Exp Ther Med. 2015 May;9(5):1813-1818.

Effect of the non-specific matrix metalloproteinase inhibitor Doxycycline on endometriotic implants in an experimental rat model.

Goktolga U¹, Cavkaytar S², Altinbas SK¹, Tapisiz OL¹, Tapisiz A³, Erdem O⁴.

 

Abstract

The aim of this study was to investigate the possible therapeutic effects of Doxycycline (Dox) on endometriotic lesions in an experimental rat model. Thirty-seven female Wistar albino rats with surgically induced endometriosiswere randomized and divided into four groups. The rats were administered 5 mg/kg/day oral Dox in Group 1 (low-dose Dox group, n=9), 20 mg/kg/day oral Dox in Group 2 (high-dose Dox group, n=10) and 1 mg/kg single dose, subcutaneous leuprolide acetate in Group 3 (leuprolide acetate group, n=9). The rats in Group 4 (control group, n=9) were given no medication. The rats received medication for three weeks and were then sacrificed to evaluate the morphological and histological features of the implants. Matrix metalloproteinase (MMP)-9 immunoreactivity of the implants was also evaluated. The size of the endometriotic implants decreased in Groups 1-3 but statistically significant differences were not observed among the groups. The mean surface area of the endometriotic implants decreased from 69.3±30.8 to 52.1±27.0 mm² in Group 1 (P>0.05), from 60.2±18.9 to 38.6±28.7 mm² in Group 2 (P>0.05) and from 58.1±33.1 to 26±9.0 mm² in Group 3 (P=0.03). The epithelial MMP-9 immunohistochemical score was significantly higher in Group 1 and lower in Group 3 when compared with the control group (Group 4) (P=0.042 and P=0.014, respectively). When the stromal MMP-9 immunohistochemical and histopathological scores of the endometriotic implants were compared, no statistically significant differences were found among the groups. Although there was no statistically significant difference, Dox reduced the endometriotic implant area in the rat endometriosis model. Further studies are required to investigate the potential efficacy of Dox in endometriosis due to its widespread use and tolerability.

 

 

AANA J. 2015 Jun;83(3):196-9.

Implementation of Mass Transfusion Protocol in the Outpatient Operating Room Setting: A Case Study.

Robins HM, Warner B.

 

Abstract

The current definition of massive transfusion is replacement of 5 U of packed red blood cells in 3 hours because of uncontrolled hemorrhage or replacement of the entire blood volume within a 24-hour period. The prompt activation of a transfusion protocol can quickly restore hemodynamic stability. Effective teamwork and communication is critical for a favorable patient outcome. This case study demonstrates the effectiveness of using a massive transfusion protocol in an outpatient setting.

 

 

Akush Ginekol (Sofiia). 2015;54 Suppl 1:32-8.

SERUM HEPCIDIN LEVELS IN ENDOMETRIOSIS.

Manolov V, Marinov B, Vasilev V.

Abstract

OBJECTIVE:

Endometriosis is a benign disease, which ranks third in mortality from gynecological morbidity after inflammatory conditions and myoma. We tried to evaluate serum iron and hepcidin levels and seek their connection with the development of endometriosis.

METHODS:

For quantification of serum hepcidin we use ELISA method. 53 women were included, average age 25.4 ± 4.3. They were divided into two groups–women with endometriosis (EM) and a control group. Samples were taken at the University hospital “Maichin dom” for a period of one year. We measure serum iron, ferritin and calculate transferrin saturation. We use the Pearson’s correlation and Student’s t-test for evaluating of statistical significance.

RESULTS:

We found statistically significant differences in serum hepcidin levels in the groups included: women with endometriosis have higher concentrations 64.3 ± 7.8 μg/L compared to the control group 19.4 ± 4.1 μg/L (r = -0.201, P < 0.001). Serum ferritin levels showed significant differences between the two groups in EM 17.9 ± 8.4 ng/ml vs control 79.5 ± 14.6 ng/ml (r = -0.249, P < 0.001). Statistically significant difference was found in serum iron levels: in EM 21.9 ± 3.2 μmol/L compared to 13.5 ± 1.9 μmol/L in the control group (P < 0.001).

CONCLUSION:

Our results support the idea that iron overload and increased serum levels of hepcidin plays an important role in the pathogenesis of endometriosis.

 

 

Biom J. 2015 Sep;57(5):808-33.

Semiparametric transformation models for multiple continuous biomarkers in ROC analysis.

Kim E¹, Zeng D², Zhou XH³.

 

Abstract

Recent technological advances continue to provide noninvasive and more accurate biomarkers for evaluating disease status. One standard tool for assessing the accuracy of diagnostic tests is the receiver operating characteristic (ROC) curve. Few statistical methods exist to accommodate multiple continuous-scale biomarkers in the framework of ROC analysis. In this paper, we propose a method to integrate continuous-scale biomarkers to optimize classification accuracy. Specifically, we develop semiparametric transformation models for multiple biomarkers. We assume that unknown and marker-specific transformations of biomarkers follow a multivariate normal distribution. Our models accommodate biomarkers subject to limits of detection and account for the dependence among biomarkers by including a subject-specific random effect. We also propose a diagnostic measure using an optimal linear combination of the transformed biomarkers. Our diagnostic rule does not depend on any monotone transformation of biomarkers and is not sensitive to extreme biomarker values. Nonparametric maximum likelihood estimation (NPMLE) is used for inference. We show that the parameter estimators are asymptotically normal and efficient. We illustrate our semiparametric approach using data from the Endometriosis, Natural History, Diagnosis, and Outcomes (ENDO) study.

 

 

Arch Gynecol Obstet. 2016 Jan;293(1):5-10.

Association of endometriosis and breast cancer: mini review of the literature.

Anifantaki F¹, Boutas I², Kalampokas T², Kalampokas E², Sofoudis C², Salakos N².

Abstract

BACKGROUND:

Endometriosis is a common, estrogen-dependent, gynecological disease, which is defined as the presence of endometrial tissue outside the uterine cavity. Current data have associated endometriosis with specific malignancies, including ovarian and breast cancer.

PURPOSE:

The purpose of our study is to summarize and present published literature providing evidence regarding the possible relationship between endometriosis and breast cancer.

METHODS:

Pubmed and Scopus databases were searched systematically for studies that sought to identify a potential association of endometriosis and breast cancer. 15 relevant articles were retrieved and included in the present review.

RESULTS:

A small number of observational studies have shown a correlation of endometriosis and breast cancer. Other studies found that the risk of breast cancer increases with age. The scenario of an early interruption of the inflammatory process, derived from endometriosis, by oophorectomy and a possible consequent decrease in the risk of breast cancer has also been proposed. The hypothesis that both conditions could be related through common mutations on BRAC1 and BRAC2 genes has also been investigated.

CONCLUSION:

The available published evidence is inconclusive. Further studies are needed to evaluate the association of endometriosis and breast cancer and the possible pathogenetic pathways that relate the two disorders.

 

 

J Assist Reprod Genet. 2015 Sep;32(9):1359-64.

Association of WNT4 polymorphisms with endometriosis in infertile patients.

Mafra F¹, Catto M², Bianco B³, Barbosa CP⁴, Christofolini D^5,6.

Abstract

PURPOSE:

Recently, several genome-wide association studies have demonstrated an association between endometriosis and markers located in or near to WNT4 gene. In order to assess the validity of the findings, we conducted a replication case-control study in a Brazilian population.

METHODS:

Genetic association study comprising 400 infertile women with endometriosis and 400 fertile women as controls. TaqMan allelic discrimination technique was used to investigate the relationship between endometriosis and four single-nucleotide polymorphisms (rs16826658, rs3820282, rs2235529, and rs7521902) in WNT4 gene. Genotype distribution, allele frequency, and haplotype analysis of the WNT4 polymorphisms were performed. A p value <0.05 was considered significant.

RESULTS:

The results revealed a significant association of rs16826658 (p = 7e-04) and rs3820282 (p = 0.048) single-nucleotide polymorphisms (SNPs) on WNT4 gene with endometriosis-related infertility, while rs2235529 and rs7521902 SNPs showed no difference between cases and controls.

CONCLUSIONS:

Our results suggested that rs16826658 and rs3820282 polymorphisms on WNT4 gene might be involved in the pathogenesis of endometriosis in the infertile women studied. Analysis of WNT4 genetic variants might help to identify patients at high risk for disease development.

 

 

J Minim Invasive Gynecol. 2015 Nov-Dec;22(7):1208-14.

Change in Pain and Quality of Life Among Women Enrolled in a Trial Examining the Use of Narrow Band Imaging During Laparoscopic Surgery for Suspected Endometriosis.

Gallicchio L¹, Helzlsouer KJ², Audlin KM³, Miller C⁴, MacDonald R³, Johnston M⁵, Barrueto FF³.

Abstract

STUDY OBJECTIVE:

To examine whether the addition of narrow band imaging (NBI) to traditional white light imaging during laparoscopic surgery impacts pain and quality of life (QOL) at 3 and 6 months after surgery among women with suspected endometriosis and/or infertility.

