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STUDY QUESTION Is large for gestational age (LGA) observed in babies born after frozen embryo transfer (FET) associated with either the freezing technique or the endometrial preparation protocol? SUMMARY ANSWER Artificial cycles are associated with a higher risk of LGA, with no difference in rate between the two freezing techniques (vitrification versus slow freezing) or embryo stage (cleaved embryo versus blastocyst). WHAT IS KNOWN ALREADY Several studies have compared neonatal outcomes after fresh embryo transfer (ET) and FET and shown that FET is associated with improved neonatal outcomes, including reduced risks of preterm birth, low birthweight, and small for gestational age (SGA), when compared with fresh ET. However, these studies also revealed an increased risk of LGA after FET. The underlying pathophysiology of this increased risk remains unclear; parental infertility, laboratory procedures (including embryo culture conditions and freezing-thawing processes), and endometrial preparation treatments might be involved. STUDY DESIGN, SIZE, DURATION A multicentre epidemiological data study was performed through a retrospective analysis of the standardized individual clinical records of the French national register of IVF from 2014 to 2018, including single deliveries resulting from fresh ET or FET that were prospectively collected in fertility centres. Complementary data were collected from the participating fertility centres and included the vitrification media and devices, and the endometrial preparation protocols. PARTICIPANTS/MATERIALS, SETTING, METHODS Data were collected from 35 French ART centres, leading to the inclusion of a total of 72 789 fresh ET, 10 602 slow-freezing FET, and 39 062 vitrification FET. Main clinical outcomes were presented according to origin of the transferred embryos (fresh, slow frozen, or vitrified embryos) and endometrial preparations for FET (ovulatory or artificial cycles), comparing five different groups (fresh, slow freezing-ovulatory cycle, slow freezing-artificial cycle, vitrification-ovulatory cycle, and vitrification-artificial cycle). Foetal growth disorders were defined in live-born singletons according to gestational age and sex-specific weight percentile distribution: SGA and LGA if <10th and ≥90th percentiles, respectively. Analyses were performed using linear mixed models with the ART centres as random effect. MAIN RESULTS AND THE ROLE OF CHANCE Transfers led to, respectively, 19 006, 1798, and 9195 deliveries corresponding to delivery rates per transfer of 26.1%, 17.0%, and 23.5% after fresh ET, slow-freezing FET, and vitrification FET, respectively. FET cycles were performed in either ovulatory cycles (n = 21 704) or artificial cycles (n = 34 237), leading to 5910 and 10 322 pregnancies, respectively, and corresponding to pregnancy rates per transfer of 31.6% and 33.3%. A significantly higher rate of spontaneous miscarriage was observed in artificial cycles when compared with ovulatory cycles (33.3% versus 21.4%, P  < 0.001, in slow freezing groups and 31.6% versus 21.8%, P  < 0.001 in vitrification groups). Consequently, a lower delivery rate per transfer was observed in artificial cycles compared with ovulatory cycles both in slow freezing and vitrification groups (15.5% versus 18.9%, P  < 0.001 and 22.8% versus 24.9%, P  < 0.001, respectively). Among a total of 26 585 live-born singletons, 16 413 babies were born from fresh ET, 1644 from slow-freezing FET, and 8528 from vitrification FET. Birthweight was significantly higher in the FET groups than in the fresh ET group, with no difference between the two freezing techniques. Likewise, LGA rates were higher and SGA rates were lower in the FET groups compared with the fresh ET group whatever the method used for embryo freezing. In a multivariable analysis, the risk of LGA following FET was significantly increased in artificial compared with ovulatory cycles. In contrast, the risk of LGA was not associated with either the freezing procedure (vitrification versus slow freezing) or the embryo stage (cleaved embryo versus blastocyst) at freezing. Regarding the vitrification method, the risk of LGA was not associated with either the vitrification medium used or the embryo stage. LIMITATIONS, REASONS FOR CAUTION No data were available on maternal context, such as parity, BMI, infertility cause, or maternal comorbidities, in the French national database. In particular, we cannot exclude that the increased risk of LGA observed following FET with artificial cycles may, at least partially, be associated with a confounding effect of some maternal factors. No information about embryo culture and incubation conditions was available. Most of the vitrification techniques were performed using the same device and with two main vitrification media, limiting the validity of a comparison of risk for LGA according to the device or vitrification media used. WIDER IMPLICATIONS OF THE FINDINGS Our results seem reassuring, since no potential foetal growth disorders following embryo vitrification in comparison with slow freezing were observed. Even if other factors are involved, the endometrial preparation treatment seems to have the greatest impact on LGA risk following FET. FET during ovulatory cycles could minimize the risk for foetal growth disorders. STUDY FUNDING/COMPETING INTEREST(S) This work has received funding from the French Biomedicine Agency (Grant number: 19AMP002). None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER N/A. [ABSTRACT FROM AUTHOR]

