Publication
Bourdon M, Santulli P, Maignien C, Gayet V, PocateCheriet K, Marcellin L, Chapron C
• 04/2018
BACKGROUND: Controlled ovarian stimulation in assisted reproduction technology (ART) may alters endometrial receptivity by an advancement of endometrial development. Recently, technical improvements in vitrification make deferred frozen-thawed embryo transfer (Def-ET) a feasible alternative to fresh embryo transfer (ET). In endometriosis-related infertility the eutopic endometrium is abnormal and its functional alterations are seen as likely to alter the quality of endometrial receptivity. One question in the endometriosis ART-management is to know whether Def-ET could restore optimal receptivity in endometriosis-affected women leading to increase in pregnancy rates. OBJECTIVE: To compare cumulative ART-outcomes between fresh versus Def-ET in endometriosis-infertile women. MATERIALS AND METHODS: This matched cohort study compared def-ET strategy to fresh ET strategy between 01/10/2012 and 31/12/2014. One hundred and thirty-five endometriosis-affected women with a scheduled def-ET cycle and 424 endometriosis-affected women with a scheduled fresh ET cycle were eligible for matching. Matching criteria were: age, number of prior ART cycles, and endometriosis phenotype. Statistical analyses were conducted using univariable and multivariable logistic regression models. RESULTS: 135 in the fresh ET group and 135 in the def-ET group were included in the analysis. The cumulative clinical pregnancy rate was significantly increased in the def-ET group compared to the fresh ET group [58 (43%) vs. 40 (29.6%), p = 0.047]. The cumulative ongoing pregnancy rate was 34.8% (n = 47) and 17.8% (n = 24) respectively in the Def-ET and the fresh-ET groups (p = 0.005). After multivariable conditional logistic regression analysis, Def-ET was associated with a significant increase in the cumulative ongoing pregnancy rate as compared to fresh ET (OR = 1.76, CI95% 1.06-2.92, p = 0.028). CONCLUSION: Def-ET in endometriosis-affected women was associated with significantly higher cumulative ongoing pregnancy rates. Our preliminary results suggest that Def-ET for endometriosis-affected women is an attractive option that could increase their ART success rates. Future studies, with a randomized design, should be conducted to further confirm those results.
Publication
ChanavazLacheray I, Darai E, Descamps P, Agostini A, Poilblanc M, Rousset P, Bolze PA, Panel P, Collinet P, Hebert T, Graesslin O, Martigny H, Brun JL, Dechaud H, Mezan De Malartic C, Piechon L, Wattiez A, Chapron C, Golfier F
• 03/2018
OBJECTIVES: The Collège national des gynécologues obstétriciens français (CNGOF), in agreement with the Société de chirurgie gynécologique et pelvienne (SCGP), has set up a commission in 2017 to define endometriosis expert centres, with the aim of optimizing endometriosis care in France. METHODS: The committee included members from university and general hospitals as well as private facilities, representing medical, surgical and radiological aspects of endometriosis care. Opinion of endometriosis patients' associations was obtained prior to writing this work. The final text was presented and unanimously validated by the members of the CNGOF Board of Directors at its meeting of October 13, 2017. RESULTS: Based on analysis of current management of endometriosis and the last ten years opportunities in France, the committee has been able to define the contours of endometriosis expert centres. The objectives, production specifications, mode of operation, missions and funding for these centres were described. The following missions have been specifically defined: territorial organization, global and referral care, communication and teaching as well as research and evaluation. CONCLUSION: Because of its daily impact for women and its economic burden in France, endometriosis justifies launching of expert centres throughout the country with formal accreditation by health authorities, ideally as part of the National Health Plan.