DESIGN:

A randomized controlled trial (Canadian Task Force classification level I).

SETTING:

The trial was conducted in 2 medical centers.

PATIENTS:

From October 2011 to November 2013, 167 patients undergoing laparoscopic examination for suspected endometriosis and/or infertility were recruited. The analytic study sample includes 148 patients with pain and QOL outcome data.

INTERVENTIONS:

Patients were randomized in a 3:1 ratio to receive white light imaging followed by NBI (WL/NBI) or white light imaging only (WL/WL).

MEASUREMENTS AND MAIN RESULTS:

Questionnaires were administered at baseline and at 3- and 6-month follow-up time points. Average and most severe pain at each time point were assessed using a 10-cm visual analog scale. QOL was measured using the Endometriosis Health Profile-30. Baseline characteristics were similar for the study groups. The WL/NBI and WL/WL groups had similar reductions in pain at 3 and 6 months. In addition, QOL improved similarly for both the WL/NBI and WL/WL groups at 3 and 6 months.

CONCLUSION:

Laparoscopic surgery for suspected endometriosis is associated with a reduction in pain and an improvement in QOL. The differences in pain reduction and QOL improvement, which are noted at 3 months and remain stable at 6 months after surgery, are similar for those undergoing surgery with WL/NBI compared with those undergoing surgery under traditional white light conditions.

 

 

Hum Reprod. 2015 Sep;30(9):1996-2004.

Reducing low-value care in endometriosis between limited evidence and unresolved issues: a proposal.

Vercellini P¹, Giudice LC², Evers JL³, Abrao MS⁴.

 

Abstract

Quantification of benefits and harms of medical interventions should be based on high-quality evidence, which is not always the case in the endometriosis field. In many clinical circumstances, healthcare decisions in women with endometriosis are taken based on suboptimal evidence or on evidence of coexistence of benefits and harms that must be balanced. In these conditions, it is important to avoid or reduce the use of low-value care, i.e. interventions with defined harms and uncertain benefits, or whose effectiveness is comparable with less expensive alternatives. In particular, we suggest that: (i) non-surgical diagnosis based on symptoms, physical findings and transvaginal ultrasonography is possible in most women with symptomatic endometriosis. Thus, except in doubtful cases, laparoscopy should be intended for surgical treatment, not for diagnostic purposes: early diagnosis and diagnostic laparoscopy are not synonymous; (ii) future trials on new drugs for endometriosisshould address those outcomes that are most important to patients, should be designed as superiority trials and should include a progestin or an estrogen-progestin as a comparator. Moreover, limitation of repetitive surgery for recurrent endometriosis is among the objectives of long-term medical treatment; (iii) indications for surgery should be the result of a balance between demonstrated benefits in terms of fertility enhancement and pain relief, specific risks associated with excision of different types of endometriotic lesions, cost-effectiveness and patient preference after detailed information; (iv) physicians, health professionals and policy makers should discriminate between screening for and diagnosis of endometriosis. Limited peritoneal foci, which are frequently observed also in asymptomatic women, regress or remain stable in about two thirds of cases. Therefore, the theoretical premises for a screening campaign are currently unclear; (v) physicians should develop the ability to effectively communicate quantitative information based on international guidelines and systematic literature reviews. This will assist a woman’s understanding of the interaction between the evidence and her priorities, facilitating the transition towards value-based medicine.

 

J Gynecol Obstet Biol Reprod (Paris). 2016 Mar;45(3):249-56.

Quality of life after deep pelvic endometriosis surgery: Evaluation of a French version of the EHP-30.

Selvi Dogan F¹, Cottenet J², Douvier S³, Sagot P³.

Abstract

OBJECTIVE:

To evaluate the changes in the quality of life of patients after deep pelvic endometriosis surgery, with a French version of EHP-30 questionnaire, and the capacity of the EHP-30 to carry out this measurement.

MATERIAL AND METHODS:

Study prospective monocentric, conducted in the obstetrics and gynecology department of the CHU Dijon during the period of October 2012 from October 2013. A EHP-30 questionnaire was given to patients before surgery. The same questionnaire was sent to their homes, away from surgery (3-6 months) to inform about their postoperative quality of life. The difference in preoperative and postoperative scores was tested using the test Wilcoxon signed ranks. A difference was considered significant if the p-value was less than or equal to 0.05. Sensitivity to change was calculated by the method of effect size (ES). The size of the effect is defined as the difference in mean preoperative and postoperative scores divided by the standard deviation of preoperative scores. A size effet of 0.20 indicates less change scores, of 0.50 a moderate change and of 0.80 a material change.

RESULTS:

We included 22 patients in total in the prospective analysis. The majority of patients had gynecological symptoms of dysmenorrhea with 69.7%, 75.7% and 75.7% dyspareunia chronic pelvic pain. Nineteen patients (57.6%) had gastro-intestinal symptoms. Urinary symptoms were less frequent. The results of the EHP-30 showed a significant improvement for the items “pain” (P=0.01), “control and powerlessness” (P=0.02), “emotional well-being” (P<0,01) “social relations” (P<0.01), “sexual intercourse” (P=0.03) and “relationship with the medical world” (P=0.05). We observed a non-significant improvement for the items “self-image” (P=0.44), “work” (P=0.48) and “relationships with children” (P=0.50). The size of the effect (ES) was low to high for all dimensions of the questionnaire, ranging from 0.1 to 0.6 for the entire group. A significant sensitivity to change was found for the items “pain” (ES=0.60), “control and powerlessness” (ES=0.62), “social relations” (ES=0.57). A moderate sensitivity to change was found for the items “emotional well-being” (ES=0.29), “relationship with the medical world” (ES=0.26). A low sensitivity to change was found for the items “relationships with children” (ES=0.06), “self-image” (ES=0.16), “work” (ES=0.18), “sexual intercourse” (ES=0.20). A size that is important to moderate effect corresponded to a statistically significant improvement of the score EHP-30.

CONCLUSION:

This study showed that the EHP-30 is a sensitive tool to change the health status and an appropriate instrument for the assessment of treatment effects in patients with deep pelvic endometriosis.

 

 

Eur J Obstet Gynecol Reprod Biol. 2015 Sep;192:41-6

Estimating cumulative live-birth rates after IVF treatment with Kaplan-Meier and competing risk methods.

Viardot-Foucault V¹, Tai BC², Chen ZJ³, Lim GH⁴, Loh SF⁵, Tan HH⁶, Nadarajah S⁶, Chan JK⁷.

Abstract

OBJECTIVE(S):

To explore the use of competing risk (CR) as compared to the commonly used Kaplan-Meier (KM) methodology in estimating the cumulative live-birth rate (CLBR) after IVF Treatment in a context of high dropout rates and informative censoring.

STUDY DESIGN:

We compare the KM and CR methodologies for estimating 2-year CLBR in a retrospective cohort of 2779 patients undergoing 5002 embryo transfers over a period of 9 years, from 2000 to 2008, at KKIVF Centre.

RESULTS:

We observed a total of 1105 LB (39.8%), and a dropout rate of 44.2% (1228 patients). The overall CLBR is lower with CR compared with KM method (39% vs 52%) after up to nine embryo-transfer cycles over a period of two years. The highest CLBR was achieved for ovulation disorders (57% vs 49%, KM vs CR) followed by male factors (54% vs 43%, KM vs CR), with poorer outcomes from patients with decreased ovarian reserve (37% vs 16%, KM vs CR) and endometriosis (36% vs 25%, KM vs CR). As dropouts in our cohort are generally older and more likely to have poorer ovarian reserves, the CR method, which accounted for these dropouts, is likely to give more meaningful estimation of IVF success rates.

CONCLUSION(S):

The CR method should be considered as a useful alternative in deriving CLBR for IVF treatment where dropout rates are high and when informative censoring is involved.

 

 

Pak J Med Sci. 2015;31(3):694-9.

Frequency and outcome of treatment in polycystic ovaries related infertility.

Arain F¹, Arif N², Halepota H³.

Abstract

BACKGROUND:

Infertility is defined as inability of couple to conceive after one year of unprotected intercourse. The prevalence of infertility in Pakistan is 21.9%. The most common cause of medically treatable infertility is polycystic ovarian syndrome (PCO). This study was conducted to see the frequency and outcome of treatment in PCOs related infertility in infertile couples coming to Mohammad Medical College Hospital, Mirpurkhas, Sindh.

METHODS:

This prospective observational study was conducted at Muhammad Medical College for three years from 2005 to 2008. Total 1289 infertile couples were included in this study.

RESULT:

The frequency of PCOs in female related infertility was 38.5%. Other causes of female infertility were in the frequency of 44% pelvic inflammatory disease, 12.3% endometriosis, 2.9% hyperprolactenemia, and 1.35% hypothyroidism. Patients with PCOS were given different treatment modalities. One hundred fifty patients with PCO were given ovulation induction with clomephene citrate and out of them 109 (72%) conceived. Sixty three women were given combination of clomephene citrate and Metformin. Out of them 50 (79%) conceived. Five patients were given gonadotrophins, Out of them 2 (40%) patients conceived. Five patients had laparoscopic drilling out of them 3 (60%) conceived.

