Should the Treatment of Patients with Repeated Embryo Implantation Failure Be Adapted as a Function of the Endometrial Cytokine Profile? A Single-Center Experience.

Repeated embryo implantation failures (RIF) is a source of distress and frustration for patients and clinicians alike. Today's approaches for treating RIF are largely empirical and have limited effectiveness. The main causes of RIF are poor endometrial receptivity and poor-quality embryos. Recent studies have suggested the involvement of immune dysregulation due to an imbalance between T-helper (Th) 1 and Th2 cytokines; this opens up perspectives for treating women with RIF and increasing the implantation rate. We conducted an interventional, longitudinal, prospective cohort study of the impact of correcting the cytokine imbalance on the clinical pregnancy rate in women with RIF. Seventy-seven women with RIF underwent an endometrial biopsy during the implantation window. The cytokine profile was evaluated by studying the activation and maturation of uterine natural killer (uNK) cells, the IL-15/Fn-14 mRNA ratio (a biomarker of uNK activation/maturation), and the IL-18/TWEAK mRNA ratio (a marker of angiogenesis and the Th1/Th2 balance). Personalized treatment was initiated for women with an abnormal endometrial cytokine profile (hyper-activation or hypo-activation). We documented the clinical pregnancy rate after subsequent embryo transfers. In total, 72.7% (56/77) of patients had an abnormal endometrial cytokine profile (hyper-activation in 68.8% (n = 53) and hypo-activation in 3.9% (n = 3). After treatment (or not) as a function of the endometrial profile, the overall clinical pregnancy rate was 30.2%. Our results indicated a potential positive effect of appropriate treatment on the ongoing pregnancy rate in women with RIF, despite the small number of cases analyzed. The results must now be validated in randomized studies with larger numbers of well-characterized patients. By applying a previously published decision tree, this treatment approach could be implemented in clinics worldwide.

The effect of obesity on uterine receptivity is mediated by endometrial extracellular vesicles that control human endometrial stromal cell decidualization and trophoblast invasion.

The objectives of the present study were to determine whether obesity impacts human decidualization and the endometrial control of trophoblast invasion (both of which are required for embryo implantation) and evaluate the potential involvement of endometrial extracellular vesicles (EVs) in the regulation of these physiological processes. Using primary human cell cultures, we first demonstrated that obesity is associated with significantly lower in vitro decidualization of endometrial stromal cells (ESCs). We then showed that a trophoblastic cell line's invasive ability was greater in the presence of conditioned media from cultures of ESCs from obese women. The results of functional assays indicated that supplementation of the culture medium with EVs from nonobese women can rescue (at least in part) the defect in in vitro decidualization described in ESCs from obese women. Furthermore, exposure to endometrial EVs from obese women (vs. nonobese women) was associated with significantly greater invasive activity by HTR-8/SVneo cells. Using mass-spectrometry-based quantitative proteomics, we found that EVs isolated from uterine supernatants of biopsies from obese women (vs. nonobese women) presented a molecular signature focused on cell remodelling and angiogenesis. The proteomics analysis revealed two differentially expressed proteins (fibronectin and angiotensin-converting enzyme) that might be involved specifically in the rescue of the decidualization capacity in ESCs from obese women; both of these proteins are abundantly present in endometrial EVs from nonobese women, and both are involved in the decidualization process. In conclusion, our results provided new insights into the endometrial EVs' pivotal role in the poor uterine receptivity observed in obese women.

The Eutopic Endometrium Proteome in Endometriosis Reveals Candidate Markers and Molecular Mechanisms of Physiopathology.

Endometriosis is a common chronic gynaecological disease causing various symptoms, such as infertility and chronic pain. The gold standard for its diagnosis is still laparoscopy and the biopsy of endometriotic lesions. Here, we aimed to compare the eutopic endometrium from women with or without endometriosis to identify proteins that may be considered as potential biomarker candidates. Eutopic endometrium was collected from patients with endometriosis (n = 4) and women without endometriosis (n = 5) during a laparoscopy surgery during the mid-secretory phase of their menstrual cycle. Total proteins from tissues were extracted and digested before LC-MS-MS analysis. Among the 5301 proteins identified, 543 were differentially expressed and enriched in two specific KEGG pathways: focal adhesion and PI3K/AKT signaling. Integration of our data with a large-scale proteomics dataset allowed us to highlight 11 proteins that share the same trend of dysregulation in eutopic endometrium, regardless of the phase of the menstrual cycle. Our results constitute the first step towards the identification of potential promising endometrial diagnostic biomarkers. They provide new insights into the mechanisms underlying endometriosis and its etiology. Our results await further confirmation on a larger sample cohort.

