With the constant development of multiplex technologies, future studies should focus on implementing these techniques, and combining them with multivariate statistical analysis. In this review, we provide an overview of multiplex immunoassay methods used in endometriosis studies and the data sets acquired by these methodologies. These data and future studies might provide novel insights for biomarker discovery and investigation of the pathogenesis in endometriosis.

 

 

J Bodyw Mov Ther. 2016 Oct;20(4):931-936

A model for radiating leg pain of endometriosis.

Bove GM¹.

 

Abstract

Endometriosis is a prevalent female health disorder that often leads to back pain and radiating leg pain. Patients with such pain often seek care from multiple health care professionals, including manual therapists. We hypothesized that endometrioma can induce nerve inflammation thus the radiating leg pain that often accompanies endometriosis. To model sciatic endometriosis in female Wistar rats, a section of uterine horn was autotransplanted to the sciatic nerve. Uterus sections with the endometrium removed and autotransplanted to the sciatic nerve served as controls. After 1, 3, and 15 months the nerves were harvested and processed for immune cell presence and for neural elements. Control nerves were harvested after 4 months. All autotransplants survived, resulting in a fusion of the uterus sections to the nerves. Macroscopically, turgid cysts apposed to the nerves characterized the complexes. Microscopically, the complexes contained recruited macrophages, indicating persistent inflammation, and were innervated by small diameter axons. Only 1 of 8 control rats developed a small cyst, presumably due to residual endometrium. The persistent immune response and innervation suggest the nerve-uterus complexes as sources of inflammation and persistent neural discharge, and thus pain. This model could shed light upon the radiating leg pain that often accompanies endometriosis. Manual therapists should be aware of the possibility of endometriosis causing symptoms and examination findings that mimic musculoskeletal etiologies.

 

 

Fertil Steril. 2017 Jan;107(1):289-296.

Gynecological and obstetrical outcomes after laparoscopic repair of a cesarean scar defect in a series of 38 women.

Donnez O¹, Donnez J², Orellana R³, Dolmans MM⁴.

Abstract

OBJECTIVE:

To evaluate gynecological and obstetrical outcomes, as well as remaining myometrial thickness, after laparoscopic repair of a cesarean scar.

DESIGN:

Observational study and prospective evaluation of the remaining myometrium before and after repair.

SETTING:

Academic department in a university hospital.

PATIENT(S):

A series of 38 symptomatic women with cesarean scar defects and remaining myometrial thickness of less than 3 mm, according to magnetic resonance imaging.

INTERVENTION(S):

Laparoscopic repair of the defect.

MAIN OUTCOMES MEASURE(S):

Increase in myometrial thickness at the site of cesarean section, gynecological and obstetrical outcomes, and histological analysis of the defect after excision.

RESULT(S):

The mean thickness of the myometrium increased significantly from 1.43 ± 0.7 mm before surgery to 9.62 ± 1.8 mm after surgery. All but three patients were free of symptoms. Among the 18 women with infertility, eight (44%) became pregnant and delivered healthy babies by cesarean section at 38-39 weeks of gestation. Histological analysis, performed in all 38 cases, revealed the presence of endometriosis in eight women (21.1%). Muscle fiber density was significantly lower compared with adjacent myometrium.

CONCLUSION(S):

In symptomatic women with residual myometrial thickness of less than 3 mm who wish to conceive, laparoscopic repair could be considered an appropriate approach.

 

 

 

Hum Reprod. 2017 Jan;32(1):94-102.

Rediscovering peritoneal macrophages in a murine endometriosis model.

Yuan M¹, Li D², An M¹, Li Q¹, Zhang L¹, Wang G³.

Abstract

STUDY QUESTION:

What are the features of peritoneal macrophage subgroups and T helper cells in the development of murine endometriosis?

SUMMARY ANSWER:

During the development of endometriosis in a murine model, large peritoneal macrophages (LPMs) and small peritoneal macrophages (SPMs) are polarized into M1 and M2 cells, respectively, and the proportions of T helper (Th) 1, Th17 and T regulatory (T_reg) cells are increased.

WHAT IS KNOWN ALREADY:

Numerous studies investigating the etiology and pathogenesis of endometriosis have focused on the polarization states of peritoneal macrophages in endometriosis models and patients, but the results are inconclusive. Further studies indicate that peritoneal macrophages are composed of two distinct subsets: LPMs and SPMs, although their roles in endometriosis are unknown.

STUDY DESIGN, SIZE, DURATION:

This study involves a prospective and randomized experiment. Fifty C57BL/6 female mice were randomly allocated to five control and five experimental groups (n = 5/group) according to the presence or absence of transplantation. The transplant periods are 0.25, 3, 14, 28 and 42 days.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

C57BL/6 mice were utilized to establish an endometriosis model by i.p. injection of allogeneic endometrial segments. Dynamic changes of peritoneal macrophage subsets and polarization profiles were evaluated by flow cytometry (FCM). Macrophage morphology and density were assessed by cell counting under a microscope. Dynamic changes of Th1, Th2, Th17 and T_reg cells were estimated by FCM.

MAIN RESULTS AND THE ROLE OF CHANCE:

Peritoneal macrophages are composed of two distinct subsets: LPMs and SPMs. The proportion of SPMs increased immediately after peritoneal injection of endometrial tissues, whereas LPMs showed an opposite trend. Peritoneal macrophages differentiated into both M1 and M2 macrophages. The bidirectional polarization of macrophages was caused by the inverse trends of polarization of LPMs and SPMs. Consistently, the proportions of Th1, Th17 and T_reg cells were all increased in mice with endometriosis.