CONCLUSION:

In contrast to the literature review Polycystic Ovarian Syndrome turned out to be the second most common cause of female related infertility. But as the international literature shows it had very good out come after medical and /or surgical treatment.

 

 

J Steroid Biochem Mol Biol. 2015 Nov;154:32-8.

Steroid receptor coactivators as therapeutic targets in the female reproductive system.

Szwarc MM¹, Lydon JP¹, O’Malley BW².

 

Abstract

The steroid receptor coactivators (SRCs/p160/NCOA) are a family of three transcriptional coregulators initially discovered to transactivate the transcriptional potency of steroid hormone receptors. Even though SRCs were also found to modulate the activity of multiple other transcription factors, their function is still strongly associated with regulation of steroid hormone action and many studies have found that they are critical for the regulation of reproductive biology. In the case of the female reproductive tract, SRCs have been found to play crucial roles in its physiology, ranging from ovulation, implantation, to parturition. Not surprisingly, SRCs’ action has been linked to numerous abnormalities and debilitating disorders of female reproductive tissues, including infertility, cancer, and endometriosis. Many of these pathologies are still in critical need of therapeutic intervention and “proof-of-principle” studies have found that SRCs are excellent targets in pathological states. Therefore, small molecule modulators of SRCs’ activity could be applied in the future in the treatment of many diseases of the female reproductive system.

 

 

Clin Exp Obstet Gynecol. 2015;42(3):292-4.

Scar endometriosis is a gynecological complication that general surgeons have to deal with.

Aytac HO, Aytac PC, Parlakgumus HA.

Abstract

BACKGROUND:

Scar endometriosis is the presence of functional endometrium tissue in surgical incisions. It is a complication that develops after obstetrical or gynecological surgical procedures. As it presents with a mass adjacent to surgical incisions, general surgeons usually deal with it. The authors’ aim was to review and discuss the differential diagnosis, treatment methods, recurrence rate, and follow up of scar endometriosis.

MATERIALS AND METHODS:

Data of patients diagnosed with incisional scar endometriosis between 2005 and 2012 were recorded retrospectively. Their initial symptoms, previous surgery histories, onset of symptoms after surgery, duration of symptoms, diagnostic modalities, treatment methods, pathological evaluations, and rate of recurrences were documented and analyzed.

RESULTS:

Seventeen patients were diagnosed to have scar endometriosis. Former surgical histories were one hysterectomy, one vaginal birth with episiotomy, and 15 cesarean sections. Sixteen of the scar endometrioses were demonstrated on pfannenstiel incision and one on episiotomy scar. Only one recurrence was seen during follow up.

CONCLUSION:

Scar endometriosis should be taken into account in the surgical practice of incisional site masses of the abdominal wall. They should be excised totally for a proper treatment. Patients must be warned about malignancy risk.

 

 

Clin Exp Obstet Gynecol. 2015;42(3):336-8.

Clinical and radiographic characteristics in pulmonary endometriosis: based on five cases.

Huang Q, Huang S, Jiang J, Cai WR, Yin KJ, Chen XJ.

Abstract

OBJECTIVE:

This study aims to improve the diagnostic and therapeutic efficacy through analysis of clinical and radiographic characteristics in pulmonary endometriosis.

MATERIALS AND METHODS:

This retrospective study was conducted from January 1998 to December 2008. The clinical and radiographic characteristics of five patients diagnosed as pulmonary endometriosis were evaluated.

RESULTS:

Among the five female patients of reproductive age, one case presented with recurrent pneumothorax, four cases presented with recurrent hemoptysis. Episode of pneumothorax and hemoptysis had the close association with the menstrual cycle. Except for pneumothorax case, the computed tomography (CT) scans during menstruation showed patchy opacification or infiltration (n = 4). Histopathologic examination of the resected specimen conformed typical endometrial tissue in the lungs. Misdiagnosis occurred involving spontaneous pneumothorax (n = 1), pulmonary tuberculosis (TB) (n = 3), and bronchiectasis (n = 1).

CONCLUSION:

Pulmonary endometriosis is prone to misdiagnosis. The combination of medical history and CT scans in association with menstrual cycle was useful to make the differential diagnosis after effective diagnostic treatment of hormone therapy.

 

 

 

 

 

Clin Exp Obstet Gynecol. 2015;42(3):339-43.

Recurrence rate of ovarian endometriosis in patients treated with laparoscopic surgery and postoperative suppressive therapy.

Dimitrijevic D, Vasiljevic M, Anicic R, Brankovic S, Ristic A, Devic A.

Abstract

INTRODUCTION:

The testing represented a prospective study that was performed at the Gynaecology and Obstetrics Clinic “Narodni Front” in Belgrade during a two-year period. The study encompassed female patients with ovarian endometrioma operated with laparoscopic surgery. The research objective was to determine the percentage of occurrence of relapses in patients operated for endometriosis of the ovary in relation to the stage of the disease and the type of performed operation, and which were receiving suppressive therapy with gonadotropin-releasing hormone (GnRH) analogues after the surgery compared to those who were not receiving suppressive therapy after the operation.

MATERIALS AND METHODS:

The recurrence of endometriosis on the ovary of the test and control groups was monitored during the first year after surgery. In all patients ultrasound checks were done every month during the first six months after surgery, and then every three months for the next six months. In all patients in whom the recurrence, i.e. endometrioma on the ovary larger than three cm was revealed postoperatively by ultrasound, the laparoscopic removal of the endometrioma was performed again as well as the histopathological examination of the material.

RESULTS AND CONCLUSION:

There was no statistically significant difference in the distribution of recurrence of endometriosis between the groups formed according to the type of surgical technique (cystectomy or cystotomy). The recurrence of endometriosis occurred later in the group of patients in which the treatment GnRH analogues was applied after the surgical treatment. The recurrence of endometriosis in more severe stages (Stage III and IV) occurs later in the group of patients in which the treatment GnRH analogues is applied after the surgical treatment.

 

 

Mol Hum Reprod. 2015 Oct;21(10):792-802.

Leptin promotes human endometriotic cell migration and invasion by up-regulating MMP-2 through the JAK2/STAT3 signaling pathway.

Ahn JH¹, Choi YS², Choi JH³.

 

Abstract

Despite evidence that leptin may play a role in the pathogenesis of endometriosis, the specific function of leptin in the migration and invasion of endometriotic cells is not well characterized. In this study, we investigated the effect of leptin on the migration, invasion and matrix metalloproteinase (MMP) expression levels of human endometriotic cells. We found that leptin stimulated the migration and invasion of endometriotic cells (11Z, 12Z and 22B) in a dose-dependent manner. Leptin receptor (ObR) siRNA significantly inhibited the migration and invasion induced by leptin in 11Z and 12Z cells. Leptin-induced migration and invasion were significantly attenuated by pretreatment with SB-3CT, a specific gelatinase (MMP-2 and MMP-9) inhibitor. In addition, leptin-induced increases in the mRNA and protein expression and enzyme activity of MMP-2 in 11Z and 12Z cells. Selectively inhibiting MMP-2 using siRNA and an inhibitor (GM6003), impaired the ability of leptin to stimulate the migration and invasion of endometriotic cells, suggesting that MMP-2 plays an essential role in leptin-induced migration and invasion. Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) inhibitor (AG490) significantly inhibited the migration, invasion and MMP-2 expression induced by leptin in endometriotic cells. Furthermore, the Extracellular signal-Regulated Kinase inhibitor PD98059 neutralized the migration and invasion promoting effects of leptin. Taken together, these results suggest that leptin may contribute to the migration and invasion abilities of endometriotic cells via the up-regulation of MMP-2 through an ObR-dependent JAK2/STAT3 signaling pathway.

 

 

Arch Gynecol Obstet. 2016 Jan;293(1):109-15.

Evaluation of the frequency of G-765C polymorphism in the promoter region of the COX-2 gene and its correlation with the expression of this gene in the endometrium of women with endometriosis.

Cavalcanti V¹, Ponce TG¹, Mafra FA¹, André GM¹, Christofolini DM¹, Barbosa CP¹, Bianco B².

Abstract

OBJECTIVE:

To evaluate the frequency of polymorphism G-765C (rs20417) of the COX-2 gene and the expression of this gene in the endometrium of women with endometriosis.

STUDY DESIGN:

This is a case-control study of 365 women with endometriosis (251 infertile and 114 fertile) submitted to laparoscopy/laparotomy with histological confirmation of endometriosis. The control group was composed of 522 fertile women without endometriosis. Of these, 37 patients from the endometriosis group and 47 from the control group were submitted to biopsy of the endometrium for analysis of the expression of the COX-2 gene. The genotypes were determined using analysis by High-Resolution Melt. Gene expression was measured by qRT-PCR with TaqMan methodology using the GAPDH gene as normalizer of the reactions.

