Comparison of #Enzian classification and revised American Society for Reproductive Medicine stages for the description of disease extent in women with deep endometriosis.

STUDY QUESTION: How is endometriosis extent described by the #Enzian classification compared to the revised American Society for Reproductive Medicine (rASRM) stages in women undergoing radical surgery for deep endometriosis (DE)? SUMMARY ANSWER: The prevalence and severity grade of endometriotic lesions and adhesions as well as the total number of #Enzian compartments affected by DE increase on average with increasing rASRM stage; however, DE lesions are also present in rASRM stages 1 and 2, leading to an underestimation of disease severity when using the rASRM classification. WHAT IS KNOWN ALREADY: Endometriotic lesions can be accurately described regarding their localization and severity by sonography as well as during surgery using the recently updated #Enzian classification for endometriosis. STUDY DESIGN, SIZE, DURATION: This was a prospective multicenter study including a total of 735 women between January 2020 and May 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Disease extent in women undergoing radical surgery for DE at tertiary referral centers for endometriosis was intraoperatively described using the #Enzian and the rASRM classification. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 735 women were included in the study. Out of 31 women with rASRM stage 1, which is defined as only minimal disease, 65% (i.e. 20 women) exhibited DE in #Enzian compartment B (uterosacral ligaments/parametria), 45% (14 women) exhibited DE in #Enzian compartment A (vagina/rectovaginal septum) and 26% (8 women) exhibited DE in #Enzian compartment C (rectum). On average, there was a progressive increase from rASRM stages 1-4 in the prevalence and severity grade of DE lesions (i.e. lesions in #Enzian compartments A, B, C, FB (urinary bladder), FU (ureters), FI (other intestinal locations), FO (other extragenital locations)), as well as of endometriotic lesions and adhesions in #Enzian compartments P (peritoneum), O (ovaries) and T (tubo-ovarian unit). In addition, the total number of #Enzian compartments affected by DE lesions on average progressively increased from rASRM stages 1-4, with a maximum of six affected compartments in rASRM stage 4 patients. LIMITATIONS, REASONS FOR CAUTION: Interobserver variability may represent a possible limitation of this study. WIDER IMPLICATIONS OF THE FINDINGS: The #Enzian classification includes the evaluation of DE in addition to the assessment of endometriotic lesions and adhesions of the ovaries and tubes and may therefore provide a comprehensive description of disease localization and extent in women with DE. STUDY FUNDING/COMPETING INTEREST(S): No funding was received for this study. All authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Adenomyotic glands are highly related to endometrial glands.

RESEARCH QUESTION: How closely related are adenomyotic and endometrial glands? DESIGN: In this study, the mRNA and protein database www.proteinatlas.org was searched for proteins expressed predominantly in the endometrial glands. Specificity was tested with tissue microarrays. Biopsy specimens of endometrial, adenomyotic tissue, or both, were collected after surgery from 21 women without endometriosis, 20 women with endometriosis, 18 women with adenomyosis together with endometriosis and 12 women with adenomyosis alone. Tissue expression was analysed by immunohistochemistry. RESULTS: Two proteins were identified: calcyphosine (CAPS), and msh homeobox 1 (MSX1). A high abundance and good specificity in endometrial glands were found. Both proteins, CAPS and MSX1, showed a high specificity for endometrium and are both localized in the luminal cells and epithelial cells of the glandular and adenomyotic glands. No significant differences were found between CAPS- and MSX1-positive endometrial glands between cases with and without endometriosis. Also, no cycle-specific different expression was found. Furthermore, a close relationship between the adenomyotic glands and the endometrial glands for CAPS (range 63.0-98.3%) and for MSX1 (range 87.1-99.3%) could be demonstrated. Only 11.2% and 6.8% negative glands for CAPS and MSX1 were identified in all tissues from all patients, respectively; none were negative for both proteins. CONCLUSIONS: Taken together, our results show that the protein expression pattern of adenomyosis is nearly identical to those of the endometrium with and without endometriosis, thus suggesting endometrial glands as the main source for adenomyotic glands.