Study Question: Is interleukin-10 (IL-10) anti-fibrotic in endometriosis?Summary Answer: IL-10 is not anti-fibrotic but pro-fibrotic in endometriosis, because IL-10 treatment of endometriotic stromal cells in vitro promotes myofibroblast proliferation and collagen type I protein expression.What Is Known Already: We previously showed that persistent activation of signal transducer and activator of transcription 3 (STAT3) via IL-6 trans-signaling promotes fibrosis of endometriosis. Studies showed marked anti-fibrotic effects of IL-10 via the STAT3 signaling pathway, which is generally considered to be anti-inflammatory, in various organs.Study Design, Size, Duration: Endometrial and/or endometriotic samples of 54 patients who had histological evidence of deep endometriosis, and endometrial samples from 30 healthy fertile women were analyzed.Participants/materials, Setting, Methods: The effects of IL-10/STAT3 signaling as well as inhibition of STAT3 activation by knockdown of STAT3 gene on the pro-fibrotic phenotype in endometrial and endometriotic stromal cells in vitro were investigated. Then, the effects of various time points of IL-10 treatment in combination with transforming growth factor (TGF)-β1 and/or IL-6/soluble IL-6 receptor (sIL-6R) on the profibrotic phenotype of endometrial and endometriotic stromal cells were investigated.Main Results and the Role Of Chance: IL-10 induced pro-fibrotic phenotype (cell proliferation, collagen type I synthesis, α-smooth muscle actin positive stress fibers and collagen gel contraction) of endometriotic stromal cells. Knockdown of STAT3 gene decreased the IL-10 induced pro-fibrotic phenotype of endometriotic stromal cells. In contrast, IL-10 had no significant effects on pro-fibrotic phenotype of endometrial stromal cells of healthy women. Sequential IL-10 treatment with or without TGF-β1 and/or IL-6/sIL-6R induced persistent activation of STAT3 and significantly increased proliferation of myofibroblasts (cells with α-smooth muscle actin positive stress fibers) and protein expression of collagen type I in endometriotic stromal cells. TGF-β1 and/or IL-6/sIL6RIL-6/sIL6R treatment significantly increased tissue inhibitor of metalloproteinase 1 (TIMP1) protein expression, whereas IL-10 had no significant effects. Knockdown of STAT3 gene significantly decreased the TGF-β1 and/or IL-6/sIL6R induced TIMP1 protein expression. In contrast, pre-treatment with IL-10 before TGF-β1 and/or IL-6/sIL-6R treatment and sequential IL-10 treatment with or without TGF-β1 and/or IL-6/sIL-6R significantly decreased proliferation of fibroblasts (cells without α-smooth muscle actin positive stress fibers) and collagen type I protein expression in endometrial stromal cells of healthy women.Large Scale Data: N/A.Limitations, Reasons For Caution: Given the large number of complex interactions and signaling pathways of pro- and anti-inflammatory mediators that are involved in the pathophysiology of endometriosis, the present study investigated only a very small portion of the whole. Further in vivo studies are required to validate the present findings.Wider Implications Of the Findings: Inflammatory mediators in the pathophysiology of endometriosis have been extensively investigated as potential therapeutic targets. However, the present study showed that anti-inflammatory signals of IL-10 and IL-6 through persistent STAT3 activation may promote endometriosis fibrosis. Therapeutic strategies, such as suppression of 'inflammation', might dysregulate the cross-regulation of 'pro- and anti-inflammatory mediators', leading to detrimental effects in patients with endometriosis, such as fibrosis. To develop new, but not deleterious, therapeutic strategies, studies are required to investigate whether, how and what 'anti-inflammatory mediators' along with pro-inflammatory mediators are involved in individual patients with endometriosis.Study Funding/competing Interest(s): This study was supported in part by KARL STORZ SE & Co. KG (Tuttlingen, Germany). The authors have no conflict of interest to disclose. [ABSTRACT FROM AUTHOR]

Purpose: To dynamically assess the evolution of live birth predictive factors' impact throughout the in vitro fertilization (IVF) process, for each fresh and subsequent frozen embryo transfers. Methods: In this multicentric study, data from 13,574 fresh IVF cycles and 6,770 subsequent frozen embryo transfers were retrospectively analyzed. Fifty-seven descriptive parameters were included and split into four categories: (1) demographic (couple's baseline characteristics), (2) ovarian stimulation, (3) laboratory data, and (4) embryo transfer (fresh and frozen). All these parameters were used to develop four successive predictive models with the outcome being a live birth event. Results: Eight parameters were predictive of live birth in the first step after the first consultation, 9 in the second step after the stimulation, 11 in the third step with laboratory data, and 13 in the 4th step at the transfer stage. The predictive performance of the models increased at each step. Certain parameters remained predictive in all 4 models while others were predictive only in the first models and no longer in the subsequent ones when including new parameters. Moreover, some parameters were predictive in fresh transfers but not in frozen transfers. Conclusion: This work evaluates the chances of live birth for each embryo transfer individually and not the cumulative outcome after multiple IVF attempts. The different predictive models allow to determine which parameters should be taken into account or not at each step of an IVF cycle, and especially at the time of each embryo transfer, fresh or frozen. [ABSTRACT FROM AUTHOR]