RESULTS:

The distribution of the genotypes and alleles in the group of fertile women with moderate/severe endometriosis showed a statistically significant difference, demonstrating association of the ancestral allele, -765G, with increased risk of endometriosis (p = 0.028; OR 0.53; CI 0.32-0.90). The mean expression of the COX-2 gene (mRNA PTGS2) in the group of women with endometriosis was statistically higher compared to the control group (3.85 versus 2.84, p = 0.028).

CONCLUSION:

The present study identified that in Brazilian women the presence of the ancestral allele, -765G, of the COX-2 gene is associated with an increased risk for development of moderate/severe endometriosisassociated with fertility, and that the eutopic endometrium of women with endometriosis showed increased expression of COX-2 when compared to the control group.

 

 

Cent Eur J Immunol. 2015;40(1):96-102

Pro-inflammatory cytokines for evaluation of inflammatory status in endometriosis.

Malutan AM¹, Drugan T¹, Costin N¹, Ciortea R¹, Bucuri C¹, Rada MP¹, Mihu D¹.

Abstract

THE AIM OF THE STUDY:

The aim of the study was to investigate the serum pro-inflammatory cytokine profile in patients with diagnosed endometriosis.

MATERIAL AND METHODS:

The study included 160 women, who were divided in two study groups (Group I – endometriosis; Group 2 – healthy). We evaluated the serum levels of interleukin (IL)-1β, IL-5, IL-6, IL-7, and IL-12, and of tumour necrosis factor α (TNF-α) with the use of Human Multiplex Cytokine Panels.

RESULTS:

The serum level of IL-1β, IL-6, and TNF-α is significantly higher in women with endometriosiscompared to women free of disease, from the control group (mean 10.777, 183.027, and 131.326, respectively, compared to 3.039, 70.043, and 75.285, respectively; p = 0.002, p < 0.001, and p = 0.015, respectively). No significant differences in the serum levels of IL-5 and IL-12 were observed between the studied groups, and IL-7 had a very low detection rate.

CONCLUSIONS:

Women with endometriosis have elevated levels of key pro-inflammatory cytokines, i.e. IL-1β, IL-6, and TNF-α. At the same time, IL-1β and IL-6 could be used as predictors for endometriosis.

 

 

Oncoimmunology. 2015 Feb 3;4(5)

Chronic inflammation in endometriosis and endometriosis-associated ovarian cancer: New roles for the “old” complement pathway.

Edwards RP¹, Huang X², Vlad AM².

 

Abstract

Immune escape is consequential for cancer development. Identifying abnormalities of the immune microenvironment during early carcinogenesis can provide insight into disease pathogenesis and unravel new preventive or therapeutic targets. We recently conducted a comprehensive immune gene expression analysis in endometriosis and endometriosis-associated ovarian cancer and explored new mechanistic roles for the complement pathway.

 

 

J Obstet Gynaecol. 2015;35(8):844-7.

Clarithromycin regresses endometriotic implants in rat endometriosis model.

Cavkaytar S¹, Tapisiz OL², Kiykac Altinbas S², Tapisiz A³, Erdem O⁴, Goktolga U².

 

Abstract

The aim of this study was to investigate the effect of clarithromycin in rat endometriosis and its association with matrix metalloproteinase-9 (MMP-9) expression. After surgical induction of endometriosis, 27 rats were randomised into three groups. Size of endometriotic implants were evalutated and rats in group I (n = 9) were given 100 mg/kg/day of oral clarithromycin, rats in group II (n = 9) were given single 1 mg/kg s.c. injection of leuprolide acetate and rats in group III (n = 9) were not given any medication for 21 days. At the end of 21 days of medication, remaining 23 rats were sacrificed to evaluate morphological and histological features of implants. There was a significant difference between the groups in implant volumes (p = 0.004) before and after medication. Regression of implants were significantly higher in groups I and II than that in control group (p = 0.009 and p = 0.011, respectively). After medication, in group I the implant volume decreased from 62 (12-166) mm(3) to 26 (3-87) mm(3) (p = 0.012) and in group II the volume decreased from 224 (76-1135) mm(3) to 62 (26-101) mm(3) (p = 0.028). There was a significant difference between groups in histopathological score (p = 0.024). The epithelial immunohistochemical score of MMP-9 was significantly lower in group II than that in control group (p = 0.014). In conclusion, clarithromycin regresses endometriotic implants in rats, but not via MMP-9.

 

 

Reprod Sci. 2016 Jan;23(1):81-6.

Fas and Fas-Ligand in Eutopic and Ectopic Endometrium of Women With Endometriosis: The Possible Immune Privilege of Ectopic Endometrium.

Sbracia M¹, Valeri C², Antonini G³, Biagiotti G⁴, Pacchiarotti A⁵, Pacchiarotti A⁵.

 

Abstract

The Fas/Fas-Ligand system is an important mediator of apoptosis. We analyzed their expression in tissue specimens obtained from 33 women with severe endometriosis and 18 women without endometriosis. Immunostaining for Fas-Ligand in the eutopic endometrium was stronger in the epithelial cells of secretory phase, while the epithelial cells of endometriotic lesions showed a significantly stronger staining for Fas-Ligand independently from the menstrual phase (P < 0.01). Immunostaining for Fas in the eutopic endometrium showed a reduced staining during the proliferative phase, whereas it was strong in the secretory phase. The epithelial cells of the ectopic endometrium showed a reduced staining for Fas independently from the menstrual phase with respect to the eutopic tissue (P < 0.01). The reduced expression of Fas in the ectopic endometrium with the contemporary higher expression of Fas-Ligand in the corresponding cells suggests a possible immune privilege of this tissue.

 

 

Front Surg. 2015 Jun 22;2:23.

Endometriosis and Vesico-Sphincteral Disorders.

Fadhlaoui A¹, Gillon T², Lebbi I³, Bouquet de Jolinière J², Feki A².

Abstract

OBJECTIVES:

The aim of this mini review is to determine the relationship between endometriosis and urinary tract symptoms and to investigate the consequences of surgical treatment of mild to severe endometriosis, especially deep lesions, on the vesico-sphincteral function (lower urinary tract function).

MATERIALS AND METHODS:

We performed a literature review by searching the MEDLINE database for articles published between 2000 and 2014, limiting the searches to the words: urinary tract, vesico-sphincteral, dysfunction, endometriosis, symptoms, and surgery.

RESULTS:

The incidence of vesico-sphincteral symptoms in endometriosis varies from 3.4 up to 15.4%. The frequency of such symptoms seems to be under estimated because of a lack of specific questionnaire including urinary symptoms. Urodynamic evaluation could help to detect unsuspected abnormalities. It seems that endometriosis surgery (particularly deep infiltrating lesions) is a purveyor of de novo urinary dysfunction, with an incidence varying from 6.8 up to 17.5%. Nerve sparing processes such as neuro-navigators or neuro-stimulators seem to be promising techniques to avoid postoperative urinary tract dysfunction.

CONCLUSION:

A precise anamnesis and the use of specific validated questionnaires (IPSS and BFLUTS) improve the screening of vesico-sphincteral symptoms in case of endometriosis. No recommendation can be found in the literature about the place of urodynamic evaluation. Most publications lack of proof and therefore do not allow making recommendations about optimal treatment of endometriotic lesions to avoid urinary tract disorders.

 

 

Clin Exp Reprod Med. 2015 Jun;42(2):67-71.

Factors influencing serum progesterone level on triggering day in stimulated in vitro fertilization cycles.

Park JH¹, Jee BC², Kim SH³.

Abstract

OBJECTIVE:

Elevated serum progesterone (P) levels on triggering day have been known to affect the pregnancy rate of in vitro fertilization (IVF). This study aimed to identify the possible factors influencing serum P levels on triggering day in stimulated IVF cycles.

METHODS:

Three hundred and thirty consecutive fresh IVF cycles were included in the study. All cycles were first attempts and were performed in a single infertility center. The indications for IVF were male factor infertility (n=114), ovulatory infertility (n=84), endometriosis (n=61), tubal infertility (n=59), unexplained infertility (n=41), and uterine factor infertility (n=39). A luteal long protocol of a gonadotropin-releasing hormone (GnRH) agonist (n=184) or a GnRH antagonist protocol (n=146) was used for pituitary suppression. Ovarian sensitivity was defined as the serum estradiol level on triggering day per 500 IU of administered gonadotropins (OS[a]) or the retrieved oocyte number per 500 IU of administered gonadotropins (OS[b]).

RESULTS:

Univariate analysis revealed that the serum P level on triggering day was associated with the serum estradiol level on triggering day (r=0.379, p<0.001), the number of follicles ≥14 mm (r=0.247, p<0.001), the number of retrieved oocytes (r=0.384, p<0.001), and ovarian sensitivity (OS[a]: r=0.245, p<0.001; OS[b]: r=0.170, p=0.002). The woman’s age, body mass index, antral follicle count, and basal serum follicle stimulating hormone and estradiol levels were not associated with serum P level on triggering day. The serum P level on triggering day did not show significant variation depending on the type or cause of infertility, pituitary suppression protocol, or the type of gonadotropins used.

CONCLUSION:

The serum P level on triggering day was closely related to the response to ovarian stimulation.