LARGE SCALE DATA:

N/A.

LIMITATIONS, REASONS FOR CAUTION:

In this study, detection was only performed in a murine endometriosis model. Clinical data and more intervention experiments are required in understanding the roles of LPMs and SPMs in endometriosis.

WIDER IMPLICATIONS OF THE FINDINGS:

The dramatic changes of LPMs and SPMs in proportion and polarization profiles clarified the varying differentiation states of peritoneal macrophages. In addition, LPMs and SPMs may play different roles in the pathogenesis of endometriosis in different stages of endometriosis. Therefore, the new classification should be included in future relevant basic and clinical studies on endometriosis.

STUDY FUNDING/COMPETING INTERESTS:

This research was supported totally by grant 81270671 from the National Natural Science Foundation of China. The authors report no conflict of interest.

 

 

Gynecol Obstet Invest. 2017;82(4):322-328.

Detecting Endometriosis in Adolescents: Why Not Start from Self-Report Screening Questionnaires for Adult Women?

Geysenbergh B¹, Dancet EAF, D’Hooghe T.

Abstract

BACKGROUND:

Endometriosis in adolescent girls is often diagnosed after a long delay. This diagnostic delay can be associated with more advanced stages of endometriosis and with a higher likelihood of fertility problems at a later age.

MATERIAL AND METHODS:

A systematic review of literature and quality assessment was performed in order to identify questionnaires that were developed to identify adult women with endometriosis. Based on these questionnaires, specific questions that had been reported to be predictive for endometriosis were selected and included in a newly composed questionnaire with the aim to identify adolescents at risk of developing endometriosis.

RESULTS:

Based on the literature, we identified 5 questionnaires developed to identify adult women with endometriosis; this questionnaire contained 6 questions that had been reported to be predictive for adult endometriosis. These questions query age of menarche, cycle duration, dysmenorrhea, pain descriptors, dyschezia and urinary symptoms and were combined into a new self-report questionnaire aimed to identify adolescents at risk to develop endometriosis.

CONCLUSION:

We developed a self-report questionnaire aimed to identify adolescents at risk to develop endometriosis based on questions from self-report questionnaires that have been reported to identify adult women with endometriosis.

 

 

J Assist Reprod Genet. 2017 Jan;34(1):117-124.

Copy number variation analysis reveals additional variants contributing to endometriosis development.

Mafra F^1,2, Mazzotti D³, Pellegrino R³, Bianco B⁴, Barbosa CP⁴, Hakonarson H³, Christofolini D⁴.

Abstract

PURPOSE:

Endometriosis is a gynecological disease influenced by multiple genetic and environmental factors. The aim of the current study was to use SNP-array technology to identify genomic aberrations that may possibly contribute to the development of endometriosis.

METHODS:

We performed an SNP-array genotyping of pooled DNA samples from both patients (n = 100) and controls (n = 50). Copy number variation (CNV) calling and association analyses were performed using PennCNV software. MLPA and TaqMan Copy-Number assays were used for validation of CNVs discovered.

RESULTS:

We detected 49 CNV loci that were present in patients with endometriosis and absent in the control group. After validation procedures, we confirmed six CNV loci in the subtelomeric regions, including 1p36.33, 16p13.3, 19p13.3, and 20p13, representing gains, while 17q25.3 and 20q13.33 showed losses. Among the intrachromosomal regions, our results revealed duplication at 19q13.1 within the FCGBP gene (p = 0.007).

CONCLUSIONS:

We identified CNVs previously associated with endometriosis, together with six suggestive novel loci possibly involved in this disease. The intergenic locus on chromosome 19q13.1 shows strong association with endometriosis and is under further functional investigation.

 

 

Fertil Steril. 2016 Dec;106(7):1552-1571.

Estrogen-progestins and progestins for the management of endometriosis.

Vercellini P¹, Buggio L², Berlanda N³, Barbara G³, Somigliana E², Bosari S².

 

Abstract

Endometriosis is characterized by frequent recurrences of symptoms and lesions even after extirpative surgery. Because medical therapies control but do not cure the disease, long periods of pharmacologic management may be needed until pregnancy desire or, sometimes, physiologic menopause. Hormonal drugs suppress ovulation and menstruation and have similar beneficial effects against pain. However, only estrogen-progestins and progestins have safety/tolerability/cost profiles that allow long-term use. These compounds induce atrophy of eutopic and ectopic endometrium, have antiinflammatory and proapoptotic properties, and can be delivered via different modalities, including oral, transdermal, subcutaneous, intramuscular, vaginal, and intrauterine routes. At least two-thirds of symptomatic women are relieved from pain and achieve appreciable improvements in health-related quality of life. Progesterone resistance may cause nonresponse in the remaining one-third. When using estrogen-progestins continuously, individualized, tailored cycling should be explained to improve compliance. All combinations demonstrated a similar effect on dysmenorrhea, independently from progestin type. Estrogen-progestins with the lowest possible estrogen dose should be chosen to combine optimal lesion suppression and thrombotic risk limitation. Progestins should be suggested in women who do not respond or manifest intolerance to estrogen-progestins and in those with dyspareunia and/or deep lesions. Progestins do not increase significantly the thrombotic risk and generally may be used when estrogens are contraindicated. Estrogen-progestins and progestins reduce the incidence of postoperative endometrioma recurrence and show a protective effect against endometriosis-associated epithelial ovarian cancer risk.