Localization of claudin-2 and claudin-3 in eutopic and ectopic endometrium is highly similar.

PURPOSE: Claudins as the major components of tight junctions are important in maintaining cell-cell integrity and thus function as a barrier. Dysregulation of the claudins is often associated with loss of the epithelial phenotype, a process called epithelial-mesenchymal transition (EMT), which most often results in gain of migrative and invasive properties. However, the role of claudins in the endometrium or endometriosis has only rarely been examined. METHODS: In this study, we investigated localization of claudin-2 and claudin-3 in the eutopic and ectopic endometrium with immunohistochemistry. A detailed quantification with HSCORE was performed for claudin-2 and claudin-3 in endometrium without endometriosis and in cases with endometriosis compared to the three endometriotic entities: peritoneal, ovarian, and deep-infiltrating endometriosis. RESULTS: We found a preferential localization of both claudins in the glandular and the luminal epithelial cells in the endometrium with and without endometriosis. Quantification of localization of both claudins showed no differences in eutopic endometrium of control cases compared to cases with endometriosis. Furthermore, both claudins are localized highly similar in the ectopic compared to the eutopic endometrium, which is in clear contrast to previously published data for claudin-3. CONCLUSION: From our results, we conclude that localization of claudin-2 and claudin-3 is highly stable in eutopic and ectopic endometrium without any loss of the epithelial phenotype and thus do not contribute to the pathogenesis of endometriosis.

Interdisciplinary Laparoscopic Implantation of Neuromodulation Leads to the Sacral Plexus for Therapy of Chronic Pelvic Pain and Neurogenic Bladder Dysfunctions.

OBJECTIVE: The aim of this study was to report on the use of laparoscopic implantation of leads on the branches of the sacral plexus for neuromodulation in the treatment of chronic pelvic pain (CPP) in a multidisciplinary setting with the help of electrophysiological neuromonitoring. MATERIALS AND METHODS: Between 2012 and 2019, six female patients complaining of chronic pain and bladder and bowel dysfunctions underwent laparoscopic exposure and nerve identification with the help of electrophysiological neuromonitoring. A lead was placed laparoscopically in direct contact with the affected nerve. Pain intensity (numerous ranking scale [NRS]), generic health status (EQ-5D-5L), Becks Depressions Inventory (BDI-V), Pain Catastrophizing Scale (PCS), and Client Satisfaction Questionnaire (CSQ-8) were assessed pre-/postoperatively as well as three and six months after surgery. Statistical analysis was performed using Mann-Whitney U and Wilcoxon rank-sum test. RESULTS: The median age was 36.5 years. NRS improved from a median of 9.5 preoperatively to 3.0 (p < 0.001) at six-month follow-up. Median EQ-5D-5L index value before treatment was 0.18, indicating a notably lowered quality of life and increased up to 0.83 after six months (p < 0.001). Preoperative median BDI-V scores indicated a major depressive mood and improved from a median of 46.0 to 12.0 after six months (p = 0.007). Preoperative PCS was elevated with a median score of 41.0 and decreased to 4.0 after six months (p < 0.001). CSQ showed that patients were satisfied with the treatment. CONCLUSIONS: This unique method is an alternative and effective treatment option for CPP even years after primary endometriosis surgery.

Patterns of missing data in the use of the endometriosis symptom diary.