 

 

Mol Med Rep. 2015 Oct;12(4):5179-84.

Comparison of ovarian cancer markers in endometriosis favours HE4 over CA125.

Mckinnon B¹, Mueller MD², Nirgianakis K², Bersinger NA¹.

 

Abstract

Endometriosis is a gynaecological condition with an associated chronic inflammatory response. The ectopic growth of ‘lesions’, consisting of endometrial cells outside the uterine cavity, stimulates an inflammatory response initiating the activation of macrophages, and resulting in increased cytokine and growth factor concentrations in the peritoneal fluid (PF). Endometriosis‑associated inflammation is chronic and long lasting. In patients with endometriosis, the risk of developing ovarian cancer within 10 years, particularly of the endometrioid or clear cell subtype, is increased 2.5‑4 times. Endometriosis creates a peritoneal environment that exposes the affected endometriotic and the normal ovarian surface epithelial cells to agents that have been suggested to be involved in the pathogenesis of cancer. Concentrations of several cytokines and growth factors were increased in the PF of patients with endometriosis. The ovarian cancer marker, CA125, was one such growth factor; however, this remains to be confirmed. Human epididymis protein 4 (HE4) was detected at high concentrations in patients with ovarian cancer and was identified as the best biomarker for the detection of ovarian cancer. The present study determined the levels of HE4 and CA125 in the peritoneal fluid of 258 patients with and 100 control individuals without endometriosis attending the Department of Obstetrics and Gynaecology, University of Berne (Berne, Switzerland) between 2007 and 2014. The cases were subdivided into groups without hormonal treatment (n=107), or treated with combined oral contraceptives (n=45), continuous gestagens (n=56) or GnRH agonists (n=50). Both of these markers were significantly increased in the non‑treated endometriosis samples compared with the control group. Hormone treatment with either of the three agents mentioned resulted in the concentration of CA125 returning to the control levels and the concentration of HE4 decreasing to below the control levels. CA125, however not HE4, significantly differed between the proliferative and secretory cycle phases. Since HE4 is sensitive to hormonal treatment and robust towards menstrual cycle variation, HE4 is potentially superior to CA125 as an endometriosis marker and therefore has greater potential as a marker for the identification of women at risk of developing ovarian cancer.

 

 

Taiwan J Obstet Gynecol. 2015 Jun;54(3):236-9.

Clinical significance of serum follistatin levels in the diagnosis of ovarian endometrioma and benign ovarian cysts.

Ant Ö¹, Özakşit G¹, Güzel Aݹ, Cavkaytar S¹, Kaba M¹, Topçu HO².

Abstract

OBJECTIVE:

To determine the clinical significance of serum follistatin levels in women with an ovarian endometrioma.

MATERIALS AND METHODS:

This is a prospective study of 89 women, 56 with an ovarian endometrioma (endometrioma group) and 33 with a benign ovarian cyst (control group) who underwent laparoscopic excision. Age, parity, body mass index, serum CA-125, serum CA 19-9, and serum follistatin levels were determined for all participants and evaluated as potential prognostic factors prior to laparoscopic cystectomy.

RESULTS:

There were no significant differences in demographic factors between the endometrioma group and the control group. However, serum follistatin levels were significantly higher in the endometrioma group (9350 ± 895 pg/mL vs. control group 725 ± 72 pg/mL, p < 0.05). The optimal diagnostic cut-off values (sensitivity and specificity) of CA-125, CA 19-9, and follistatin for ovarian endometrioma were 23.2 IU/mL (82.14% and 72.73%), 30.14 IU/mL (45.28% and 87.50%), and 2350 pg/mL (53.7% and 60.61%), respectively.

CONCLUSION:

Despite the increased serum follistatin levels in patients with ovarian endometrioma, CA-125 was determined to be a more sensitive and specific marker than follistatin for the diagnosis of ovarian endometrioma and endometriosis.

 

Taiwan J Obstet Gynecol. 2015 Jun;54(3):294-6.

Elevation of plasma D-dimer levels associated with rupture of ovarian endometriotic cysts.

Tanaka K¹, Kobayashi Y², Dozono K¹, Shibuya H¹, Nishigaya Y¹, Momomura M¹, Matsumoto H¹, Iwashita M¹.

Abstract

OBJECTIVE:

The marker for the early diagnosis of endometriotic cyst rupture is unknown. We report a preliminary study designed to evaluate the relationship between plasma D-dimer levels and endometriotic cyst rupture in clinical case series.

MATERIALS AND METHODS:

We reviewed the patients’ records of endometriotic cyst rupture cases, and the background (i.e., age, body mass index, and parity) and preoperative laboratory assessments (i.e., white blood cell count, levels of serum C-reactive protein, serum CA125, and plasma D-dimer) of the patients were compared with those of unruptured cases.

RESULTS:

Emergency surgery cases of endometriotic cyst rupture (n = 6) and planned surgery cases of unruptured endometriotic cysts as controls (n = 16) were reviewed. Backgrounds of the patients were not significantly different between the two groups. The plasma D-dimer level was significantly higher in the rupture cases (8.5 μg/mL vs. 0.20 μg/mL, p < 0.001). Differences in white blood cell count and serum C-reactive protein level, but not serum CA125 level, were found to be statistically significant between groups.

CONCLUSION:

An elevation of plasma D-dimer level is associated with endometriotic cyst rupture.

 

 

Taiwan J Obstet Gynecol. 2015 Jun;54(3):306-12

Primary umbilical endometrioma: Analyzing the pathogenesis of endometriosis from an unusual localization.

Calagna G¹, Perino A², Chianetta D³, Vinti D², Triolo MM², Rimi C⁴, Cucinella G², Agrusa A³.

Abstract

OBJECTIVE:

This report presents a rare case of symptomatic primary umbilical endometriosis and reviews the literature on the topic with the aim to clarify some questions on the origin of endometriosis.

CASE REPORT:

A 33-year-old woman with cyclic umbilical bleeding was found to have umbilical endometriosis. She had no history of pelvic or abdominal surgery. There was no past history of endometriosis or endometriosis-associated symptoms. An omphalectomy was performed after explorative laparoscopy to carefully inspect the abdominopelvic cavity and assess any coexisting pelvic endometriotic lesions. Histological examination confirmed the diagnosis of umbilical endometriosis.

CONCLUSION:

Umbilical endometriosis is a rare but under-recognized phenomenon. Primary lesions are difficult to recognize, but probably represent an independent nosological entity. The possibility of endometriosis must be considered during the evaluation of an umbilical mass despite the absence of previous surgery. Complete excision and successive histology are highly recommended.

 

 

Hum Reprod Update. 2015 Nov-Dec;21(6):809-25

The impact of endometrioma on IVF/ICSI outcomes: a systematic review and meta-analysis.

Hamdan M¹, Dunselman G², Li TC³, Cheong Y⁴.

Abstract

BACKGROUND:

Endometriosis is a disease known to be detrimental to fertility. Women with endometriosis, and the presence of endometrioma, may require artificial reproductive techniques (ART) to achieve a pregnancy. The specific impact of endometrioma alone and the impact of surgical intervention for endometrioma on the reproductive outcome of women undergoing IVF/ICSI are areas that require further clarification. The objectives of this review were as follows: (i) to determine the impact of endometrioma on IVF/ICSI outcomes, (ii) to determine the impact of surgery for endometrioma on IVF/ICSI outcome and (iii) to determine the effect of different surgical techniques on IVF/ICSI outcomes.

METHODS:

We performed a systematic review and meta-analysis examining subfertile women who have endometrioma and are undergoing IVF/ICSI, and who have or have not had any surgical management for endometrioma before IVF/ICSI. The primary outcome was live birth rate (LBR). Our secondary outcomes were clinical pregnancy rate (CPR), mean number of oocyte retrieved (MNOR), miscarriage rate (MR), fertilization rate, implantation rate, antral follicle count (AFC), total stimulating hormone dose, and any rates of adverse effects such as cancellation and associated complications during the IVF/ICSI treatment.

RESULTS:

We included 33 studies for the meta-analysis. The majority of the studies were retrospective (30/33), and three were RCTs. Compared with women with no endometrioma undergoing IVF/ICSI, women with endometrioma had a similar LBR (odds ratio [OR] 0.98; 95% CI [0.71, 1.36], 5 studies, 928 women, I(2) = 0%) and a similar CPR (OR 1.17; 95% CI [0.87, 1.58], 5 studies, 928 women, I(2) = 0%), a lower mean number of oocytes retrieved (SMD -0.23; 95% CI [-0.37, -0.10], 5 studies, 941 cycles, I(2) = 37%) and a higher cycle cancellation rate compared with those without the disease (OR 2.83; 95% CI [1.32, 6.06], 3 studies, 491 women, I(2) = 0%). Compared with women with no surgical treatment, women who had their endometrioma surgically treated before IVF/ICSI had a similar LBR (OR 0.90; 95% CI [0.63, 1.28], 5 studies, 655 women, I(2) = 32%), a similar CPR (OR 0.97; 95% CI [0.78, 1.20], 11 studies, 1512 women, I(2) = 0%) and a similar mean number of oocytes retrieved (SMD -0.17; 95% CI [-0.38, 0.05], 9 studies, 810 cycles, I(2) = 63%).