For patients with non-obstructive azoospermia, the outcome of testicular sperm extraction correlates with self-esteem, sexual health and the quality of the couple's relationship.

BACKGROUND: A very small number of studies have indicated that azoospermia or negative testicular sperm extraction (TESE) outcomes are linked to depression or erectile dysfunction. However, the data are often weak, conflicting and gathered with non-validated questionnaires. Hence, we performed a cross-sectional study of 44 men with non-obstructive azoospermia. Levels of self-esteem and the quality of the couple's sex life and overall relationship were assessed with validated questionnaires before and after the TESE procedure as a function of the TESE outcome. RESULTS: A positive TESE outcome (n = 24) was associated with a statistically significant increase in self-esteem (particularly with regard to family aspects), sexual health and couples' adjustment quality. In contrast, a negative TESE outcome (n = 20) was associated with statistically significant decreases in self-esteem, erectile function, intercourse satisfaction, orgasmic function, couples' adjustment quality and all aspects of the couple's relationship (consensus, cohesion, satisfaction and affection). CONCLUSION: For men with non-obstructive azoospermia (NOA), negative TESE outcomes may have a negative impact on self-esteem and the quality of the couple's sex life and overall relationship. This should be borne in mind when counselling men with NOA and their partners to (ideally) help them to cope with and decrease the harmful impacts of azoospermia and negative TESE.

RESUME: INTRODUCTION: Quelques études concernant l'azoospermie ou les résultats négatifs de l'extraction de sperme testiculaire (TESE) montrent que ces résultats peuvent être liés à la dépression ou aux dysfonctions érectiles. Cependant, les données sont souvent faibles, contradictoires et recueillies à l'aide de questionnaires non validés. Nous avons donc réalisé une étude transversale auprès de 44 hommes atteints d'azoospermie non obstructive (ANO). Les niveaux d'estime de soi et la qualité de la vie sexuelle du couple et de la relation globale ont été évalués à l'aide de questionnaires validés avant et après la procédure TESE en fonction du résultat de la TESE. RéSULTATS: Un résultat positif de TESE (n = 24) a été associé à une augmentation statistiquement significative de l'estime de soi (en particulier en ce qui concerne les aspects familiaux), de la santé sexuelle et de la qualité de l'adaptation du couple. En revanche, un résultat négatif de TESE (n = 20) a été associé à une diminution statistiquement significative de l'estime de soi, de la fonction érectile, de la satisfaction des rapports sexuels, de la fonction orgasmique, de la qualité de l'adaptation du couple et de tous les aspects de la relation de couple (consensus, cohésion, satisfaction et affection). CONCLUSION: Chez les hommes atteints d'ANO, une TESE négative peut avoir un impact négatif sur l'estime de soi et la qualité de la vie sexuelle et de la relation globale du couple. Il convient de garder cela à l'esprit lors du conseil aux hommes atteints d'ANO et à leurs partenaires afin de les aider (idéalement) à faire face aux impacts néfastes de l'azoospermie et de la TESE négative et à les réduire.

Preimplantation factor modulates trophoblastic invasion throughout the decidualization of human endometrial stromal cells.