BACKGROUND: Endometriosis is a common, chronic condition in women of reproductive age that is characterized by the presence of functional endometriotic lesions outside the uterus. The Endometriosis Symptom Diary (ESD) is an electronic patient-reported outcome (ePRO) instrument that assesses women's experience of endometriosis symptoms, with pain scored using a 0-10 numeric rating scale. This study investigated patterns of data missing from the ESD in the VALEPRO study. METHODS: Post hoc analyses of missing data were conducted. RESULTS: Of 272 participants using the ESD, 26.5% had no missing diary entries, 46.7% had > 0-5% of entries missing, 13.2% had > 5-10% of entries missing and 13.6% had > 10% of entries missing over the entire study period. The duration of missing episodes (defined as ≥1 consecutive days with missing diary entries) was generally short; most (81.4%) were 1 day. The difference in mean worst pain scores between missing and complete episodes per participant was - 0.1, suggesting that missing episodes were not related to severity of pain. Entries were significantly more likely to be missing on Fridays (18.5%) and Saturdays (22.9%) compared with other days of the week (p < 0.0001). Participants in the USA had significantly more long missing episodes than those in Germany (proportions of missing episodes longer than 1 day, 22.6 and 10.5%, respectively; p < 0.0001). The proportions of women with ≥1 missing entry were 50.0, 70.2 and 79.8% for women with elementary education, secondary education, and a college or university education, respectively. The proportions of women with ≥1 missing entry were similar for those with and without children (72.2 and 74.3%, respectively). CONCLUSIONS: Most participants were highly compliant with entering data in the ESD and the amount of missing data was low. Entries were significantly more likely to be missing on Fridays and Saturdays compared with other days of the week, and participants in the USA had significantly more long missing episodes than participants in Germany. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01643122 , registered 4 July 2012.

Erucin and benzyl isothiocyanate suppress growth of late stage primary human ovarian carcinoma cells and telomerase activity in vitro.

In the present study we analysed the effects of isothiocyanates (ITCs)--plant-derived sulphur-containing constituents known for their potential chemotherapeutic activity--on growth inhibition and programmed death in primary ovarian carcinoma cells from ascites of human patients. Twenty-four hour exposure of carcinoma cells to 5-50 µM erucin or benzyl ITC led to a concentration-dependent viability loss, as determined by erytrosin B cell staining. This concurred with an increase in internucleosomal DNA fragmentation, mitochondrial membrane depolarization and downregulation of Akt as indicator for apoptosis induction. Cell accumulation at the G2/M phase was evident after 48 h of erucin treatment. Telomerase, a selective target of cancer cells, was suppressed by erucin. Although pre-treatment of cells with the thiol antioxidant N-acetylcysteine could completely prevent initialization of the apoptotic process, it failed to abolish ITC-mediated telomerase suppression. Taken together, in our study, ITC exerted comparable cytotoxic efficacy against primary ovarian cancer cells as reported for corresponding cell lines. The clinical significance of this observation should be addressed in future studies and the role of telomerase further investigated.

How to close a colpotomy? Barbed suture and conventional suture effects on soft tissue: an ex vivo pilot study.

OBJECTIVE: To evaluate the effects of different suture materials and techniques on soft tissue in relation to defined tensions and time points. MATERIALS AND METHODS: Two bovine intestine samples, 4 × 4 cm size and ~3 mm thickness, were adapted with interrupted and continuous techniques using three types of suture materials: Vicryl (polyglactin 910), PDS II (polydioxanone), and V-Loc 180 (knotless, barbed polyglyconate). Four stitches or loops 9 mm apart with three knots, and 10 mm end length were performed by one gynecologist. Forces were applied from 6 newtons (N) to 14 N continuously. Outcome measures included breakage of tissue, tearing of thread, and shortening of the end length of thread. They were evaluated immediately and then at first, third, and fifth minute. RESULTS: Tissue breakage using No. 3/0 suture materials appears in the applied force from 10 N. polydioxanone causes more tissue tearing than polyglactin 910. The least to withstand tension is knotless polyglyconate. Interrupted stitches hold the sutured sites better than continuous stitches in all groups of threads. Shortening of the knotless polyglyconate end length by half took place with 6 N force. CONCLUSION: Simulating reparation of colpotomy, the ex vivo study supports that polyglactin 910 appears better in holding soft tissue than polydioxanone and knotless polyglyconate.

Intra-abdominal adhesion formation: does surgical approach matter? Questionnaire survey of South Asian surgeons and literature review.