CONCLUSIONS:

Women with endometrioma undergoing IVF/ICSI had similar reproductive outcomes compared with those without the disease, although their cycle cancellation rate was significantly higher. Surgical treatment of endometrioma did not alter the outcome of IVF/ICSI treatment compared with those who did not receive surgical intervention. Considering that the reduced ovarian reserve may be attributed to the presence of endometrioma per se, and the potential detrimental impact from surgical intervention, individualization of care for women with endometrioma prior to IVF/ICSI may help optimize their IVF/ICSI results.

 

 

Reprod Sci. 2015 Sep;22(9):1171-80.

Inhibition of MAPK and VEGFR by Sorafenib Controls the Progression of Endometriosis.

Leconte M¹, Santulli P², Chouzenoux S³, Marcellin L⁴, Cerles O³, Chapron C⁴, Dousset B¹, Batteux F⁵.

Abstract

INTRODUCTION:

Sorafenib is a strong multikinase inhibitor targeting 2 different pathways of endometriosispathogenesis: RAF kinase and vascular endothelial growth factor receptor (VEGFR). We investigate whether Sorafenib could control the growth of endometriotic lesions both in vitro and in vivo.

METHODS:

Stromal primary cells were extracted from endometrial and endometriotic biopsies from patients with (n = 10) and without (n = 10) endometriosis. Proliferation, apoptosis, mitogen-activated protein kinases, and VEGFR-2 autophosphorylation were explored with and without Sorafenib treatment. Human endometriotic lesions were implanted in 30 nude mice randomized according to Sorafenib or placebo treatment.

RESULTS:

Treating endometriotic cells with Sorafenib abrogated the phosphorylation of extracellular signal-regulated kinase in stromal cells of women with endometriosis compared to controls. In addition, this study highlights the antiangiogenic role of Sorafenib which translates as a decreased phosphorylated VEGFR-2-VEGFR-2 ratio in endometriosis. Using a xenogenic mouse model of endometriosis, we confirmed that Sorafenib regulates the endometriosis activity in vivo by targeting endometriosis-related proliferation and inflammation.

CONCLUSION:

Our data suggest that Sorafenib controls the growth of endometriotic lesions in vitro and in vivo.

 

 

Reprod Sci. 2015 Dec;22(12):1632-42.

Immunohistochemical Investigation of Metastasis-Related Chemokines in Deep-Infiltrating Endometriosis and Compromised Pelvic Sentinel Lymph Nodes.

Borrelli GM¹, Abrão MS², Taube ET³, Darb-Esfahani S³, Köhler C⁴, Kaufmann AM⁵, Chiantera V⁵, Mechsner S⁶.

 

Abstract

Endometriosis is a prevalent benign disease, despite sharing several similarities with malignancies, such as the possibility of lymphatic spread. In malignancies, chemokines play a sovereign role in the process of metastasis. Metastasis-related chemokine axes have not yet been assessed in deep-infiltrating endometriosis (DIE), and this investigation was the aim of our study. The expression of these chemokines was investigated by immunohistochemistry in rectovaginal DIE lesions and in matched pelvic sentinel lymph nodes (PSLNs) of patients with endometriosis (n = 27), and their expression in the eutopic endometrium (EE) of endometriosis-free women (n = 20) was used as controls. Their staining pattern in rectovaginal DIE, in endometriotic lesions affecting the PSLN as well as in the EE of patients without endometriosis was characterized for the first time. Overall, these chemokines were highly expressed in DIE and endometriosis in PSLN. Chemokines might be involved in the spread of endometriosis and should be further investigated.

 

 

Reprod Sci. 2015 Sep;22(9):1053-9.

Pathogenetic Mechanisms of Deep Infiltrating Endometriosis.

Tosti C¹, Pinzauti S¹, Santulli P², Chapron C², Petraglia F³.

 

Abstract

Endometriosis is a benign gynecologic disease, affecting women of reproductive age associated with chronic pelvic pain, dysmenorrhea, dyspareunia and infertility. Ovarian endometrioma (OMA), superficial peritoneal endometriosis (SPE), and deep infiltrating endometriosis (DIE) are, till now, recognized as major phenotypes. The discussion is to know whether they share the same pathogenetic mechanisms. Till today, DIE is recognized as the most severe clinical form of endometriosis and has a complex clinical management. The DIE lesions have been considered in the present article, without distinguishing between the anterior (bladder) or the posterior (vagina, uterosacral ligaments, rectum, and ureter) compartment. The present knowledge indicates that hormonal function (estrogen and progesterone receptors) and immunological factors, such as peritoneal macrophages, natural killer cells, and lymphocytes, are critically altered in DIE. The aggressive behavior of DIE may be explained by the highly decreased apoptosis (nuclear factor kappa-light-chain-enhancer of activated B cells [NF-kB], B-cell lymphoma 2 [Blc-2], and anti-Mullerian hormone) and by the increased proliferation activity related to oxidative stress (NF-kB, reactive oxygen species, extracellular regulated kinase (ERK), advanced oxidation protein product). Invasive mechanisms are more expressed (matrix metalloproteinases and activins) in DIE in comparison to the OMA and SPE. Correlated with the increased invasiveness are the data on very high expression of neuroangiogenesis (nerve growth factor, vascular endothelial growth factor, and intercellular adhesion molecule) genes in DIE. Therefore, at the present time, several of the DIE pathogenetic features result specific in comparison to other endometriosis phenotypes, pleading for the existence of a specific entity. These evidence of specific pathogenetic features of DIE may explain the more severe symptomatology related to this form of endometriosis and suggest possible future target medical treatments.

 

 

Reprod Sci. 2016 Jan;23(1):87-91.

Impaired Development of Early Endometriotic Lesions in CD44 Knockout Mice.

Knudtson JF¹, Tekmal RR², Santos MT², Binkley PA², Krishnegowda N², Valente P³, Schenken RS².

 

Abstract

Previous studies have shown endometrial cell (EC) CD44 and peritoneal mesothelial cell (PMC)-associated hyaluronan (hyaluronic acid [HA]) are involved in the attachment of endometrial stroma and epithelial cells to peritoneal mesothelium. Here we assess the CD44-HA interaction in the formation of the early endometriotic lesion using CD44(-/-) (knockout) mice. Using an established murine model and crossover technique, endometrial tissue from donor mice (wild type [WT] and CD44(-/-)) was used to induce endometriosis in recipient mice (WT and CD44(-/-)). Endometriotic lesions were visualized by fluorescent microscopy and confirmed by hematoxylin and eosin staining. Early endometriotic lesions were decreased when CD44(-/-) endometrium was placed in WT recipients and when WT endometrium was placed in CD44(-/-) recipients (P = .002). Early endometriotic lesions were also significantly decreased when both peritoneal and endometrial tissues lacked CD44 expression (P < .01). These studies demonstrate that both EC and PMC CD44 play a role in the development of early endometriotic lesion.

 

 

J Pediatr Adolesc Gynecol. 2016 Apr;29(2):97-103.

Prevalence of Pain Symptoms Suggestive of Endometriosis Among Finnish Adolescent Girls (TEENMAPS Study).

Suvitie PA¹, Hallamaa MK², Matomäki JM³, Mäkinen JI², Perheentupa AH⁴.

Abstract

STUDY OBJECTIVE:

To evaluate the prevalence of pain symptoms suggestive of endometriosis among adolescent girls aged 15-19 years.

DESIGN:

Cross-sectional study.

SETTING:

University hospital.

PARTICIPANTS:

Adolescent girls aged 15-19 years attending elementary school, high school, or vocational institute at 3 cities in Southwest Finland in 2010-2011.

INTERVENTIONS:

The school nurses distributed a detailed questionnaire to 2582 girls who were attending school at the time of the study. Completion of the questionnaire was voluntary and anonymous.

MAIN OUTCOME MEASURES:

Prevalence and severity of dysmenorrhea, acyclic abdominal pain, dyspareunia, dyschezia, and dysuria. Severity was evaluated with an 11-point numerical rating scale (NRS).

RESULTS:

A total of 1103 eligible answers were analyzed. The prevalence of dysmenorrhea was 68% (738/1092) with mean NRS of 7.0 (SD = 2.0). Acyclic abdominal pain, dyspareunia, dyschezia, and dysuria were less frequent (19% [207/1085], 12% [53/458], 8% [87/1088] and 5% [50/1084], respectively). The prevalence of severe dysmenorrhea (NRS 8-10) was 33% (355/1089). Severe dysmenorrhea was associated with increased risk of concurrent acyclic abdominal pain (odds ratio [OR] = 2.7; 95% confidence interval [CI], 2.0-3.6), dyschezia (OR = 2.5; 95% CI, 1.6-3.9), and regular absenteeism from school or hobbies (OR = 10.0; 95% CI, 4.2-23.6). Using different criteria, 2%-10% (21-106/1103) of all girls could be identified as having symptoms suggestive of endometriosis. Five percent of girls (n = 53/1103) had severe dysmenorrhea, used oral contraceptive pills, and reported inadequate relief from pain medication.