BACKGROUND: Successful human embryo implantation requires the differentiation of endometrial stromal cells (ESCs) into decidual cells during a process called decidualization. ESCs express specific markers of decidualization, including prolactin, insulin-like growth factor-binding protein-1 (IGFBP-1), and connexin-43. Decidual cells also control of trophoblast invasion by secreting various factors, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases. Preimplantation factor (PIF) is a recently identified, embryo-derived peptide with activities at the fetal-maternal interface. It creates a favorable pro-inflammatory environment in human endometrium and directly controls placental development by increasing the human trophoblastic cells' ability to invade the endometrium. We hypothesized that PIF's effects on the endometrium counteract its pro-invasive effects. METHODS: We tested sPIF effect on the expression of three decidualization markers by RT-qPCR and/or immunochemiluminescence assay. We examined sPIF effect on human ESC migration by performing an in vitro wound healing assay. We analyzed sPIF effect on endometrial control of human trophoblast invasion by performing a zymography and an invasion assay. RESULTS: Firstly, we found that a synthetic analog of PIF (sPIF) significantly upregulates the mRNA expression of IGFBP-1 and connexin-43, and prolactin secretion in ESCs - suggesting a pro-differentiation effect. Secondly, we showed that the HTR-8/SVneo trophoblastic cell line's invasive ability was low in the presence of conditioned media from ESCs cultured with sPIF. Thirdly, this PIF's anti-invasive action was associated with a specifically decrease in MMP-9 activity. CONCLUSION: Taken as a whole, our results suggest that PIF accentuates the decidualization process and the production of endometrial factors that limit trophoblast invasion. By controlling both trophoblast and endometrial cells, PIF therefore appears to be a pivotal player in the human embryo implantation process.

Office hysteroscopy before first in vitro fertilization. A randomized controlled trial.

BACKGROUND: Implantation failure remains a mystery since decades. This procedure needs a "top quality embryo" and a "normal" uterine cavity. To assess uterine cavity before first in vitro fertilization (IVF), many diagnostic tools could be used. Hysteroscopy remains the gold standard to diagnose and treat intra-uterine anomalies. However, it is not clearly recommanded to offer an office hysteroscopy before first IVF when transvaginal ultrasound (TVUS) and hysterosalpingography (HSG) were normal. PURPOSE: This study aimed to assess the role of office hysteroscopy before first IVF when no intra-uterine anomalies are suspected. BASIC PROCEDURES: We conducted a randomized controlled trial including 171 women scheduled for their first IVF. Women were assigned to either Group I: office hysteroscopy before IVF or Group II: immediate IVF. We included women aged less than 40 years, having regular cycles, FSH levels less than10UI/l, antral follicular count ≥12, normal TVUS and HSG. Their body mass index (BMI) ranged from 19 to 30 kg/m2. We excluded patients known having severe endometriosis, polycystic ovarian syndrome (PCOS) and oocyte receivers. The primary outcome were livebirth rate and clinical pregnancy rate. MAIN FUNDINGS: Between january 2016 and september 2017, we randomly assigned 171 women to either Group I (n = 84) or Group II (n = 87). Hysteroscopy was done in the mid-follicular phase immediately before IVF. Baseline characteristics and IVF features were comparable between groups except for the IVF protocol. Live birth rate was 23,9% in Group I versus 19,3% in Group II. (p = 0,607). Clinical Pregnancy rate was 32,4% in Group I versus 21,7% in Group II. (p = 0,326). No statistical significance was observed for neither miscarriage rate nor multiple pregnancy rate. Hysteroscopy showed 30% unsuspected intra-uterine anomalies: 11 intra-uterine adhesions, 7 polyps, 7 clinical endometritis and one fibroid print. Therapeutic hysteroscopy was done only for 6 intra-uterine adhesions and 3 polyps. Other anomalies did not require operative hysteroscopy. Visual analog score during hysteroscopy was 4,69 +/-2,892. 5 women (6%) of Group I experienced discomfort during diagnostic hysteroscopy. Only one patient had vagal syncope. No further complications were observed. PRINCIPAL CONCLUSIONS: Office hysteroscopy before first IVF seems not improve IVF results. Minimal intra-uterine anomalies not diagnosed by transvaginal ultrasound and hysterosalpingography do not seem to reduce IVF results.