Publication
Borghese B, Santulli P, Marcellin L, Chapron C
• 03/2018
Endometriosis and adenomyosis are histologically defined. The frequency of endometriosis cannot be precisely estimated in the general population. Endometriosis is considered a disease when it causes pain and/or infertility. Endometriosis is a heterogeneous disease with three well-recognized subtypes that are often associated with each other: superficial endometriosis (SUP), ovarian endometrioma (OMA), and deep infiltrating endometriosis (DIE). DIE is frequently multifocal and mainly affects the following structures: the uterosacral ligaments, the posterior vaginal cul-de-sac, the bladder, the ureters, and the digestive tract (rectum, recto-sigmoid junction, appendix). The role of menstrual reflux in the pathophysiology of endometriosis is major and explains the asymmetric distribution of lesions, which predominate in the posterior compartment of the pelvis and on the left (NP3). All factors favoring menstrual reflux increase the risk of endometriosis (early menarche, short cycles, AUB, etc.). Inflammation and biosteroid hormones synthesis are the main mechanisms favoring the implantation and the growth of the lesions. Pain associated with endometriosis can be explained by nociception, hyperalgia, and central sensitization, associated to varying degrees in a single patient. Typology of pain (dysmenorrhea, deep dyspareunia, digestive or urinary symptoms) is correlated with the location of the lesions. Infertility associated with endometriosis can be explained by several non-exclusive mechanisms: a pelvic factor (inflammation), disrupting natural fertilization; an ovarian factor, related to oocyte quality and/or quantity; a uterine factor disrupting implantation. The pelvic factor can be fixed by surgical excision of the lesions that improves the chance of natural conception (NP2). The uterine factor can be corrected by an ovulation-blocking treatment that improves the chances of getting pregnant by in vitro fertilization (NP2). The impact of endometrioma exeresis on the ovarian reserve (NP2) should be considered when a surgery is scheduled. Endometriosis is a multifactorial disease, resulting from combined action of genetic and environmental factors. The risk of developing endometriosis for a first-degree relative is five times higher than in the general population (NP2). Identification of genetic variants involved in the disease has no implication for clinical practice for the moment. The role of environmental factors, particularly endocrine disrupters, is plausible but not demonstrated. Literature review does not support the progression of endometriosis over time, either in terms of the volume or the number of the lesions (NP3). The risk of acute digestive occlusion or functional loss of a kidney in patients followed for endometriosis seems exceptional. These complications were revealing the disease in the majority of cases. IVF does not increase the intensity of pain associated with endometriosis (NP2). There is few data on the influence of pregnancy on the lesions, except the possibility of a decidualization of the lesions that may give them a suspicious aspect on imaging. The impact of endometriosis on pregnancy is debated. There is an epidemiological association between endometriosis and rare subtypes of ovarian cancer (endometrioid and clear cell carcinomas) (NP2). However, the relative risk is moderate (around 1.3) (NP2) and the causal relationship between endometriosis and ovarian cancer is not demonstrated so far. Considering the low incidence of endometriosis-associated ovarian cancer, there is no argument to propose a screening or a risk reducing strategy for the patients.
Publication
Santulli P, Collinet P, Fritel X, Canis M, d'Argent EM, Chauffour C, Cohen J, Pouly JL, Boujenah J, Poncelet C, Decanter C, Borghese B, Chapron C
• 03/2018
The management of endometriosis related infertility requires a global approach. In this context, the prescription of an anti-gonadotropic hormonal treatment does not increase the rate of non-ART (assisted reproductive technologies) pregnancies and it is not recommended. In case of endometriosis related infertility, the results of IVF management in terms of pregnancy and birth rates are not negatively affected by the existence of endometriosis. Controlled ovarian stimulation during IVF does not increase the risk of endometriosis associated symptoms worsening, nor accelerate the intrinsic progression of endometriosis and does not increase the rate of recurrence. However, in the context of IVF management for women with endometriosis, pre-treatment with GnRH agonist or with oestrogen/progestin contraception improve IVF outcomes. There is currently no evidence of a positive or negative effect of endometriosis surgery on IVF outcomes. Information on the possibilities of preserving fertility should be considered, especially before surgery.