AIM: The impact of postsurgical intra-abdominal adhesions, which represent a considerable burden for patients and health services, is often underestimated. Various factors influence adhesion formation, including the surgical approach. This study aimed to further understand the condition by investigating surgeons' perceptions of adhesion formation, particularly differences after laparoscopic and open surgery, and by performing a selective literature review. MATERIALS AND METHODS: South Asian surgeons attending endoscopy symposia in India and in Germany completed Likert-scale-based questionnaires on awareness of adhesion formation and associated consequences in gynecology. MEDLINE and PubMed were searched for articles published in 2000-2010 comparing laparoscopy and laparotomy in relation to adhesion formation. The results of the questionnaire study were then considered in view of findings from this review. RESULTS: In total, 43.1% (97/225) of questionnaires were completed. Respondents considered that laparoscopy caused fewer adhesions than laparotomy for all gynecological procedures. Although they believed their knowledge of adhesion formation was satisfactory, they widely underestimated the risk, giving estimated rates of 12.5% after laparoscopy and 36.3% after laparotomy. Twenty-eight studies were identified in the review. Most concluded that laparoscopy was less likely to cause adhesions than laparotomy but further statistical analysis was precluded because so many different definitions and classifications of adhesions had been used. CONCLUSIONS: The risk of adhesion formation was widely underestimated in the study group. Both the questionnaire study and the review concluded that laparoscopy results in less adhesion than laparotomy but further statistical comparison necessitates the development of standard definitions and classifications of adhesions.

Laparoscopic myomectomy in patients with uterine myomas associated with infertility.

Although myomectomy is widely accepted in women of childbearing age who wish to retain their fertility, the extent to which myomas affect fertility and whether their removal improves this remain unclear. This study aimed to elucidate the favourable surgical approach in women with uterine myomas and infertility. This retrospective, follow-up study was carried out in three centres in Germany. Data on women who had undergone myomectomy via laparoscopy, laparotomy or conversion to laparotomy in 2000-04 were collected and analysed. Fertility outcome after myomectomy was assessed by follow-up postal questionnaire in a subgroup of women with myoma-associated infertility. Data on 159 women with otherwise unexplained infertility were included (mean age 35 years (range 17-47), mean number of myomas 2.4 (range 1-8) and mean myoma size 6.1 cm (range 0.5-20)). Women who underwent laparoscopy had fewer complications. 39.6% (63/159) of women completed the questionnaire, which showed that the pregnancy rate after myomectomy was 46% in this group. No uterine rupture occurred. Laparoscopy is associated with fewer postoperative complications and since no preoperative or intraoperative factors seem to influence the fertility outcome in women with uterine myomas, it is the treatment of choice in these patients.

Feasibility of laparoscopic management of acute haemoperitoneum secondary to ruptured ovarian cysts in a haemodynamically unstable patient.

Acute haemoperitoneum in patients with coagulation disorders or those under anticoagulation therapy is a diagnostic and therapeutic dilemma. Since radiological imaging is often insufficient for establishing the origin of the bleeding, a laparoscopic approach can be considered before a laparotomy is performed in haemodynamically unstable patients. A 32-year-old woman receiving coumadin therapy presented with acute lower abdominal complaints. Due to suspicion of a tubo-ovarian abscess after the initial ultrasound, a conservative treatment was administered. A routine blood count after 12 hours showed a significant reduction in haemoglobin. During the CT scan, the patient developed unstable haemodynamics. Based on deteriorating coagulation parameters, mass transfusion and stabilization of the coagulation were performed but were not successful. Therefore an interventional laparoscopy was performed and a ruptured ovarian cyst was found to be the cause of bleeding. A ruptured ovarian cyst might be the cause of an acute abdomen and haemoperitoneum in young women. Therefore cyclus anamnesis and the exclusion of other obvious reasons for acute mass bleeding, i.e. ectopic pregnancy, can justify the laparoscopic approach after stabilization of the coagulation parameters. Long-term combined oral contraceptive therapy is indispensable for the prevention of these sorts of bleeding complications.