CONCLUSION:

One-third (355/1089) of 15- to 19-year-old girls had severe menstrual pain and 14% (49/355) of them were regularly absent from school or hobbies. Five percent of all teenage girls (53/1103) were poor responders to conventional therapy for primary dysmenorrhea.

 

 

 

Int J Womens Health. 2015 Jul 1;7:663-72.

Endometriosis and ovarian cancer: links, risks, and challenges faced.

Pavone ME¹, Lyttle BM².

 

Abstract

Endometriosis is a benign gynecological condition characterized by specific histological, molecular, and clinical findings. It affects 5%-10% of premenopausal women, is a cause of infertility, and has been implicated as a precursor for certain types of ovarian cancer. Advances in technology, primarily the ability for whole genome sequencing, have led to the discovery of new mutations and a better understanding of the function of previously identified genes and pathways associated with endometriosis associated ovarian cancers (EAOCs) that include PTEN, CTNNB1 (β-catenin), KRAS, microsatellite instability, ARID1A, and the unique role of inflammation in the development of EAOC. Clinically, EAOCs are associated with a younger age at diagnosis, lower stage and grade of tumor, and are more likely to occur in premenopausal women when compared with other ovarian cancers. A shift from screening strategies adopted to prevent EAOCs has resulted in new recommendations for clinical practice by national and international governing bodies. In this paper, we review the common histologic and molecular characteristics of endometriosis and ovarian cancer, risks associated with EAOCs, clinical challenges and give recommendations for providers.

 

 

Biomed Rep. 2015 Jul;3(4):559-565.

Association between matrix metalloproteinase-2 and matrix metalloproteinase-9 polymorphisms and endometriosis: A systematic review and meta-analysis.

Xin L¹, Hou Q¹, Xiong QI², Ding X¹.

 

Abstract

Matrix metalloproteinase-2 (MMP-2)-735C/T and MMP-9-1562C/T polymorphisms have been indicated in the predisposition to endometriosis. However, due to the small sample sizes of previous studies, the results remain inconclusive. The present meta-analysis was conducted to detect the association between the two genetic polymorphisms and the risk of endometriosis by pooling all the available data. Electronic databases, including PubMed, Embase, Web of Science and CNKI, were searched comprehensively for studies examining a link between MMP-2 and MMP-9 polymorphisms and endometriosis. The strength of the association was assessed based on the pooled odds ratio with a 95% confidence interval, which was calculated using either the fixed- or random-effect model. Following the inclusion criteria, 6 case-control studies were included. The total number of participants was 2,486 (558 cases and 797 controls concerning the MMP-9-1562C/T polymorphism, and 525 cases and 606 controls concerning the MMP-2-735C/T polymorphism). No significant association was identified between the MMP-2-735C/T or MMP-9-1562C/T polymorphism and endometriosis. In further stratified analysis, no significant association was identified between the MMP-9-1562C/T polymorphism and endometriosis. The present meta-analysis revealed no association between the MMP-2-735C/T and MMP-9-1562C/T polymorphisms and the risk of developing endometriosis. Considering the limitations of the meta-analysis, well-designed studies with larger sample sizes are required.

 

 

Gynecol Endocrinol. 2015;31(8):595-8.

Focusing on surgery results in infertile patients with deep endometriosis.

Angioni S¹, Cela V², Sedda F¹, Stochino Loi E¹, Cofelice V¹, Pontis A³, Melis GB¹.

 

Abstract

Infertility is a common problem in patients with endometriosis and the involved mechanisms are still not completely known. The management of infertility in endometriosis patients includes surgery as well as assisted reproductive technology. Laparoscopic surgery has shown better results in infertility patients with endometriosis in comparison to laparotomy procedures. Laparoscopic surgery has proposed benefits in both minimal to moderate diseases. However, while there may be some benefits with severe diseases, there is still not enough evidence to recommend laparoscopic surgery as the recommended surgery when the main goal is to obtain fertility. We performed a MEDLINE search for articles on fertility in women with deep infiltrating endometriosis (DIE) published between 1990 and April 2015 using the following keywords: “endometriosis”, “deep infiltrative endometriosis”, “infertility”, “fertility after surgery”, “laparoscopy surgery”, “laparotomy”, “pregnancy”, “fertility outcome”, “bladder endometriosis”, and “ureteral endometriosis”. The aim of this review was to analyze the results of available clinical studies (randomized controlled or not controlled studies; retrospective cohort studies; or case-control and prospective studies) and guidelines on surgical treatment of infertile endometriosis patients, and pregnancy outcomes after surgery.

 

 

J Anat. 2015 Dec;227(6):781-5.

Prospects for regenerative medicine approaches in women’s health.

Schenke-Layland K^1,2,3, Brucker SY^1,4.

 

Abstract

Novel regenerative strategies, stem cell-based therapies or the development of advanced human cell-based in vitro-manufactured preclinical test systems offer great potential to generate advances in clinical practice in the field of women’s health. This review aims to provide a brief overview of the current advances in the field.

 

 

JSLS. 2015 Jul-Sep;19(3).

Appendiceal Nodules in the Setting of Endometriosis Can Be Carcinoid Tumors.

Padovesi Mota IL¹, Klajner S², da Costa Gonçalves MO³, Passman LJ⁴, Podgaec S¹.

Abstract

INTRODUCTION:

Endometriosis is occasionally found in the appendix, particularly in severe forms of deep infiltrating disease. Carcinoid tumor is the most common neoplasm of the appendix and may be overlooked or misdiagnosed when there are multiple endometriosis lesions in the pelvis.

CASE DESCRIPTION:

We describe two cases of carcinoid tumor diagnosed in patients who underwent surgery to treat endometriosis, in whom the diagnosis of appendiceal endometriosis was presumed.

DISCUSSION:

In the context of endometriosis, surgery is indicated when the appendix is affected. Despite the more likely diagnosis of appendiceal endometriosis, carcinoid tumors cannot be ruled out by imaging examinations.

 

 

Am J Cancer Res. 2015 Apr 15;5(5):1706-17.

Down regulation of MiR-93 contributes to endometriosis through targeting MMP3 and VEGFA.

Lv X¹, Chen P², Liu W¹.

Abstract

OBJECTIVE:

This study aimed to explore the role of miRNAs in pathogenesis of endometriosis.

METHODOLOGY:

Endometrial samples from 57 females with endometriosis and 44 non-endometriotic controls were compared for the expression of a selected group of miRNAs. The regulatory function on downstream target was also explored.

RESULTS:

The expression of miR-93 and miR106a was significantly reduced in endometriotic samples compared to that in non-endometriotic samples. High levels of MMP3 and VEGFA were detected in more than 50% ectopic endometrium tissues. A negative association was found between the expression of miR-93 and the protein levels of MMP3 (Pearson correlation, r=-0.39, P=0.0025) or VEGFA (Pearson correlation, r=-0.37, P=0.0047) in samples from endometriosis patients. Mechanistically, miR-93 targeted MMP3 and VEGFA by directly binding to the 3’UTR of MMP3 and VEGFA mRNAs, and thereby inhibited the proliferation, migration and invasive capability of endometrial stromal cells (ESCs).

CONCLUSION:

The finding of this study suggests that deregulation of miR-93 contribute to endometriosis by up-regulation of MMP3 and VEGFA and thus provide potential therapeutic targets for the treatment of endometriosis.

 

Georgian Med News. 2015 Jul-Aug;(244-245):7-11

mRNA TLR2 AND TLR4 EXPRESSION IN THE ENDOMETRIUM TISSUE IN WOMEN WITH ENDOMETRIOSIS ASSOSIATED WITH INFERTILITY.

Koval H¹, Chopiak V¹, Kamyshnyi А¹.

 

Abstract

Endometriosis is an important medical and social problem as it causes stable pelvic pains, afflicts women of the reproductive age, provokes infertility characterized by poor outcome of treatment. In recent times much attention is paid to the mechanisms of congenital immunity as possible mediators of the development of endometriosis and targets of therapy. The work deals with the investigation of the levels of mRNA TLR2 and TLR4 expression in the tissue of eutopic endometrium in women with endometriosis and infertility in comparison with women afflicted with infertility of a tubular character with the aim to define the role of TLR2 and TLR4 in the development of infertility in case of endometriosis. The study was conducted by means of polymerase chain reaction (PCR) real-time method. The results of the study are indicative of an increased TLR2 and TLR4 expression (especially TLR2) in the endometrium in women with endometriosis. The results obtained may be indicative of an important role of TLR2 and TLR4 in the development of endometrioid ectopia and should be considered while treating infertility in women with endometriosis.

 

 

Facts Views Vis Obgyn. 2015;7(2):109-18.

Surgery for endometriosis-associated infertility: do we exaggerate the magnitude of effect?