Adiponectin regulates glycogen metabolism at the human fetal­maternal interface

Throughout the entire first trimester of pregnancy, fetal growth is sustained by endometrial secretions, i.e. histiotrophic nutrition. Endometrial stromal cells (EnSCs) accumulate and secrete a variety of nutritive molecules that are absorbed by trophoblastic cells and transmitted to the fetus. Glycogen appears to have a critical role in the early stages of fetal development, since infertile women have low endometrial glycogen levels. However, the molecular mechanisms underlying glycogen metabolism and trafficking at the fetal­maternal interface have not yet been characterized. Among the various factors acting at the fetal­maternal interface, we focused on adiponectin ­ an adipocyte-secreted cytokine involved in the control of carbohydrate and lipid homeostasis. Our results clearly demonstrated that adiponectin controls glycogen metabolism in EnSCs by (i) increasing glucose transporter 1 expression, (ii) inhibiting glucose catabolism via a decrease in lactate and ATP productions, (iii) increasing glycogen synthesis, (iv) promoting glycogen accumulation via phosphoinositide-3 kinase activation and (v) enhancing glycogen secretion. Furthermore, our results revealed that adiponectin significantly limits glycogen endocytosis by human villous trophoblasts. Lastly, we demonstrated that once glycogen has been endocytosed into placental cells, it is degraded into glucose molecules in lysosomes. Taken as a whole, the present results demonstrate that adiponectin exerts a dual role at the fetal­maternal interface by promoting glycogen synthesis in the endometrium and conversely reducing trophoblastic glycogen uptake. We conclude that adiponectin may be involved in feeding the conceptus during the first trimester of pregnancy by controlling glycogen metabolism in both the uterus and the placenta.

Catamenial pneumothorax revealing diaphragmatic endometriosis: a case report and revue of literature.

Catamenial pneumothorax (CP) is a rare entity of spontaneous, recurring pneumothorax in women. We aim to discuss the etiology, clinical course, and surgical treatment of a 42-year-old woman with CP. This patient had a right-sided spontaneous pneumothoraces occurred one week after menses. She had under-gone video-assisted thoracoscopic surgery (VATS) because of a persistent air leak under chest tube. VATS revealed multiple diaphragmatic fenestrations with an upper right nodule. Defects were removed and a large part of the diaphragm was resected. Pleural abrasion was then performed over the diaphragm. Diaphragmatic endometriosis was confirmed by microscopic examination. Medical treatment with GnRH agonists was prescribed, and after recovery, the patient has been symptoms free for 20 months.

Om.breast cancer in very young women aged 25 year-old or below in the center of Tunisia and review of the literature.

Breast cancer in very young women under 40 or 35 years attracted a widespread attention. Few studies have focused on women aged below 25 years. The aim of this study was to evaluate the situation of breast cancer in women ≤25 years in the center of Tunisia. Retrospective review from 1993 to 2013. Clinical, histopathological, therapeutic and outcome data were recorded. Cases were classified into different molecular subtypes based on the immunohistochemistry-based definitions. The series included 25 patients. The mean duration of symptoms was 7.5 months. The most common presenting symptom was a palpable mass. Four patients had at least one relative diagnosed with breast cancer. Mammography combined with ultrasound was suggestive of malignancy in 60 % of cases. Curative surgical treatment could be offered in 19 cases. The mean tumor size was 39 mm. Nodal metastases were detected in 9/18 cases. Twenty cases could be classified into: luminal A (5 cases), luminal B (6 cases), Her-2 (1 case), triple negative (6 cases) and unclassified (2 cases). Two women experienced locoregional recurrence and 6 had distant recurrence. Asynchronous contralateral breast cancer occurred in one case. The overall survival at 5 and 10 years was 85 and 75 % respectively. The survival was significantly lower in grade III tumors (p = 0.04) and triple negative tumors (p = 0.03). Breast cancer in women ≤25 years is uncommon. An adequate medical education of young women and physicians is necessary.

Impact of accreditation training for residents on sonographic quality in gynecologic emergencies.