The Prevention of Positioning Injuries During Gynecologic Surgery. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry Number 015/077, October 2020).

Purpose Positioning injuries are relatively common, forensically highly relevant complications of gynecologic surgery. The aim of this official AWMF S2k-guideline is to provide statements and recommendations on how to prevent positioning injuries using the currently available literature. The literature was evaluated by an interdisciplinary group of experts from professional medical societies. The consensus on recommendations and statements was achieved in a structured consensus process. Method The current guideline is based on the expired S1-guideline, which was updated by a systematic search of the literature and a review of relevant publications issued between February 2014 and March 2019. Statements were compiled and voted on by a panel of experts. Recommendations The guideline provides general and specific recommendations on the prevention, diagnosis and treatment of positioning injuries.

Role of TGF-betas in normal human endometrium and endometriosis.

Endometriosis is characterized by presence of endometrial tissue outside the uterus. Prevalence is estimated at 6-10% in the general female population and many patients experience pain and/or infertility. Diagnosis is achieved by laparoscopic intervention followed by histological confirmation of viable endometriotic tissue. Mild cases are managed medically with contraceptive steroids and non-steroidal anti-inflammatory agents. Surgery provides relief to women in pain but symptoms recur in 75% of cases within 2 years. Starting with menstruation, we have categorized endometriosis into six stages, namely (1) shedding of cells, (2) cell survival, (3) escape from immune surveillance, (4) adhesion to peritoneum, (5) angiogenesis and (6) bleeding. In most of these biological processes, which resemble metastasis, transforming growth factor-beta (TGF-betas) and their high-affinity receptors are involved directly or indirectly. TGF-betas are abundantly and differentially expressed in the endometrium under hormonal control. Although they are preferentially synthesized in the stroma, glands and macrophages also secrete TGF-betas into the uterine fluid, where interaction with preimplantation embryos is suspected. Because mRNA and protein expression of all three TGF-betas is increased around menstruation, we suggest that TGF-betas might be involved in initiation of menstruation. Furthermore, because of high postmenstrual TGF-beta3 levels, we suppose that it might participate in scarless postmenstrual regeneration of endometrium. Our suggestions pave the way to novel routes of investigation into the roles of TGF-betas during menstruation and endometriosis.

Impact of endometriosis on quality of life: a pilot study.

Endometriosis affects 6-10% of women in reproductive age, 35-50% of whom experience pain, infertility or both. Mild cases are managed medically but surgery provides relief to women in pain. However, symptoms recur in 75% of cases within 2 years. We investigated the impact of endometriosis on quality of life among 65 women aged 18-60 years working at a city supermarket in Giessen, Germany. Of the 65 women, 12 had undergone surgeries, 22 had dysmenorrhoea, 24 dyspareunia and 3 were infertile. Of the 22 women with dysmenorrhoea, 10 had difficulties performing gardening, housework, sports and leisure activities. Five of these 10 women experienced social isolation, 6 professional setbacks; 6 declined efficiency at work and 3 had taken time off work. Of the 24 women with dyspareunia, 7 experienced minimal, 12 light and 5 moderate to strong pain. Only 16 of these 24 women discussed the problem with their partners. This study demonstrates that pain is a major cause of physical, psycho-social, emotional and professional or work related impairment among women with endometriosis. Because endometriosis is likely to impose emotional and financial burdens, we suggest that future studies should be extended to include interviews with family members.

Squamous-cell carcinoma in mature cystic teratoma of the ovary: systematic review and analysis of published data.