Study Question: Is activation of signal transducer and activator of transcription 3 (STAT3) via interleukin-6 (IL-6) trans-signaling involved in fibrosis of endometriosis?Summary Answer: Persistent activation of STAT3 via IL-6 trans-signaling is involved in fibrosis of endometriosis.What Is Known Already: Our previous study showed that sustained low-grade inflammation promotes a fibrotic phenotype in endometriotic stromal cells. However, the underlying mechanisms of the establishment of non-resolving, low-grade inflammation in endometriosis remain to be clarified.Study Design, Size, Duration: Endometrial and/or endometriotic samples of 60 patients who had histological evidence of deep endometriosis and endometrial samples from 32 healthy fertile women were analyzed.Participants/materials, Setting, Methods: The effects of priming with ligands of Toll-like receptors (TLRs) 2, 3 and 4 on secretion of inflammatory mediators (tumor necrosis factor-α, C-X-C motif chemokine ligand-10 [CXCL-10], IL6 and IL-10) after a second challenge with TLR ligands in endometrial and endometriotic stromal cells were investigated. Then, the effects of IL-6/soluble (s) IL-6 receptor (R)/STAT3 signaling, as well as inhibition of STAT3 activation by knockdown of STAT3 or pharmacological inhibition (S3I-201), on the pro-fibrotic phenotype in endometrial and endometriotic stromal cells in vitro were investigated.Main Results and the Role Of Chance: Priming with TLR ligands for 4 h had no significant effects, whereas 24 h of priming significantly decreased secretion of IL-6, after a second challenge in endometrial stromal cells of healthy women. In endometriotic stromal cells, whereas 24 h of priming had no significant effects, priming with TLR ligands for 4 h significantly increased secretion of IL-6 after a second challenge. IL-6/soluble IL-6 receptor (sIL-6R) induced a pro-fibrotic phenotype (cell proliferation, collagen type I synthesis, α-smooth muscle actin positive stress fibers, cell migration and collagen gel contraction) as well as nuclear factor-kappa B (NF-κB) activation of endometriotic stromal cells. In contrast, IL-6/sIL-6R had no significant effects on either a pro-fibrotic phenotype or NF-κB activation of endometrial stromal cells of healthy women. Stimulation with transforming growth factor (TGF)-β1 and/or IL-6/sIL-6R for 1 h and 48 h activated STAT3, but induced very low or no suppressor of cytokine signaling (SOCS) 1 and 3 protein expression in endometriotic stromal cells. In endometrial stromal cells of healthy women, IL-6/sIL-6R-induced STAT3 and SOCS1/3 expression at 1 h, whereas no STAT3 activation was detected at 48 h. Knockdown of STAT3 gene or S3I-201 (a STAT3 inhibitor) decreased the IL-6/sIL-6R-induced pro-fibrotic phenotype as well as NF-κB activation and TGF-β1-induced cell proliferation of endometriotic stromal cells.Large Scale Data: N/A.Limitations, Reasons For Caution: In vivo studies are required to confirm the present in vitro results. However, it remains challenging to mimic non-resolving chronic inflammation in animal models, as active inflammation can resolve spontaneously.Wider Implications Of the Findings: Dysfunction of negative regulators of IL-6/sIL-6R/STAT3 signaling may cause persistent activation of STAT3 in endometriosis. Since STAT3 activation in the endometrium is essential for successful embryo implantation, treatment with STAT3 inhibitors would not be appropriate for women wishing to conceive. However, targeting impaired negative regulation of IL-6/sIL-6R/STAT3 signaling may still represent a promising avenue for the treatment of endometriosis.Study Funding/competing Interest(s): This study was supported in part by the KARL STORZ SE & Co. KG (Tuttlingen, Germany). There are no conflicts of interest. [ABSTRACT FROM AUTHOR]

Objectives Patients with RA have a higher prevalence of infertility than the general population. This study sought to examine the impact of RA disease activity and treatments on ovarian reserve measured by serum anti-Müllerian hormone (AMH) levels in the ESPOIR cohort. We sought to better define the indications for fertility preservation. Methods Patients and serum analysis data were derived from the French national cohort ESPOIR. Enrolled patients (n  = 102; 18–37-year-olds) fulfilled ACR/EULAR 2010 criteria for RA. Serum AMH levels were measured at T0, T6, T12, T24 and T36 months post-diagnosis. The impacts of RA activity (DAS28 and CRP level) and treatments (MTX only or with other medications) were evaluated at each study visit. Results A gradual decrease in patients' serum AMH levels was observed over time, in line with the descending curve described for healthy women. Serum AMH levels of RA patients in comparison with the values considered normal for age did not reveal any significant differences (P > 0.05). We did not observe any impact of RA treatments. We demonstrated an inverse correlation between AMH variation and disease activity (DAS28: r = –0.27, P = 0.003; CRP: r = –0.16, P = 0.06). Conclusion This is the first study to determine serum AMH levels of a large cohort of RA patients over 36 months. Rapid disease activity control appears to be required to limit changes in the ovarian reserve. Fertility preservation is not likely to be necessary if inflammation is promptly controlled. ClinicalTrials.gov Identifier NCT03666091. [ABSTRACT FROM AUTHOR]

Copyright of Médecine de la Reproduction is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Médecine de la Reproduction is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Endometriosis are characterized by dense fibrous tissue. Numerous studies have investigated roles of inflammation on the pathophysiology of endometriosis. However, the interplay of inflammation and fibrosis remains to be clarified. Here we show that low levels of interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNFα) promoted a fibrotic phenotype, whereas high levels of IL-1β and TNFα inactivated the fibrotic phenotype of endometriotic stromal cells (Ectopic-ES). IL-1β 10 pg/mL and TNFα 100 and 1,000 pg/mL had minimal effects, whereas the highest dose of IL-1β (100 pg/mL) significantly decreased collagen gel contraction in Ectopic-ES. Furthermore, in Ectopic-ES, low levels of IL-1β (1 pg/mL) and/or TNFα 10 pg/mL significantly increased Col I mRNA expression, whereas higher doses of IL-1β (10 and/or 100 pg/mL) and/or TNFα (100 and/or 1,000 pg/mL) significantly decreased Col I and/or αSMA mRNA expression and the percentage of cells with Col I + and/or αSMA + stress fibers. In contrast, in either menstrual endometrial stromal cells of patients with endometriosis or those of healthy women, varying doses of IL-1β and/or TNFα had no significant effects on either Col I or αSMA mRNA/protein expression. The present findings bring into question whether we should still continue to attempt anti-inflammatory treatment strategies for endometriosis. [ABSTRACT FROM AUTHOR]