 

 

 

 

 

Gynecol Obstet Invest. 2017;82(5):453-461

Prevalence and Symptomatic Burden of Diagnosed Endometriosis in the United States: National Estimates from a Cross-Sectional Survey of 59,411 Women.

Fuldeore MJ¹, Soliman AM.

Abstract

BACKGROUND/AIMS:

To estimate the prevalence of diagnosed endometriosis (DE) in women in the United States and assess the associated symptomatic burden.

METHODS:

An online, cross-sectional survey of women aged 18-49 years was conducted from August 6, 2012, through November 14, 2012. Survey data (weighted by age, race, education, income, geographical distribution, and propensity score) were used to estimate the prevalence and symptomatic burden of DE in women in the United States. Weighted logistic regressions were used to assess differences in symptom burden between women with and without endometriosis.

RESULTS:

The prevalence of DE was estimated at 6.1% (2,922 of 48,020 women surveyed); 52.7% of women were 18-29 years of age when they were diagnosed with endometriosis. Most (86.2%) women experienced symptoms before diagnosis. More women with (vs. without) DE had menstrual pelvic pain/cramping (52.7 vs. 45.2%), non-menstrual pelvic pain/cramping (36.7 vs. 14.3%), infertility (11.6 vs. 3.4%), and dyspareunia (29.5 vs. 13.4%). Women with endometriosis were also more likely to report severe symptoms (OR (95% CI) 2.7 (2.3-3.1) for menstrual pelvic pain/cramping, 2.2 (1.7-2.9) for non-menstrual pelvic pain/cramping, and 2.4 (1.8-3.2) for dyspareunia).

CONCLUSION:

The prevalence of DE among US women is notable, and affected women experience a substantial symptom burden.

 

 

Reprod Sci. 2016 Dec;23(12):1616-1619.

Endometriosis and Stem Cell Trafficking.

Pluchino N¹, Taylor HS².

 

Abstract

Adult stem cells have a major role in endometrial physiology, remodeling, and repair, but they also have a critical role in the development and progression of endometriosis. Bone marrow-derived stem cells (BMDSCs) engraft eutopic endometrium and endometriotic lesions, showing stromal and epithelial fate. Nevertheless, circulating BMDSCs are in limited supply, and the presence of endometriosis depletes stem cells from the blood circulation, preventing their homing in the uterus. Furthermore, stem cells migrate from endometriotic lesion into the uterus, leading to a dysfunctional endometrium. Stem cell trafficking is a central feature of endometriosis. Understanding molecular mechanisms regulating cell mobility and engraftment in endometriosis may reveal new targets for treatment.

 

 

Reprod Sci. 2016 Dec;23(12):1656-1661.

Oxidative Stress in Granulosa-Lutein Cells From In Vitro Fertilization Patients.

Ávila J^1,2, González-Fernández R¹, Rotoli D^1,3, Hernández J⁴, Palumbo A^5,6.

 

Abstract

Ovarian aging is associated with gradual follicular loss by atresia/apoptosis. Increased production of toxic metabolites such as reactive oxygen species (ROS) and reactive nitrogen species as well as external oxidant agents plays an important role in the process of ovarian senescence and in the pathogenesis of ovarian pathologies such as endometriosis and polycystic ovary syndrome (PCOS). This review provides a synthesis of available studies of oxidative stress (OS) in the ovary, focusing on the most recent evidence obtained in mural granulosa-lutein (GL) cells of in vitro fertilization patients. Synthesis of antioxidant enzymes such as peroxiredoxin 4, superoxide dismutase, and catalase and OS damage response proteins such as aldehyde dehydrogenase 3, member A2 decreases with aging in human GL cells, favoring an unbalance in ROS/antioxidants that mediates molecular damage and altered cellular function. The increase in OS in the granulosa cell correlates with diminished expression of follicle-stimulating hormone receptor (FSHR) and a dysregulation of the FSHR signaling pathway and may be implicated in disrupted steroidogenic function and poor response to FSH in women with aging. Women with endometriosis and PCOS have lower antioxidant production capacity that may contribute to abnormal follicular development and infertility. Further investigation of the signaling pathways involved in cellular response to OS could shed light into molecular characterization of these diseases and development of new treatment strategies to improve reproductive potential in these women.

 

 

J Ultrasound Med. 2016 Dec;35(12):2699-2715.

Gel Sonovaginography: A New Way of Evaluating a Variety of Local Vaginal and Cervical Disorders.

Sibal M¹.

 

Abstract

Gel sonovaginography is a new way of assessing local cervical and vaginal disorders, in which regular transvaginal sonography is known to have limitations. In gel sonovaginography, 20 mL of ultrasound gel is instilled into the vagina, followed by examination with a transvaginal transducer. In a study involving 28 women with known or suspected disorders such as cervical and vaginal cancer, cervical polyps, vaginal septa, and deep infiltrating endometriosis, a substantial improvement in visualization and assessment of local lesions and structures was noted with gel sonovaginography. This simple technique appears to be valuable for accurate diagnosis of local cervical and vaginal disorders.

 

 

Hum Reprod. 2017 Jan;32(1):175-184.

The cannabinoid receptor CB1 contributes to the development of ectopic lesions in a mouse model of endometriosis.

Sanchez AM¹, Quattrone F¹, Pannese M¹, Ulisse A¹, Candiani M², Diaz-Alonso J^3,4, Velasco G^3,4,5, Panina-Bordignon P⁶.

Abstract

STUDY QUESTION:

Does signaling via the cannabinoid (CB₁) receptor play a role in the pathogenesis of endometriosis in a mouse model?