Up to a quarter of ovarian masses originate from germ cells, and many of these are mature cystic teratomas. The secondary development of malignancy is a rare but well-known phenomenon in patients with ovarian teratomas. Squamous-cell carcinoma accounts for 80% of secondary malignant transformations of ovarian teratomas. We aimed to do an up-to-date systematic review of this rare malignant transformation. 64 suitable studies provided information on 277 patients. Squamous-cell carcinoma in mature cystic teratoma was mainly found in women aged more than 50 years, with high concentrations of squamous-cell-carcinoma antigen and cancer antigen CA125, and with ovarian tumours more than 100 mm in size. Patients with FIGO stage Ia tumours had better survival than those with more advanced disease. Complete resection together with hysterectomy, bilateral salpingo-oophorectomy and lymphadenectomy for patients with advanced disease, followed by adjuvant chemotherapy with an alkylating drug was associated with higher survival, radiotherapy was not. We make proposals for investigation and treatment of this rare disorder.

Impaired Localization of Claudin-11 in Endometriotic Epithelial Cells Compared to Endometrial Cells.

Claudins are the major components of tight junctions and are often deregulated in human cancer, permitting escape of cancer cells along with the acquisition of invasive properties. Similarly, endometrial cells also show invasive capabilities; however, the role of tight junctions in endometriosis has only rarely been examined. In this study, we analyzed the protein expression and localization of claudin-7 and claudin-11 in human eutopic and ectopic endometrium and endometrial cell lines. We identified claudin-7 primarily at the basolateral junctions of the glandular epithelial cells in eutopic endometrium as well as in the ectopic lesions in nearly all glands and cysts. Quantification of claudin-7 localization by HSCORE showed a slight increase in peritoneal and deep infiltrating endometriosis (DIE) compared to eutopic endometrium. In contrast, claudin-11 was localized mainly in the apicolateral junctions in nearly all glandular epithelial cells of the eutopic endometrium. Interestingly, we observed a deregulation of claudin-11 localization to a basal or basolateral localization in ovarian (P < .001), peritoneal (P < .01), and DIE (P < .05) and a moderately decreased abundance in ovarian endometriosis. In endometrial cell lines, claudin-7 was only present in epithelial Ishikawa cells, and silencing by small-interfering RNA increased cell invasiveness. In contrast, claudin-11 could be demonstrated in Ishikawa and endometriotic 12Z and 49Z cells. Silencing of claudin-11 decreased invasiveness of 12Z slightly but significantly in 49Z. We suggest that although claudin-7 and claudin-11 can be found in nearly all eutopic and ectopic epithelial cells, the impaired localization of claudin-11 in ectopic endometrium might contribute to the pathogenesis of endometriosis.

Similar Characteristics of Endometrial and Endometriotic Epithelial Cells.

Epithelial-mesenchymal transition (EMT) is characterized by the loss of epithelial and acquisition of mesenchymal cell characteristics. Our aim was to assess the epithelial phenotype in the pathogenesis of endometriosis with epithelial and mesenchymal markers. We used 2 structural (keratin-18, -19 [K18, K19]), 1 membrane-associated (mucin-1 [MUC1]), and 2 mesenchymal proteins (vimentin; zinc finger E-box-binding homeobox 1, [ZEB1]) to compare epithelial and mesenchymal characteristics in eutopic endometrium with the 3 endometriotic entities, peritoneal, ovarian, and deep infiltrating endometriosis (DIE). Quantitation showed no differences for K18, K19, and MUC1 between endometrium with and without endometriosis. Also, K18 was not different between endometrium and endometriotic lesions. In contrast, K19 and MUC1 were modestly but significantly decreased in the endometriotic lesions compared to endometrium. However, the maintained expression of epithelial markers in all investigated tissues, regardless of the pathological condition, clearly indicates no loss of the epithelial phenotype. This is further supported by the reduced presence of epithelial vimentin in endometriotic lesions which is in contrast to an increase in stromal vimentin in ectopic endometrium, especially in ovarian endometriosis. The ZEB1 increase in endometriotic lesions, especially in DIE, on the other hand suggests a role of partial EMT in the development of endometriotic lesions, possibly connected with the gain of invasive capabilities or stemness. Taken together, although we found some hints for at least a partial EMT, we did not observe a severe loss of the epithelial cell phenotype. Thus, we propose that EMT is not a main factor in the pathogenesis of endometriosis.