Background and Purpose: A high recurrence rate after medical treatment is a major clinical problem for patients with endometriosis. Here, we have evaluated the in vitro effects of combined treatment with MK2206 (an AKT inhibitor) + chloroquine on cell growth and regrowth of endometriotic stromal cells and the in vivo effects on endometriotic implants in a mouse xenograft model of endometriosis.Experimental Approach: We evaluated the effects of autophagy inhibition by knockdown of the ATG13, Beclin-1 and ATG12 genes and pharmacological agents (chloroquine, bafilomycin A1 or 3-methyalanine) individually and in combination with MK2206 on cell growth and/or cell regrowth of endometriotic stromal cells in vitro. Furthermore, we evaluated treatment with MK2206 + chloroquine on endometriotic implants in a mouse xenograft model of endometriosis.Key Results: Combined treatment with MK2206 and chloroquine markedly reduced cell growth and regrowth after discontinuation of treatment in endometriotic stromal cells compared with cells treated with either drug alone. Autophagy inhibition by ATG13, Beclin-1 or ATG12 gene knockdown only affected regrowth of endometriotic stromal cells, but not endometrial stromal cells from the same patients, after a 72 h discontinuation of the combined treatment. Furthermore, combined treatment reduced the size of endometriotic implants, whereas no effects on endometriotic implants treated with either drug alone were observed in a mouse xenograft model of endometriosis.Conclusions and Implications: The present findings suggest that a novel strategy for treatment of endometriosis may involve decreasing the number of endometriotic cells that can survive treatment and then preventing regrowth by autophagy inhibition. [ABSTRACT FROM AUTHOR]

Introduction: Optimal surgical treatment of rectovaginal endometriosis remains a controversial topic. The objective of this study was to evaluate long-term postoperative outcomes after rectal shaving or colorectal resection for rectovaginal endometriosis.Material and Methods: 195 patients underwent surgery (172 managed by shaving, 23 by colorectal resection) between January 2000 and June 2013 for rectovaginal endometriosis (>2 cm) involving at least the serosa of the rectum. Primary outcome measures were pain and fertility. Secondary outcome measures were complications, recurrence rates and quality of life.Results: Mean follow-up was 60 ± 42 months in the shaving group and 67 ± 47 months in the resection group. The mean VAS score for pelvic pain between the pre and postoperative period decreased from 5.5 ± 3.5 (shaving group) and 7.3 ± 2.9 (resection group) to 2.3 ± 2.4 (p < 0.001) and 2.0 ± 1.8 (p < 0.001), respectively. For dysmenorrhea, the mean baseline VAS score fell postoperatively from 7.7 ± 2.8 (shaving group) and 8.2 ± 2.6 (resection group) to 3.3 ± 2.9 (p < 0.001) and 2.7 ± 2.7 (p < 0.001), respectively. Pregnancy rates were 73% for shaving and 69% for resection. Major complications occurred in 4% of patients in the shaving group and in 26% in the resection group (p = 0.001). Thirteen patients (7.6%) from the shaving group and none from the resection group were reoperated for suspicion of endometriosis recurrence (p = 0.37). Postoperative quality of life scores revealed no differences between the two groups.Conclusion: Our study demonstrates that rectal shaving, when feasible for rectovaginal nodule (>2 cm) infiltrating the digestive serosa, has equal impact on pain and pregnancy rates compared with colorectal resection at long-term follow-up, with low complication and favorable pregnancy rates. [ABSTRACT FROM AUTHOR]

Background: Hysteroscopic reliability may be influenced by the experience of the operator and by a lack of morphological diagnostic criteria for endometrial malignant pathologies. The aim of this study was to evaluate the diagnostic accuracy and the inter-observer agreement (IOA) in the management of abnormal uterine bleeding (AUB) among different experienced gynecologists.Methods: Each gynecologist, without any other clinical information, was asked to evaluate the anonymous video recordings of 51 consecutive patients who underwent hysteroscopy and endometrial resection for AUB. Experts (>500 hysteroscopies), seniors (20-499 procedures) and junior (≤19 procedures) gynecologists were asked to judge endometrial macroscopic appearance (benign, suspicious or frankly malignant). They also had to propose the histological diagnosis (atrophic or proliferative endometrium; simple, glandulocystic or atypical endometrial hyperplasia and endometrial carcinoma). Observers were free to indicate whether the quality of recordings were not good enough for adequate assessment. IOA (k coefficient), sensitivity, specificity, predictive value and the likelihood ratio were calculated.Results: Five expert, five senior and six junior gynecologists were involved in the study. Considering endometrial cancer and endometrial atypical hyperplasia, sensitivity and specificity were respectively 55.5 % and 84.5 % for juniors, 66.6 % and 81.2 % for seniors and 86.6 % and 87.3 % for experts. Concerning endometrial macroscopic appearance, IOA was poor for juniors (k = 0.10) and fair for seniors and experts (k = 0.23 and 0.22, respectively). IOA was poor for juniors and experts (k = 0.18 and 0.20, respectively) and fair for seniors (k = 0.30) in predicting the histological diagnosis.Conclusions: Sensitivity improves with the observer's experience, but inter-observer agreement and reproducibility of hysteroscopy for endometrial malignancies are not satisfying no matter the level of expertise. Therefore, an accurate and complete endometrial sampling is still needed. [ABSTRACT FROM AUTHOR]