SUMMARY ANSWER:

Mice treated with a CB₁ agonist developed larger ectopic lesions, while less severe lesions developed in the absence of functional CB₁ expression.

WHAT IS KNOWN ALREADY:

The expression of components of the endocannabinoid system has been demonstrated in both mouse and human uteri. CB₁ receptors are expressed in human epithelial and stromal cell lines derived from eutopic endometrium and deep infiltrating endometriosis nodules.

STUDY DESIGN, SIZE, DURATION:

This was a randomized study in a mouse model of endometriosis. In a first set of experiments, mice with endometriosis were treated with the CB₁ receptor agonist methanandamide (MET) (5 mg/kg, n = 20) on Days 1-5 and 8-12. In a second set of experiments, endometriosis development was evaluated in CB₁^-/- mice and in their wild-type (WT) littermates.

PARTICIPANTS/MATERIALS, SETTING, METHODS:

Endometriosis-like lesions were induced in Balb/c and C57/Bl6 mice. Two weeks after disease induction, the lesions were counted, measured and either included for immunohistochemistry analysis or frozen for gene expression profiling by semi-quantitative real-time PCR. To limit the role of chance, the experiments were conducted under standardized laboratory conditions with appropriate controls.

MAIN RESULTS AND THE ROLE OF CHANCE:

The lesion total volume was significantly higher in MET-treated compared with vehicle-treated mice (P < 0.05). Expression levels of mRNA for survivin, N-cadherin, integrin β1 and interleukin-6 were increased in the ectopic endometrium of MET-treated versus vehicle-treated mice (P < 0.05). CB₁^-/- recipients that received endometrial tissue fragments from CB₁^-/- donors, WT recipients that received endometrial tissue fragments from CB₁^-/- donors and CB₁^-/- recipients that received endometrial tissue fragments from WT donors all showed a significant reduction in total lesion volume and lower expression of survivin and N-cadherin compared with WT recipients receiving uterine fragments from WT donors (P < 0.05).

LARGE SCALE DATA:

N/A.

LIMITATIONS, REASONS FOR CAUTION:

We provide evidence that endocannabinoid signaling via CB₁ receptor plays a role in the development of endometriosis in a mouse model. However, the relative contribution of the CB₁-mediated signaling pathways active in inflammatory, uterine and peritoneal cells remains to be ascertained. Since the study was performed in a mouse model, the significance of the findings in the human system warrants further investigation.

WIDER IMPLICATIONS OF THE FINDINGS:

Clarifying the function and regulation of CB₁ and its molecular interactions with endogenous ligands, and how endocannabinoids levels are regulated in women with endometriosis, represent critical areas of research for the potential development of a novel medical treatment of the disease.

STUDY FUNDING/COMPETING INTERESTS:

A.M.S. was supported by a fellowship from Fondazione Giorgio Pardi. The authors have no conflicts of interest to declare.

 

 

Reprod Biomed Online. 2017 Feb;34(2):162-165.

No need for luteal phase support in IVF cycles after mild stimulation: proof-of-concept study.

Ferraretti AP¹, Devroey P², Magli MC², Gianaroli L².

 

Abstract

This is a pilot study performed in a private IVF unit. The objective of the study was to investigate whether luteal support is required in IVF cycles after mild stimulation with clomiphene citrate and low FSH doses. The study included 15 patients with good prognosis (defined as ≤38 years old with normal ovarian reserve and normovulatory cycles, body mass index <29 kg/m², no previous cycles, no severe endometriosis, no history of recurrent miscarriage, no endocrine/autoimmune diseases and no surgical semen extraction from the partner) undergoing IVF with mild stimulation. Patients were monitored during the luteal phase by serum progesterone and LH. The luteal support was started only when necessary. No patient needed luteal phase support because the resultant steroid environment was different from that associated with conventional stimulation techniques. The live birth rate was 40% (6/15) and the implantation rate 30% (6/20). There are several benefits to mild stimulation, including low cost, less patient distress and improved endometrial receptivity. Our study supports the concept that mild stimulation may have an additional benefit during the luteal phase, by obviating the need for luteal phase support.

 

 

Eur Rev Med Pharmacol Sci. 2016 Oct;20(20):4380-4389.

Disulfiram, as a candidate NF-κB and proteasome inhibitor, prevents endometriotic implant growing in a rat model of endometriosis.

Celik O¹, Ersahin A, Acet M, Celik N, Baykus Y, Deniz R, Ozerol E, Ozerol I.

Abstract

OBJECTIVE:

Disulfiram (DSF) exerts its therapeutic effects through oxidative, proteasome, and nuclear factor kappa beta (NF-κB) pathways. The study was planned to test the impact of DSF on growing of endometriotic implants in rats with experimentally induced endometriosis.

PATIENTS AND METHODS:

Thirty rats were labeled as the control (n = 8), sham (n = 6), GnRH-agonist (n = 8) and the DSF (n = 8) groups. The rats in the group 3 exposed to single dose leuprolide acetate. The rats in group 4 were treated with DSF for 21 days. The serum activity of oxidant and antioxidant markers, total oxidant status (TOS), total antioxidant status (TAS), interleukin-1β, and tumor necrosis factor-α (TNF-α) were determined. Implants were processed for NF-κB, PCNA, and CD34 immunostaining.

RESULTS:

The serum concentration of malondialdehyde in the DSF group was significantly higher than those in other groups. The concentration of TAS, TNF-α, and interleukin-1β in the DSF group considerably decreased compared to control group. Following treatment with DSF while the percentage of Grade 1 and 2 implants increased the percentage of Grade 3 and 4 implants decreased. The implants disappeared totally in two cases in the DSF group and one case in the GnRH-agonist group. The mean H-Scores of implant NF-κB and PCNA in DSF treated animals were found to significantly lower than those of the control group.