OBJECTIVES: To assess the impact of an educational intervention based on an original accreditation training program on the quality of emergency sonography performed by obstetrics and gynecology (Ob/Gyn) residents. METHODS: We conducted a prospective before-after study on residents who performed bedside standardized sonographic examinations as first-line investigations in patients seen at our gynecologic emergency department. In both periods, the residents followed a 1-hour class taught by a board-certified Ob/Gyn sonography expert (opinion leader) and received a written standardized imaging protocol. An accreditation training process was implemented for the new residents at the beginning of the second period: 5 complete sonographic examinations were required for each resident, and facilitated feedback from the opinion leader was performed using a dedicated sonographic quality score. During both periods, all consecutive sonograms were collected and stored. The primary outcome was the sonographic quality score. A mixed model for repeated measures was used to compare scores in both periods from 20 consecutive sonographic examinations performed by 5 residents who were different in each period. RESULTS: The mixed model analysis showed an increase in quality scores in the post-accreditation training compared to the pre-accreditation training period (estimated coefficient ± SD, 4.13 ± 0.51; t = 8.16). The sonographic examination order also had a significant effect in both periods (estimated coefficient ± SD, 0.11 ± 0.03; t = 3.99). CONCLUSIONS: An accreditation training process including facilitated feedback from a local opinion leader improved the quality of sonographic examinations performed by Ob/Gyn residents in women presenting to a gynecologic emergency department.

[Clinicopathologic characteristics and prognosis factors of uterine sarcomas in central Tunisia]. / Caractéristiques clinicopathologiques et facteurs pronostiques des sarcomes utérins dans le centre tunisien.

To analyze the clinical and pathological features of uterine sarcomas treated at our referral medical center. The aim of the study is also to analyze their prognosis factors. We performed a retrospective analysis of 40 women with uterine sarcoma treated at the Obstetrics and Gynecology department - Sousse - Tunisia between 1997 and 2010. Tumor stage was assessed according to the FIGO 1988 classification. Patient's outcomes were recorded and analyzed using SPSS 18.0 program. Forty patients were included in the study. Leiomyosarcoma represents 65% of cases (n=26) and carcinosarcoma 20 % (n=8). Mean age at the time of diagnosis was 53 years (range: 35-82 years). The most common symptoms were vaginal bleeding and pelvic pain (respectively 72.5% and 45%). Mean interval time from onset of symptoms and pathological diagnosis of sarcoma was 16 weeks (range: 0 to 96 weeks). Definitive diagnosis of sarcoma was achieved after pathological analysis in 62.5%. Most common histological type was leiomyosarcoma in 65 % of cases. A total of 36 patients underwent total hysterectomy with bilateral salpingo-oophorectmy. In four cases pelvic lymphadenectomy was also performed. 75% (n=30) were in FIGO stage I. Eleven patients underwent external pelvic radiotherapy and chemotherapy was administrated in three cases. At the time of study, mean follow up was 30.9 months (range: 0 to 120 months). The 5-year global survival and free survival were 17.5% and 15%, respectively. In multivariate analysis tumor stage was found to be the strongest prognostic factor. Mean survival was 71 months in FIGO stage I, 13.4 months in FIGO stage II, 10 months in FIGO stage III and 4,8 months in FIGO stage IV(p<0,001). Uterine sarcomas are rare. Leiomyosarcoma is the most common histological type. Pathological diagnosis is usually achieved after radical surgery. Prognosis is poor and is correlated with tumor stage.

Sublingual misoprostol for first trimester termination of pregnancy.

OBJECTIVES: To compare blood loss, efficiency, and acceptability of repeated doses of sublingual misoprostol with the standard Tunisian regimen of mifepristone-misoprostol for first trimester medical abortion. METHODS: A prospective randomized trial of 252 healthy pregnant women requesting medical abortion in the first trimester (up to 56 days). Participants were randomized to receive 200mg of oral mifepristone followed by 400 microg of oral misoprostol (group 1) or 800 microg of sublingual misoprostol repeated every 4 hours for up to a maximum of 3 doses (group 2). Primary outcome was blood loss assessed by decrease in hematocrit. RESULTS: Mean decrease in hematocrit at follow-up was significantly greater in group 1 than in group 2 (3.65%+/-1.18% vs 2.69%+/-1.89%, respectively; P=0.02). There was no difference in efficiency rates between groups 1 and 2 (94.5% vs 92.1%; P=0.7). Comparable proportions of women experiencing at least one adverse effect after misoprostol administration were reported in groups 1 and 2 (81.7% vs 79.4%; P=0.75). CONCLUSION: Compared with the most widely used regimen in Tunisia (mifepristone-misoprostol), sublingual misoprostol alone induces less blood loss (although not clinically significant); it is less expensive and offers reduced interval time to expulsion.