Copyright of MT: Médecine de la Reproduction, Gynécologie et Endocrinologie is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of MT: Médecine de la Reproduction, Gynécologie et Endocrinologie is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of MT: Médecine de la Reproduction, Gynécologie et Endocrinologie is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of MT: Médecine de la Reproduction, Gynécologie et Endocrinologie is the property of John Libbey Eurotext Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Study Question: Can deep infiltrating endometriotic stromal cells (DES) sense changes in extracellular matrix (ECM) stiffness and respond to them?Summary Answer: Soft matrices inhibit cell proliferation and inactivate the fibrotic phenotype of DES in vitro.What Is Known Already: Deep infiltrating endometriosis (DIE) is characterized histologically by dense fibrous tissue. Tissue stiffening is a hallmark of fibrosis. Studies show that matrix stiffness is involved in the progression of numerous diseases, including cancer and fibrosis. However, no studies to date have investigated whether tissue stiffening could influence cell behavior in DIE. Previous in vitro studies typically analyzed cells grown on rigid plastic or glass substrates with stiffness in the gigapascal (gPa) range, which is much stiffer than that occurring in vivo. To investigate how changes in ECM stiffness affect the behavior of DES, it is critical to model in vivo tissue compliance conditions in vitro.Study Design, Size, Duration: For this laboratory study, paired endometrial and endometriotic samples from 40 patients who had histological evidence of DIE and endometrial samples from 23 patients without endometriosis were analyzed (uterine fibroma: n = 10, tubal infertility: n = 13).Participants/materials, Setting, Methods: All participants were 20-37 years old and had regular menstrual cycles of 26-32 days. The abundance of F-actin, alpha smooth muscle actin (αSMA), Ki67, and procollagen type I in DES and endometrial stromal cells (EES) on polyacrylamide gel substrates of varying stiffness (2, 4, 8, 16 and/or 30 kPa) was determined by immunofluorescence confocal microscopy. mRNA level of type I collagen, matrix metalloproteinase-1 (MMP-1), MMP-14 and cyclin D1 was measured by real-time PCR. The cellular proliferation index (CPI), assessed as the percentage of Ki67-positive cells among the total number of nuclei stained by 4',6-diamidino-2-phenylindole (DAPI) was determined.Main Results and the Role Of Chance: Increased matrix stiffness induced F-actin stress fiber formation in both EES and DES, whereas αSMA-containing stress fibers were induced only in DES. Furthermore, increased stiffness increased the CPI in both EES (16 or 30 kPa versus 2 kPa, P < 0.05) and DES (16 or 30 kPa versus 2, 4 or 8 kPa, P < 0.05). Increased stiffness increased the percentage of procollagen I-positive cells as well as mRNA levels of type I collagen in both EES and DES in a matrix stiffness-dependent manner (2, 8 and 30 kPa) (P < 0.05). Increased stiffness also increased MMP-14 mRNA levels in EES (30 versus 2 kPa, P < 0.05), but decreased MMP-1 mRNA levels in DES in a matrix stiffness-dependent manner (2, 8 and 30 kPa; P < 0.05). Treatment with transforming growth factor (TGF)-β1 further increased type I collagen mRNA levels in both EES and DES when compared with cells grown on a substrate of the same stiffness (2, 8 or 30 kPa, with versus without TGF-β1, P < 0.05). Treatment with TGF-β1 also increased MMP-1 (8 or 30 kPa, P < 0.05 versus no TGF-β1) and MMP-14 mRNA levels (2, 8 or 30 kPa, P < 0.05 versus no TGF-β1) in EES, but decreased MMP-1 mRNA levels (2, 8 or 30 kPa, P < 0.05 versus no TGF-β1) in DES. On a soft substrate (2 kPa), both EES and DES exhibited a small rounded morphology with diffuse labeling for F-actin. No F-actin-positive stress fibers were observed in either EES or DES grown on 2 kPa substrates. There were more Ki67-positive EES when grown on 2, 4 or 8 kPa compared with Ki67-positive DES (P < 0.05).Limitations, Reasons For Caution: A tremendous gap exists between the present in vitro model and in vivo deep endometriotic tissues. Cell culture systems that more closely mimic the cellular complexity typical of in vivo endometriotic tissues are required to develop novel strategies for treatment of DIE. A disadvantage of polyacrylamide is its cytotoxicity but in the two-dimensional culture models used here, where cells are seeded above the polyacrylamide gel, this should not have a major impact. Finally, the soft substrates we used in vitro (2 and 4 kPa) may represent the elasticity of the endometrium in vivo, however, currently there are no data regarding tissue stiffness in DIE in vivo.Wider Implications Of the Findings: Hormonal suppressive therapy is not usually effective for treating DIE. Interrupting the mechanical interactions between endometriotic fibroblasts and aberrant ECM may be a novel strategy for treatment of DIE.Study Funding/competing Interests: This study was supported in part by Karl Storz Endoscopy & GmbH (Tuttlingen, Germany). No competing interests are declared. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the efficiency of an original slow freezing protocol on the quality and function of human ovarian cortex. Methods: Human ovarian tissues were cryopreserved using a freezing medium supplemented with propanediol and raffinose as cryoprotectants and antioxidants (L-glutamine, taurine). Samples were then frozen using a faster cooling rate than the usual one. Viability and morphology of follicles, DNA fragmentation in follicles and stroma as well as histology of the vascular endothelium were analyzed before and after freezing/thawing. Moreover, a functional analysis was performed based on the evaluation of follicular growth and development in thawed ovarian tissues that were cultured in vitro. Results: Our freezing/thawing protocol allows preservation of a high proportion of viable follicles and the preservation of the different follicle developmental stages ( p > 0.05 versus fresh control). 70.5 ± 5.2 % of follicles retained an intact morphology after cryopreservation ( p = 0.04). Stroma cells but not follicles exhibited a slight increase of DNA fragmentation after thawing ( p < 0.05). Microvessel endothelium within thawed tissues appeared to be preserved. Granulosa cells showed signs of proliferation in follicles cultured for 12 days. Secretion of 17β-oestradiol significantly increased during in vitro culture. Conclusions: This protocol leads to good preservation of ovarian integrity and functionality post-thawing and thus appears as a suitable technique of ovarian tissue cryopreservation in clinical settings. Further research could be extended to optimize conditions of in vitro culture. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of obesity in the safety of laparoscopic hysterectomy. Study Design: A retrospective study was conducted using a database of 2271 women undergoing laparoscopic hysterectomy for benign diseases between January 1995 and December 2008 at the Centre Hospitalier Universitaire Estaing (Clermont-Ferrand, France). Patients were divided into two groups according to the body mass index: <30 kg/m2 ( n=2088) and ≥30 kg/m2 ( n=183). Primary outcomes were differences in conversion rates, operating time, estimated blood loss, intraoperative complications, and early postoperative complications. Results: There was no difference in the operative time (121.3 versus 122.5 minutes; P=.71), in the difference between pre- and postoperative hemoglobin levels (1.8 versus 1.6 g/dL; P=.28), and in the conversion rate (4.6% versus 5.5%; P=.62) comparing the two groups. The overall intraoperative complication rate was 14.03% ( n=293) and 13.66% ( n=25) for nonobese and obese patients ( P=.89), respectively. The overall postoperative complication rate was 8.81% ( n=184) and 7.65% ( n=14), respectively. Conclusions: Obesity does not have an adverse effect on the feasibility and safety of laparoscopic hysterectomy in experienced hands. [ABSTRACT FROM AUTHOR]