CONCLUSIONS:

By decreasing NF-κB expression, angiogenesis, and cell proliferation DSF prevents the growth of endometriotic implants.

 

 

Abdom Radiol (NY). 2016 Dec;41(12):2380-2400

Deep pelvic endometriosis: a radiologist’s guide to key imaging features with clinical and histopathologic review.

Darvishzadeh A¹, McEachern W², Lee TK³, Bhosale P⁴, Shirkhoda A⁵, Menias C⁶, Lall C⁵.

 

Abstract

While endometriosis typically affects the ovaries, deep infiltrating endometriosis can affect the gastrointestinal tract, urinary tract, and deep pelvis, awareness of which is important for radiologists. Symptoms are nonspecific and can range from chronic abdominal and deep pelvic pain to nausea, vomiting, diarrhea, constipation, hematuria, and rectal bleeding. Ultrasound and computed tomography may show nonspecific soft-tissue density masses causing bowel obstruction and hydronephrosis. This constellation of presenting symptoms and imaging evidence is easily mistaken for other pathologies including infectious gastroenteritis, diverticulitis, appendicitis, and malignancy, which may lead to unnecessary surgery or mismanagement. With this, deep pelvic endometriosis should be considered in the differential diagnosis in a female patient of reproductive age who presents with such atypical symptoms, and further work up with magnetic resonance imaging is imperative for accurate diagnosis, treatment selection, and preoperative planning.

 

 

Biomed Res Int. 2016;2016:5791510

Activin A Stimulates Aromatase via the ALK4-Smad Pathway in Endometriosis.

Zheng J¹, Qu J², Lu P², Hou Z², Cui Y², Mao Y², Qi X², Ji H², Liu J².

 

Abstract

Endometriosis is an estrogen-dependent disease. We previously found that the expression of Activin A was upregulated in the peritoneal fluid of patients with endometriosis. The results of the present study indicated that Activin A induced estradiol secretion and P450arom expression in endometrial stromal cells (ESCs) derived from endometriosis patients. The mechanism of estrogenic synthesis was regulated by the Activin-Smad pathway in endometrial lesions. The data showed that the effect of Activin A on ESCs was partially abrogated by pretreatment with an inhibitor of ALK4 (the type I receptor, ActRIB) and Smad4-siRNA. Cumulatively, these data suggest that Activin A promotes the secretion of estradiol from ESCs by increasing the expression of P450arom via the ALK4-Smad pathway. These findings indicate the ALK4-Smad pathway may promote ectopic lesion survival and development.

 

 

Rom J Morphol Embryol. 2016;57(2 Suppl):825-829.

Umbilical hernia masking primary umbilical endometriosis – a case report.

Brătilă E¹, Ionescu OM, Badiu DC, Berceanu C, Vlădăreanu S, Pop DM, MehedinŢu C.

 

Abstract

Endometriosis is a gynecologic condition affecting mainly the pelvic organs. However, extrapelvic endometriosis has been reported in almost all parts of the body. Umbilical endometriosis, either primary or secondary, is uncommon and has a documented neoplastic risk. We present the case of a 46-year-old woman with a large umbilical hernia associating primary umbilical endometriosis discovered during surgery and confirmed later by pathological and immunohistochemical exams. The patient underwent omphalectomy and partial omentum resection, alongside with mesh abdominal wall repair. The patient was informed about the recurrence risk and was asymptomatic at follow-up consults.

 

 

Rom J Morphol Embryol. 2016;57(2 Suppl):849-852.

Müllerianosis of the urinary bladder: a rare case report and review of the literature.

Stanimir M¹, ChiuŢu LC, Wese S, Milulescu A, Nemeş RN, Bratu OG.

 

Abstract

The aim of this paper is to report a very rare case of müllerianosis (endosalpinx, endometrium, and endocervix) in a post-menopausal woman. Müllerianosis of the bladder is a very rare disease, which affects mainly the women of the reproductive age group, but with a good prognosis if the transitional bladder carcinoma is resolved. We present the case of a 64-year-old woman complaining of left lower abdomen pain, repeated lower and upper tract urinary infections, emergency urinary incontinence and hematuria. The surgical history shows that she underwent a hysterectomy, caesarean section and appendectomy. The clinical examination emphasizes a normal abdomen, with a normal aspect of the post-operative scars and a second-degree cystocele. An abdominal computed tomography (CT) scan with contrast and a cystography were performed and showed a 16 mm lesion-like tumor on the left bladder wall respectively a third-degree vesicoureteral reflux. These investigations were followed by a cystoscopy and transurethral resection of the bladder tumor (TURBT). The histopathology report described three types of tissues: endometriosis, endocervicosis and endosalpingiosis. Sequent to these results, a partial cystectomy with the re-implantation of the left ureter was performed. Once again, the results of the specimen confirm the diagnosis of müllerianosis. The immediate post-operative outcomes were good, the patient having no pains and no more hematuria. Six month later, a tension-free vaginal tape obturator (TVT-O) operation was carried out for urinary incontinence and two years later, a correction for a post-surgical abdominal hernia was performed. Müllerianosis of the bladder is a very rare disease, which affects mainly the women at the procreation age, but with a good prognosis. The differential diagnosis with a malignant tumor is very important to be carefully made. Currently, there is no golden standard to treat this disease. The cystoscopy and the histopathological examination of the specimen are indispensable for the certainty diagnosis.