Rizk B¹, Turki R², Lotfy H³, Ranganathan S¹, Zahed H⁴, Freeman AR¹, Shilbayeh Z¹, Sassy M⁵, Shalaby M⁶, Malik R⁷.

Abstract

OBJECTIVE:

Surgery remains the mainstay in the diagnosis and management of endometriosis. The number of surgeries performed for endometriosis worldwide is ever increasing, however do we have evidence for improvement of infertility after the surgery and do we exaggerate the magnitude of effect of surgery when we counsel our patients? The management of patients who failed the surgery could be by repeat surgery or assisted reproduction. What evidence do we have for patients who fail assisted reproduction and what is their best chance for achieving pregnancy?

MATERIAL AND METHODS:

In this study we reviewed the evidence-based practice pertaining to the outcome of surgery assisted infertility associated with endometriosis. Manuscripts published in PubMed and Science Direct as well as the bibliography cited in these articles were reviewed. Patients with peritoneal endometriosis with mild and severe disease were addressed separately. Patients who failed the primary surgery and managed by repeat or assisted reproduction technology were also evaluated. Patients who failed assisted reproduction and managed by surgery were also studied to determine of the best course of action.

RESULTS:

In patients with minimal and mild pelvic endometriosis, excision or ablation of the peritoneal endometriosis increases the pregnancy rate. In women with severe endometriosis, controlled trials suggested an improvement of pregnancy rate. In women with ovarian endometrioma 4 cm or larger ovarian cystectomy increases the pregnancy rate, decreases the recurrence rate, but is associated with decrease in ovarian reserve. In patients who have failed the primary surgery, assisted reproduction appears to be significantly more effective than repeat surgery. In patients who failed assisted reproduction, the management remains to be extremely controversial. Surgery in expert hands might result in significant improvement in pregnancy rate.

CONCLUSION:

In women with minimal and mild endometriosis, surgical excision or ablation of endometriosis is recommended as first line with doubling the pregnancy rate. In patients with moderate and severe endometriosissurgical excision also is recommended as first line. In patients who failed to conceive spontaneously after surgery, assisted reproduction is more effective than repeat surgery. Following surgery, the ovarian reserve may be reduced as determined by Anti Mullerian Hormone. The antral follicle count is not significantly reduced. In women with large endometriomas > 4 cm the ovarian endometrioma should be removed. In women who have failed assisted reproduction, further management remains controversial in the present time.

 

 

Adv Exp Med Biol. 2015;868:49-79.

Small RNAs: Their Possible Roles in Reproductive Failure.

Hale BJ¹, Keating AF, Yang CX, Ross JW.

 

Abstract

Posttranscriptional gene regulation is a regulatory mechanism which occurs “above the genome” and confers different phenotypes and functions within a cell. Transcript and protein abundance above the level of transcription can be regulated via noncoding ribonucleic acid (ncRNA) molecules, which potentially play substantial roles in the regulation of reproductive function. MicroRNA (miRNA), endogenous small interfering RNA (endo-siRNA), and PIWI-interacting RNA (piRNA) are three primary classes of small ncRNA. Similarities and distinctions between their biogenesis and in the interacting protein machinery that facilitate their function distinguish these three classes. Characterization of the expression and importance of the critical components for the biogenesis of each class in different tissues contributes a clearer understanding of their contributions in specific reproductive tissues and their ability to influence fertility in both males and females. This chapter discusses the expression and potential roles of miRNA, endo-siRNA, and piRNA in the regulation of reproductive function. Additionally, this chapter elaborates on investigations aimed to address and characterize specific mechanisms through which miRNA may influence infertility and the use of miRNA as biomarkers associated with several reproductive calamities such as defective spermatogenesis in males, polycystic ovarian failure, endometriosis and obesity, and chemical-induced subfertility.

 

 

Biomed Res Int. 2015;2015:141485.

Immunomodulatory Role of Adipose-Derived Stem Cells on Equine Endometriosis.

Falomo ME¹, Ferroni L², Tocco I³, Gardin C², Zavan B².

 

Abstract

Endometriosis is a degenerative process due to a chronic inflammatory damage leading to extracellular matrix components deposition and glandular fibrosis. It is known that mesenchymal stem cells secrete a wide range of bioactive molecules, some of them modulating the immune inflammatory response, and others providing regeneration and remodeling of injured tissue. We have performed in vitro experiments in order to analyze the capability of allogenic equine adipose-derived stem cells (ADSCs) to infiltrate mares’ endometrial tissues and to stimulate the expression of cytokines and metallopeptidases. Differences in the biologic response to the exposure to ADSCs between pathological and healthy endometrial tissue have been identified. These results could challenge researchers to progress forward with future studies for the development of a biological therapy with a possible application in translational medicine.

 

 

 

Obstet Gynecol. 2015 Sep;126(3):617-27.

Hormonal Add-Back Therapy for Females Treated With Gonadotropin-Releasing Hormone Agonist for Endometriosis: A Randomized Controlled Trial.

DiVasta AD¹, Feldman HA, Sadler Gallagher J, Stokes NA, Laufer MR, Hornstein MD, Gordon CM.

Abstract

OBJECTIVE:

To assess whether add-back therapy with norethindrone acetate or norethindrone acetate plus conjugated equine estrogens is superior to maintain bone health in adolescents and young women using gonadotropin-releasing hormone agonists for endometriosis. Gonadotropin-releasing hormone agonists are associated with deleterious effects on bone. Hormonal add-back may mitigate these effects.

METHODS:

Adolescents and young women (n=51) received a random, double-blind assignment to add-back with norethindrone acetate (5 mg/day) plus conjugated equine estrogens (0.625 mg/day) or norethindrone acetate plus placebo for 12 months. Body composition, bone mineral content, and bone mineral density (BMD) were obtained by dual-energy X-ray absorptiometry every 6 months. Quality-of-life measures were collected every 3 months. Intention-to-treat comparison of outcomes was conducted by repeated-measures analysis of variance.

RESULTS:

Thirty-four adolescents and young women completed the trial; dropouts did not differ from those who completed the trial. Bone mineral density was normal at baseline. At 12 months, total body bone mineral content and BMD had increased in the norethindrone acetate plus conjugated equine estrogens group (bone mineral content +37 g, P<.001 and BMD +0.012 g/cm, P=.05), but not in those receiving norethindrone acetate plus placebo (bone mineral content P=.19 and BMD P=.95). Lean mass increased only in those receiving conjugated equine estrogens (+1.4 kg, P=.001). Improvements in physical functioning domains of quality-of-life assessments were greater with norethindrone acetate plus conjugated equine estrogens (P=.005). No differences were seen at the hip or lumbar spine by dual-energy X-ray absorptiometry. No significant adverse events occurred.

CONCLUSION:

Hormonal add-back successfully preserved bone health and improved quality of life for adolescents and young women with endometriosis during 12 months of gonadotropin-releasing hormone agonist therapy. Combination norethindrone acetate plus conjugated equine estrogens add-back appears to be more effective for increasing total body bone mineral content, areal BMD, and lean mass than norethindrone acetate monotherapy.

 

 

Urol Int. 2015;95(2):227-32.

Statin Use Is Associated with Bladder Pain Syndrome/Interstitial Cystitis: A Population-Based Case-Control Study.

Huang CY¹, Chung SD, Kao LT, Lin HC, Wang LH.

Abstract

INTRODUCTION:

Statin may induce epithelial dysfunction of the bladder urothelium. Epithelial dysfunction was proposed as one of the major potential etiologies for bladder pain syndrome/interstitial cystitis (BPS/IC). In this study, we examined the association between statin use and BPS/IC using a population-based study.

SUBJECTS AND METHODS:

This case-control study used the Taiwan Longitudinal Health Insurance Database. In total, 815 female subjects with BPS/IC and 4075 randomly selected female controls were included. We used a conditional logistic regression to compute the odds ratio (OR) for having previously used statins between cases and controls.

RESULTS:

A conditional logistic regression analysis showed that the OR of prior statin users for cases was 1.52 (95% confidence interval (CI): 1.19-1.94) compared to controls after adjusting for diabetes, hypertension, coronary heart disease, obesity, chronic pelvic pain, irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, depression, panic disorder, migraines, sicca syndrome, allergies, endometriosis, and asthma. Furthermore, adjusted ORs of regular and irregular statin use for cases were 1.58 (95% CI: 1.20-2.08) and 1.53 (95% CI: 1.02-2.31), respectively, compared to controls.

CONCLUSION:

We concluded that there was an association between statin use and BPS/IC.

 

 

BMJ Case Rep. 2015 Jul 16;2015.

Intussusception of the vermiform appendix.

Dickson-Lowe RA¹, Ibrahim S¹, Munthali L², Hasan F³.

 

Abstract

Appendicitis is a common presentation to an acute general surgical on call team. It can be a difficult diagnosis at times, particularly in sexually active young women, in whom it is often surgically challenging. This case is of a relatively straightforward diagnosis, taken for laparoscopic appendicectomy that resulted in performing an open right hemicolectomy for a necrotic, intussuscepted appendix. Histology ultimately revealed the cause of intussusception and resultant infarction of the appendix to be endometriosis.