Background: As discontinuation in in vitro fertilization (IVF) programs has been associated with a poor prognosis, one hypothesis is that some couple-specific predictive factors in IVF may be shared with opposite effect by both success (i.e. live birth) and treatment discontinuation processes. Our objective was to perform a joint analysis of these two processes to examine the hypothesis of a link between the two processes. Methods: Analyses were conducted on a retrospective cohort of 3,002 women who began IVF between 1998 and 2002 in two French IVF centers: a Parisian center and a center in a medium-sized city in central France. A shared random effects model based on a joint modelization of IVF treatment success and discontinuation was used to study the link between the two processes. Results: Success and discontinuation processes were significantly linked in the medium-sized city center, whereas they were not linked in the Parisian center. The center influenced risk of treatment discontinuation but not chance of success. The well-known inverse-J relation between the woman's age and chance of success was observed, as expected. Risk of discontinuation globally increased as the woman's age increased. Conclusions: The link between success and discontinuation processes could depend on the fertility center. In particular, the woman's decision to pursue or to discontinue IVF in a particular center could depend on the presence of other IVF centers in the surrounding area. [ABSTRACT FROM AUTHOR]

BACKGROUND: The aim of this study was to investigate HOXA-10 expression in endometrium from infertile patients with different forms of endometriosis; with uterine fibromas, or with unexplained infertility and from normal fertile women. [ABSTRACT FROM PUBLISHER]

We recently demonstrated that CO2 pneumoperitoneum at low intraperitoneal pressure (IPP) had few if any short-term effects on peritoneal dissemination when an ovarian cancer cell line was inoculated just prior to surgery. The objective of the present study was to evaluate the impact of surgical peritoneal environment on postoperative tumor growth and dissemination over time when tumors were present before surgery. On day-7, C57BJ6 mice received an intraperitoneal inoculation of a mouse ovarian cancer cell line (ID8). On day 0, mice were randomized into four groups: anesthesia alone, CO2 pneumoperitoneum at a low (2 mmHg) or high (8 mmHg) IPP, or laparotomy. Groups were further subdivided into four groups of eight animals each and a laparotomy was performed to evaluate dissemination on postoperative day (POD) 1, 2, 7 or 14. Peritoneal dissemination score was significantly higher in the laparotomy group compared with in the remaining three groups on PODs 2 and 7. We detected no significant differences in the peritoneal dissemination scores among the low-IPP, high-IPP, and anesthesia groups on PODs 2 and 7. However, there were no significant differences in the peritoneal dissemination score among the three surgical groups on POD 14. Histopathological examination demonstrated that the incidence of invasion of cancer cells into the muscle layers was significantly higher in the laparotomy group than in the low-IPP and anesthesia groups on POD 14. There were no significant differences in tumor growth among the four groups. The present findings suggest that CO2 pneumoperitoneum at either high or low IPP has few if any short-term effects on peritoneal dissemination when tumors are well established before surgery. [ABSTRACT FROM AUTHOR]