 

 

Eur J Obstet Gynecol Reprod Biol. 2017 Feb;209:25-33.

Combined effect of vascular endothelial growth factor and its receptor polymorphisms in endometriosis: a case-control study.

Cardoso JV¹, Abrão MS², Vianna-Jorge R³, Ferrari R⁴, Berardo PT⁵, Machado DE⁶, Perini JA⁷.

Abstract

OBJECTIVE:

Endometriosis is a multifactorial gynecological disease, whose pathogenesis is crucially dependent on angiogenesis, which is signaled via vascular endothelial growth factor (VEGF) and its receptor (VEGFR2). We hypothesize that single nucleotide polymorphisms (SNPs) in VEGF and VEGFR2 genes may influence the onset and/or the progression of endometriosis. The main aim of this study was to investigate the contribution of VEGF and VEGFR2 SNPs as risk factors for endometriosis, as well as their association with endometriosis symptoms.

STUDY DESIGN:

A case-control study was conducted, involving 293 endometriosis patients and 223 controls, who were submitted to laparoscopic or laparotomy surgery at hospitals from the Brazilian public health system. Genotyping of VEGF (-2578C>A, -460T>C, -1154G>A, +405G>C and +936C>T) and VEGFR2 (-604T>C, 1192C>T) SNPs was performed by TaqMan real-time polymerase chain reaction. The association between SNPs and endometriosis, deep infiltrating endometriosis (DIE) or endometriosis symptoms was estimated by odds ratios (OR) with their 95% confidence intervals (CI), which were calculated using multivariate logistic regression models.

RESULTS:

VEGF variant alleles -2578A and -1154A were associated with increased endometriosis risk (OR: 1.39, 95% CI: 1.04-1.87 and OR: 1.63, 95% CI: 1.12-2.37, respectively), whereas VEGF 405C and VEGFR2 1192T were associated with lower risk of endometriosis (OR: 0.66, 95% CI: 0.43-1.00 and OR: 0.58, 95% CI: 0.40-0.84, respectively). The combination of wild-type genotypes of both VEGF -2578C>A and -1154G>A with variant genotypes of both VEGF +405G>C and VEGFR2 1192C>T showed the best protective effect against the development of endometriosis, either considering all cases (OR: 0.33, 95% CI: 0.12-0.89) or only DIE (OR: 0.30, 95% CI: 0.10-0.87). The combination of variant genotypes of VEGF -2578C>A, -1154G>A, +405G>C and VEGFR2 1192C>T was also protective against DIE (OR: 0.67, 95% CI: 0.46-0.96). VEGFR2 1192C>T were associated with reduced cyclical urinary complaints (OR: 0.40, 95% CI: 0.18-0.88).

CONCLUSIONS:

Our results indicate that VEGF SNPs -2578C>A and -1154G>A increase endometriosis risk, whereas VEGF +405G>C and VEGFR2 1192C>T are protective against disease development, with VEGFR2 1192C>T also reducing cyclical urinary symptoms. The combined analysis of VEGF-VEGFR2 genotypes suggests a gene-gene interaction in endometriosis susceptibility.

 

 

Arch Gynecol Obstet. 2017 Feb;295(2):367-374.

Perivaginal benign masses: diagnosis and therapy in a series of 66 women.

Liaci AL¹, Boesmueller H², Huebner M¹, Brucker SY¹, Reisenauer C³.

Abstract

PURPOSE:

Benign perivaginal masses (PVM) are relatively rare. The aim of this study is, to create a higher awareness for these entities and to point out reliable diagnostics and an accurate treatment.

METHODS:

The medical records of the Department of Obstetrics and Gynecology Tuebingen were searched for number and type of urogynecological surgery in general, and a surgery, which took place particularly owing to benign PVM, over a period of 5 years. Diagnostics, treatment, histology and postoperative management were summarized and analyzed. Vaginal endometriosis manifestations were not considered.

RESULTS:

Between 2011 and 2015 a total number of 4.157 women underwent urogynecological surgery, 65 (1.6%) of these particularly because of benign PVM. The benign PVM in the patient cohort were composed as follows: urethral diverticula (UD), squamous epithelial inclusion cysts, periurethral cysts, Gartner’s duct cysts, Müllerian cysts, pseudocysts, abscesses, epidermal inclusion cysts, angiofibromas, angiomyofibroblastomas, leiomyomas, solitary fibrous tumor and masses due to alloplastic materials. The PVM occurred singly or multiply. They were asymptomatic or accompanied by symptoms. Case history, clinical examination, pelvic floor sonography, urethrocystoscopy and MRI are essential tools for diagnostics. PVM simulated cystoceles and recto/enteroceles, were cause of an overactive bladder, dyspareunia, pain or were concomitants in women with stress urinary incontinence. The PVM were excised in 65 out of 66 cases, in one case an infected UD regressed completely under conservative antibiotic therapy.

CONCLUSIONS:

The awareness for benign PVM is helpful for their diagnostics and management. As secondary pathology, intradiverticular stones and malignancy have to be considered.

 

 

Hormones (Athens). 2016 Jul;15(3):423-434.

The human Ec peptide: the active core of a progression growth factor with species-specific mode of action.

Papageorgiou E¹, Philippou A¹, Armakolas A¹, Christopoulos PF¹, Dimakakos A¹, Koutsilieris M¹.