Enhanced polarizing microscopy as a new tool in aneuploidy research in oocytes.

Chromosomal non-disjunction in female meiosis gives rise to reduced fertility and trisomy in humans. Human oocytes, especially from aged women, appear especially susceptible to non-disjunction. The oocyte spindle is crucial for high fidelity of chromosome segregation at meiotic divisions, and alterations in spindle morphology are therefore indicators of adverse conditions during oocyte development that may result in meiotic aneuploidy. In the past, oocytes had to be fixed for spindle analysis, precluding direct non-invasive identification of aneugens and adverse maturation conditions that affect spindle integrity and chromosome behaviour. Aneuploidy research for detection of spindle aberrations was therefore mainly focused on in vivo or in vitro exposed, fixed animal oocytes or cytogenetic analysis of spread oocytes. Orientation independent enhanced polarizing microscopy with nearly circularly polarized light and electronically controlled liquid crystal compensator optics is a new tool to study spindle morphology non-invasively in vivo for qualitative as well as quantitative analysis. Image generation by polarization microscopy depends on the intrinsic optical properties of the spindle with its paracrystalline microtubule lattice. When polarized light passes through such a lattice it induces a splitting of the beam and shift in the plane of vibration and retardation of light (termed birefringence and retardance). Studies of animal oocytes and follicle-cell denuded human oocytes fertilized by intracytoplasmic sperm injection for assisted conception have demonstrated the safety and efficacy of enhanced polarization microscopy. The method can be employed in aneuploidy research for non-invasive dose-response studies to detect spindle aberrations, for instance, in combination with cytogenetic analysis. Due to the non-invasive nature of the technique it may be employed in routine analysis of human oocytes to assess risks by lifestyle factors, and occupational and adverse environmental exposures.

Corrigendum to "Selective Progesterone Receptor Modulators for the Medical Treatment of Uterine Fibroids with a Focus on Ulipristal Acetate".

[This corrects the article DOI: 10.1155/2018/1374821.].

Lysophosphatidic acid triggers cathepsin B-mediated invasiveness of human endometriotic cells.

Extracellular lysophosphatidic acid (LPA) and the G-protein-coupled LPA receptors (LPAR) are involved in cell migration and invasion and found in the human endometrium. However, underlying mechanisms resulting in cellular invasion have been rarely investigated. We used stromal endometrial T-HESC, epithelial endometriotic 12Z, 49Z and Ishikawa cells. Interestingly, proliferation of T-HESC cells was strongly increased after LPA treatment, whereas the epithelial cell lines only showed a moderate increase. LPA increased invasion of 12Z and 49Z strongly and significantly. The LPAR inhibitor Ki16425 (LPAR1/3) attenuated significantly LPA-induced invasiveness of 12Z, which was confirmed by LPAR1 and LPAR3 siRNAs, showing that both LPA receptors contribute to invasiveness of 12Z cells. Investigation of cell invasion with an antibody-based protease array revealed mainly differences in cathepsins and especially cathepsin B between 12Z compared to the less invasive Ishikawa. Stimulation with LPA showed a time- and dose-dependent increased secretion of cathepsin B which was inhibited by the Gq inhibitor YM-254890 and Gi/o inhibitor pertussis toxin in the 12Z cells, again highlighting the importance of LPAR1/3. The activity of intracellular and secreted cathepsin B was significantly upregulated in LPA-treated samples. Inhibition of cathepsin B with the specific inhibitor CA074 significantly reduced LPA-increased invasion of 12Z. Our results reveal a novel role of LPA-mediated secretion of cathepsin B which stimulated invasion of endometriotic epithelial cells mainly via LPAR1 and LPAR3. These findings may deepen our understanding how endometriotic cells invade into ectopic sites, and provide new insights into the role of LPA and cathepsin B in cellular invasion.