The mechanisms promoting postoperative peritoneal tumor dissemination are unclear. This study aimed to investigate postoperative tumor dissemination over time on both tissue and molecular levels. For this study, C57BL6 mice were randomized into four groups: anesthesia alone (control), carbon dioxide (CO2) pneumoperitoneum at low (2 mmHg) or high (8 mmHg) intraperitoneal pressure (IPP), and laparotomy. A mouse ovarian cancer cell line (ID8) was injected intraperitoneally just before surgery. The groups were further subdivided into three groups, and a laparotomy was performed to evaluate tumor dissemination on postoperative day (POD) 7, 14, or 42. The incidence of cancer cell invasion into the muscle layers of the abdominal wall was significantly higher in the laparotomy and high-IPP groups than in the low-IPP and control groups on PODs 7 and 42. Expression levels of beta 1 integrin, cMet, urokinase-type plasminogen activator (uPA), urokinase-type plasminogen activator receptor (uPAR), and type-1 plasminogen activator inhibitor (PAI-1) mRNA in the disseminated nodules were not significantly different among the four groups on POD 7. However, the expression levels of all these genes in the disseminated nodules in the laparotomy group were significantly higher on POD 14 than on POD 7. They then returned to control levels on POD 42. There were no significant differences in the expression levels of any of these genes among the groups on POD 42. The current study suggests that the molecular mechanisms underlying postoperative peritoneal tumor dissemination may differ between a laparotomy and CO2 pneumoperitoneum. Therefore, strategies targeting postoperative tumor dissemination likely will need to account for the surgical environment. [ABSTRACT FROM AUTHOR]

This case-control study was associated with a regional register of ectopic pregnancy between 1993 and 2000 in France. It included 803 cases of ectopic pregnancy and 1,683 deliveries and was powerful enough to investigate all ectopic pregnancy risk factors. The main risk factors were infectious history (adjusted attributable risk = 0.33; adjusted odds ratio for previous pelvic infectious disease = 3.4, 95% percent confidence interval (CI): 2.4, 5.0) and smoking (adjusted attributable risk = 0.35; adjusted odds ratio = 3.9, 95% CI: 2.6, 5.9 for >20 cigarettes/day vs. women who had never smoked). The other risk factors were age (associated per se with a risk of ectopic pregnancy), prior spontaneous abortions, history of infertility, and previous use of an intrauterine device. Prior medical induced abortion was associated with a risk of ectopic pregnancy (adjusted odds ratio = 2.8, 95% CI: 1.1, 7.2); no such association was observed for surgical abortion (adjusted odds ratio = 1.1, 95% CI: 0.8, 1.6). The total attributable risk of all the factors investigated was 0.76. As close associations were found between ectopic pregnancy and infertility and between ectopic pregnancy and spontaneous abortion, further research into ectopic pregnancy should focus on risk factors common to these conditions. In terms of public health, increasing awareness of the effects of smoking may be useful for ectopic pregnancy prevention. [ABSTRACT FROM PUBLISHER]

International guidelines are published to provide standardized information and fertility preservation (FP) care for adults and children. The purpose of the study was to conduct a modified Delphi process for generating FP guidelines for BGD. A steering committee identified 42 potential FP practices for BGD. Then 114 key stakeholders were asked to participate in a modified Delphi process via two online survey rounds and a final meeting. Consensus was reached for 28 items. Among them, stakeholders rated age-specific information concerning the risk of diminished ovarian reserve after surgery as important but rejected proposals setting various upper and lower age limits for FP. All women should be informed about the benefit/risk balance of oocyte vitrification—in particular about the likelihood of live birth according to age. FP should not be offered in rASRM stages I and II endometriosis without endometriomas. These guidelines could be useful for gynecologists to identify situations at risk of infertility and to better inform women with BGDs who might need personalized counseling for FP. [ABSTRACT FROM AUTHOR]

Two progesterone presentations, a vaginal application of 90 mg progesterone per day (Crinone) or 300 mg progesterone administered orally (Utrogestan), were compared for luteal phase support of patients undergoing an in-vitro fertilization (TVT) procedure. A total of 283 patients were randomly allocated to either treatment The treatment started within 24 h after the embryo transfer procedure and continued until day 30 in cases of implantation. Efficacy was assessed using the pregnancy and delivery rates. Safety was assessed through specific symptoms and usual safety monitoring. The pregnancy rates per transfer were not significantly different in the Crinone and Utrogestan groups at days 12 (Crinone 353%, Utrogestan 29.9%, P=0.55), 30 (Crinone 28.8%, Utrogestan 25.0%, P= 0.61) and 90 (Crinone 25.9%, Utrogestan 22.9%, P= 0.69). No differences in the spontaneous abortion rates were seen thereafter. The delivery rates (number of deliveries per patient; Crinone 23.0%, Utrogestan 22.2%, P= 1.00), as well as the ratio of newborn babies per embryo transferred (Crinone 11.7%, Utrogestan 11.1%, P=0.91), were not significantly different. Safety parameters were similar in both groups, except for drowsiness, which was more significantly frequent in the oral progesterone group than in the Crinone group at all time points. No serious adverse events were recorded in this study. The fact that Crinone matches the efficacy of the larger doses of progesterone used orally reflects an advantage of the transvaginal route of administration which avoids the metabolic inactivation of progesterone during its first liver pass. [ABSTRACT FROM PUBLISHER]

From their experience and from data in the literature, the authors try to define the respective place of the different treatments for endometriosis, especially those of operative laparoscopy. In cases of endometriosis-associated infertility, operative laparoscopy is the first line treatment and assisted reproductive technology (ART) the second one. Gonadotrophin-releasing hormone (GnRH) analogues are only useful in cases of extensive endometriosis to render surgery easier, and for ART. The average pregnancy rate following laparoscopic treatment is ∼50% (range 34–80%). It is poorly related to the type of endometriosis except in cases of large adhesions and tubal involvement. However, duration of infertility, age and sperm quality have a direct influence on it. Therefore the authors propose a scheme for the management of endometriosis-associated infertility. In cases of pain, laparoscopic surgery can also be used; however, drugs have a more important role in these cases, to avoid recurrent surgery. [ABSTRACT FROM PUBLISHER]