Abstract

OBJECTIVE:

Preferential IGF-1Ec expression has been firmly associated with skeletal muscle repair mechanisms, post-infarction remodeling of the myocardium, the pathophysiology of endometriosis and prostate cancer biology. Therefore, we have studied the possible biological significance of synthetic Ec peptide, a putative cleavage product of IGF-1Ec in PC-3 cells and C2C12 myoblasts.

DESIGN:

We had previously designed and synthesized commercially peptides corresponding to the human Ec and its mouse igf1 counterpart as well as synthetic peptides that correspond to parts of the hEc. Using proliferation and mitogenic signaling assays, we tested their effect on PC-3 cells and C2C12 myoblasts at different doses and in different culture conditions.

RESULTS:

Human Ec, hEc, was documented as exerting progression but not competence growth factor actions, activating ERK1/2 without affecting Akt phosphorylation in PC-3 cells. A narrow concentration range of hEc (5-50nM) stimulated the growth of PC-3 cells grown in culture media supplemented with 10% FBS. hEc did not stimulate the growth of PC-3 cells cultured with media containing 0.5% FBS or in mouse C2C12 myoblasts under any culture conditions. The activity of hEc was blocked by a neutralizing anti-human IGF-1Ec antibody but not by a neutralizing anti-human IGF-1 receptor antibody. The synthetic mouse Ec was inactive in human PC-3 cells; however, it stimulated significantly the proliferation of mouse C2C12. By analyzing the bioactivity of synthetic hEc fragments, we documented that hEc’s active core is located in the last 4aa of its C-terminal end.

CONCLUSION:

The hEc peptide is an important progression factor for human PC-3 prostate cancer cells.

 

 

 

Am J Obstet Gynecol. 2017 May;216(5):451-458.

Googling endometriosis: a systematic review of information available on the Internet.

Hirsch M¹, Aggarwal S¹, Barker C², Davis CJ¹, Duffy JMN³.

Abstract

BACKGROUND:

The demand for health information online is increasing rapidly without clear governance.

OBJECTIVE:

We aim to evaluate the credibility, quality, readability, and accuracy of online patient information concerning endometriosis.

STUDY DESIGN:

We searched 5 popular Internet search engines: aol.com, ask.com, bing.com, google.com, and yahoo.com. We developed a search strategy in consultation with patients with endometriosis, to identify relevant World Wide Web pages. Pages containing information related to endometriosis for women with endometriosis or the public were eligible. Two independent authors screened the search results. World Wide Web pages were evaluated using validated instruments across 3 of the 4 following domains: (1) credibility (White Paper instrument; range 0-10); (2) quality (DISCERN instrument; range 0-85); and (3) readability (Flesch-Kincaid instrument; range 0-100); and (4) accuracy (assessed by a prioritized criteria developed in consultation with health care professionals, researchers, and women with endometriosis based on the European Society of Human Reproduction and Embryology guidelines [range 0-30]). We summarized these data in diagrams, tables, and narratively.

RESULTS:

We identified 750 World Wide Web pages, of which 54 were included. Over a third of Web pages did not attribute authorship and almost half the included pages did not report the sources of information or academic references. No World Wide Web page provided information assessed as being written in plain English. A minority of web pages were assessed as high quality. A single World Wide Web page provided accurate information: evidentlycochrane.net. Available information was, in general, skewed toward the diagnosis of endometriosis. There were 16 credible World Wide Web pages, however the content limitations were infrequently discussed. No World Wide Web page scored highly across all 4 domains.

CONCLUSION:

In the unlikely event that a World Wide Web page reports high-quality, accurate, and credible health information it is typically challenging for a lay audience to comprehend. Health care professionals, and the wider community, should inform women with endometriosis of the risk of outdated, inaccurate, or even dangerous information online. The implementation of an information standard will incentivize providers of online information to establish and adhere to codes of conduct.

 

Expert Opin Ther Targets. 2017 Jan;21(1):67-75.

Targeting mast cells: a new way to treat endometriosis.

Binda MM¹, Donnez J², Dolmans MM^1,3

Abstract

INTRODUCTION:

Endometriosis is a chronic estrogen-dependent inflammatory disease of unclear etiology that affects 15-20% of women of reproductive age. Efforts are now focusing on understanding new mechanisms involved in its physiopathology, like novel target pathways and different molecules. There is evidence that mast cells (MCs) play a role in this disease. This article summarizes recent achievements in preclinical studies and clinical activities investigating the role of MCs in endometriosis. Targeting MCs might offer new alternatives to treat this disease. Areas covered: A systematic literature search was performed (PubMed, Cochrane Library and ClinicalTrials.gov) using the keywords ‘endometriosis and mast cells’. All relevant articles (34) found in PubMed were examined and their reference lists reviewed in order to pinpoint further studies for potential inclusion. Expert opinion: Since endometriosis is a multifactorial disease, and considering that numbers of MCs and activated MCs were clearly increased in endometriotic lesions in both animals and humans, use of MC stabilizers and inhibitors may prove to be effective to treat endometriosis and its associated pain. However, more data from preclinical studies and clinical trials will help to better define the status of MCs in the treatment of this pathology.

 

 

 

Sci Rep. 2016 Nov 14;6:36994.

The sensitivity of the DNA damage checkpoint prevents oocyte maturation in endometriosis.

Hamdan M^1,2, Jones KT³, Cheong Y¹, Lane SI³.