Fertility following laparoscopic treatment of benign adnexal cysts without ovarian suture was studied retrospectively. Patients with endometriomas or who were previously infertile were excluded. Thirty-eight patients treated conservatively were included, 10 after partial resection of functional cysts, 23 after an ovarian cystectomy and six after treatment of a paraovarian cyst. One patient had two cysts. The overall intrauterine pregnancy rate was 92%; one patient had an ectopic pregnancy (2.6%). From these results, we conclude that fertility following laparoscopic treatment of adnexal cysts appears to be normal. Technical guidelines to improve laparoscopic cystectomy are proposed. Key words: adnexal cysts/fertility/laparoscopic cystectomy are proposed. [ABSTRACT FROM PUBLISHER]

Endometriosis is defined as the presence of endometrial glands and stroma within extrauterine sites. Our previous study revealed an epithelial to mesenchymal transition (EMT)-like process in red peritoneal endometriosis, whereas membrane localization of E-cadherin was well maintained in epithelial cells of deep infiltrating endometriosis (DIE). Here we show that endometrial epithelial cells (EEE) grown on polyacrylamide gel substrates (PGS) of 2 kilopascal (kPa), a soft matrix, initiate a partial EMT-like process with transforming growth factor-β1 (TGF-β1) stimulation. Increasing matrix stiffness with TGF-β1 stimulation reduced the number of cell-cell contacts. Cells that retained cell-cell contacts showed decreased expression of E-cadherin and zonula occludens 1 (ZO-1) to cell-cell junctions. Few deep endometriotic epithelial cells (DEE) grown on 30-kPa PGS, which may mimic in vivo tissue compliance of DIE, retained localization of E-cadherin to cell-cell junctions with TGF-β1 treatment. Immunohistochemical analysis showed no phosphorylated Smad 2/3 nuclear localization in E-cadherin+ epithelial cells of DIE. We hypothesize that EEE may undergo an EMT-like process after attachment of endometrium to peritoneum in a TGF-β1-rich microenvironment. However, TGF-β1 signaling may be absent in DIE, resulting in a more epithelial cell-like phenotype in a rigid microenvironment. [ABSTRACT FROM AUTHOR]

Endometriosis is a common gynecological disorder responsible for infertility and pelvic pain. A complete cure for patients with endometriosis awaits new targets and strategies. Here we show that U0126 (a MEK inhibitor) and MK2206 (an AKT inhibitor) synergistically inhibit cell growth of deep endometriotic stromal cells (DES) grown on polyacrylamide gel substrates (PGS) of varying stiffness (2 or 30 kilopascal [kPa]) or plastic in vitro. No significant differences in cell proliferation were observed among DES, endometrial stromal cells of patients with endometriosis (EES) from the proliferative phase (P), EES-S (secretory phase) and EES-M (menstrual phase) compared to cells grown on a substrate of the same stiffness at both higher (U0126 [30 μM] and MK2206 [9 μM]) and lower (U0126 [15 μM] and MK2206 [4.5 μM]) combined doses. However, cell re-growth of DES after drug discontinuation was higher than that of EES-P and EES-S when cells were grown on rigid substrates at both combined doses. Combination U0126 and MK2206 treatment is more effective than each drug alone in cell growth inhibition of DES. However, further studies are required to investigate the mechanisms underlying high cell survival and proliferation after drug discontinuation for developing target therapies that prevent recurrence. [ABSTRACT FROM AUTHOR]

One case of unicornuate uterus with a cavitary rudimentary horn and unilateral extensive endometriosis was treated by laparoscopy, after three months of treatment with GnRH analogues. The rudimentary horn and the corresponding tube were removed. The post-operative course was uneventful. Laparoscopic radical management of this malformation reduces both peritoneal damage and economic cost. [ABSTRACT FROM PUBLISHER]

: BACKGROUND The aim of this study was to identify risk factors for the removal of normal ovarian tissue during laparoscopic cystectomy for endometriosis. : METHODS A total of 121 patients who had histologically confirmed ovarian endometriosis and 56 control patients who had other histologically confirmed benign cysts were included for the present analysis. The blocks of removed tissue were sectioned at 120 µm intervals and a total of five sections were analyzed for each ovarian cyst. Eight variables (age, pre-operative medical treatment, previous surgery for ovarian endometriosis, single or multiple cysts, size of the largest cyst, side of cyst, co-existence of deep endometriosis, revised American Society for Reproductive Medicine classification) were evaluated using a generalized linear modeling analysis to identify major factors associated with the removal of normal ovarian tissue. : RESULTS Normal ovarian tissue adjacent to the cyst wall was detected in 71 patients (58.7%) with endometriosis, whereas normal ovarian tissue was removed from only three patients (5.4%) with other benign cysts. A significant factor that was independently associated with the removal of normal ovarian tissue with ovarian endometriosis was pre-operative medical treatment. : CONCLUSIONS The present retrospective, controlled study suggests that pre-operative medical treatment might be a risk factor for the removal of normal ovarian tissue during laparoscopic cystectomy for ovarian endometriosis. [ABSTRACT FROM AUTHOR]