 

Abstract

Mouse oocytes respond to DNA damage by arresting in meiosis I through activity of the Spindle Assembly Checkpoint (SAC) and DNA Damage Response (DDR) pathways. It is currently not known if DNA damage is the primary trigger for arrest, or if the pathway is sensitive to levels of DNA damage experienced physiologically. Here, using follicular fluid from patients with the disease endometriosis, which affects 10% of women and is associated with reduced fertility, we find raised levels of Reactive Oxygen Species (ROS), which generate DNA damage and turn on the DDR-SAC pathway. Only follicular fluid from patients with endometriosis, and not controls, produced ROS and damaged DNA in the oocyte. This activated ATM kinase, leading to SAC mediated metaphase I arrest. Completion of meiosis I could be restored by ROS scavengers, showing this is the primary trigger for arrest and offering a novel clinical therapeutic treatment. This study establishes a clinical relevance to the DDR induced SAC in oocytes. It helps explain how oocytes respond to a highly prevalent human disease and the reduced fertility associated with endometriosis.

 

 

J Comput Assist Tomogr. 2016 Nov/Dec;40(6):886-891.

The Role of Computed Tomography Colonography in Detecting Bowel Involvement in Women With Deep Infiltrating Endometriosis: Comparison With Clinical History, Serum Ca125, and Transvaginal Sonography.

Baggio S¹, Zecchin A, Pomini P, Zanconato G, Genna M, Motton M, Montemezzi S, Franchi M.

Abstract

OBJECTIVE:

We wanted to assess the diagnostic value of computed tomographic colonography (CTC) in recognizing bowel endometriosis in comparison with serum Ca125, transvaginal sonography (TVS), and presence of intestinal symptoms.

METHODS:

We included in this study 92 women undergoing surgery for symptomatic DIE. Preoperative evaluation included clinical history, Ca125 serum value, and TVS. CTC was performed in 37/92 patients (40.2%), and the results were compared to the other preoperative tools and to surgical exploration, considered the clinical reference standard.

RESULTS:

Surgery confirmed bowel endometriosis in 49/92 subjects (53.3%). Presence of intestinal symptoms, serum Ca125 values, and TVS were significantly correlated to intestinal involvement, but CTC had the highest accuracy in detecting bowel endometriosis with a sensitivity of 68%, a specificity of 67%, a PPV of 81%, and a NPV of 50% (P = 0.04).

CONCLUSIONS:

CTC proved to be an accurate and low invasive imaging technique to detect DIE of the bowel and compared favorably with clinical evaluation, serum Ca125 determination, and TVS.

 

 

Behav Neurol. 2016;2016:2964712.

Neuroprotective Effects of Bone Marrow Mesenchymal Stem Cells on Bilateral Common Carotid Arteries Occlusion Model of Cerebral Ischemia in Rat.

Pourheydar B¹, Soleimani Asl S², Azimzadeh M³, Rezaei Moghadam A⁴, Marzban A⁵, Mehdizadeh M⁶.

 

Abstract

Cell therapy is the most advanced treatment of the cerebral ischemia, nowadays. Herein, we discuss the neuroprotective effects of bone marrow mesenchymal stem cells (BMSCs) on rat hippocampal cells following intravenous injection of these cells in an ischemia-reperfusion model. Adult male Wistar rats were divided into 5 groups: control, sham (surgery without blockage of common carotid arteries), ischemia (common carotid arteries were blocked for 30 min prior to reperfusion), vehicle (7 days after ischemia PBS was injected via the tail vein), and treatment (injections of BMSC into the tail veins 7 days after ischemia). We performed neuromuscular and vestibulomotor function tests to assess behavioral function and, finally, brains were subjected to hematoxylin and eosin (H&E), anti-Brdu immunohistochemistry, and TUNEL staining. The ischemia group had severe apoptosis. The group treated with BMSCs had a lower mortality rate and also had significant improvement in functional recovery (P < 0.001). Ischemia-reperfusion for 30 min causes damage and extensive neuronal death in the hippocampus, especially in CA1 and CA3 regions, leading to several functional and neurological deficits. In conclusion, intravenous injection of BMSCs can significantly decrease the number of apoptotic neurons and significantly improve functional recovery, which may be a beneficial treatment method for ischemic injuries.

 

 

Vet World. 2016 Oct;9(10):1056-1062

Determination of ceruloplasmin, some other acute phase proteins, and biochemical parameters in cows with endometritis.

Kaya S¹, Merhan O², Kacar C¹, Colak A³, Bozukluhan K⁴.

Abstract

AIM:

The aim of this study is to determine serum ceruloplasmin levels in cows with endometritis of varying degrees of severity and to establish whether or not there is a correlation between acute phase protein (APP) levels and biochemical parameters.

MATERIAL AND METHODS:

The study was conducted with 100 Brown Swiss cows (3-8 years of age) on days 28-32 postpartum. Cows were divided into endometritis (mild, moderate, and severe endometriosis) and healthy groups based on ultrasonography, vaginoscopy, and cytological examination. Blood samples were collected from all cows. Levels of haptoglobin (Hp), serum amyloid A (SAA), ceruloplasmin, albumin, and some biochemical parameters were analyzed.

RESULTS:

Hp, SAA, and ceruloplasmin levels were higher in cows with endometritis than in healthy cows (p=0.001), and the levels of these APPs increased as endometritis became more severe (p=0.001). Some significant correlations were found between APPs and the biochemical parameters that were analyzed. In conclusion, it was determined that ceruloplasmin levels increase significantly in the presence of endometritis and proportionate to the severity of endometritis. A significant correlation was found between ceruloplasmin levels and Hp and SAA levels.

CONCLUSION:

It was concluded that ceruloplasmin levels can be used in the diagnosis of endometritis as an alternative to Hp and SAA levels.