Publication
Ferreux L, Bourdon M, Sallem A, Santulli P, BarraudLange V, Le Foll N, Maignien C, Chapron C, de Ziegler D, Wolf JP, PocateCheriet K
• 03/2018
STUDY QUESTION: The aim of this study was to evaluate the live birth rate (LBR) after frozen-thawed Day 5 (D5) and Day 6 (D6) blastocyst transfers. SUMMARY ANSWER: LBR following frozen-thawed blastocyst transfer is significantly lower with D6 than with D5 blastocyst regardless of embryo quality. WHAT IS KNOWN ALREADY: During fresh embryo transfer cycles, pregnancy rates (PR) are significantly higher when transferring blastocysts expanded on D5 compared with slow developing blastocysts (D6). In programmed thawed blastocyst transfer (TBT) cycles, the same clinical outcomes should be expected when transferring D5 or D6 blastocysts because of endometrial/embryonic synchronization due to hormonal priming of endometrial receptivity. However, the impact of delayed blastocyst expansion at D6 on clinical outcomes remains unclear. Some reports have shown higher PRs after D5 TBT compared with those of D6, while others have shown equivalent TBT outcomes after D5 and D6 cryopreserved blastocysts transfers. STUDY, DESIGN, SIZE, DURATION: This retrospective cohort follow-up study included 1347 single autologous frozen-thawed blastocyst transfers performed between January 2012 and December 2015 at a tertiary care university hospital. PARTICIPANTS/MATERIALS, SETTING, METHODS: All of the patients scheduled for TBT were allocated to two groups according to the day of blastocyst expansion: on D5 (n = 994) or on D6 (n = 353). The primary outcome was LBR per embryo transfer in the first blastocyst thawing cycle. Secondary outcomes were clinical pregnancy rate (cPR), early miscarriage rate and neonatal outcomes following TBT for the two groups. Statistical analyses were conducted using univariate and multivariate logistic regression model. MAIN RESULTS AND THE ROLE OF CHANCE: The LBR was significantly increased in the D5 group compared to the D6 group [294/994 (29.6%) versus 60/353 (17.0%); P < 0.001]. The cPR was also higher when blastocysts were vitrified on D5 compared with those vitrified on D6 [429/994 (43.2%) versus 95/353 (26.9%); P < 0.001]. No significant differences were found between groups in terms of early miscarriage rate (P = 0.862). More good-quality embryos (defined as an B3-B4 or B5 embryo ≥BB according to the grading scale proposed by Gardner) were transferred in the D5 group than in the D6 group [807 (81.2%) versus 214 (60.6%); P < 0.001]. However, a comparison of TBT cycles with equal embryo quality (good versus low) also supported the superiority of D5 blastocysts. Concerning neonatal outcomes, the D5 group infants had a lower mean birth weight compared to those of the D6 group (P = 0.001). In addition, a significantly shorter gestational age at birth is reported in the D5 blastocyst group as compared to the D6 group (P = 0.004). After multivariate logistic regression taking into account potential confounders such as the women's age, number of previous IVF/ICSI procedures, the day of the blastocyst vitrification (D5 or D6) and embryo quality, blastocyst expansion at D6 was independently associated with a significant decrease in LBR compared to D5 expanded-blastocysts (OR 0.52; 95% CI 0.38-0.72; P < 0.001). LIMITATIONS, REASONS FOR CAUTION: The poor predictive value of the morphological approach in embryo selection could constitute a limitation in this study. However, blastocyst quality was evaluated similarly in both groups. WIDER IMPLICATIONS OF THE FINDINGS: The LBR following frozen-thawed blastocyst transfer was significantly lower with D6 than with D5 blastocysts, regardless of their quality. These results could affect cryopreservation procedures as they suggest that the use of D5-expanded blastocysts for TBT may be preferred in order to shorten the time of conceiving. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. None of the authors have any competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.
Publication
Sallem A, Santulli P, BarraudLange V, Le Foll N, Ferreux L, Maignien C, Bourdon M, Chapron C, de Ziegler D, Wolf JP, PocateCheriet K
• 02/2018
PURPOSE: The aims of this study were to investigate the possible benefits of extending the culture of poor-quality day-2 embryos (PQE) versus good-quality embryos (GQE) and to identify factors associated with pregnancy and live birth when transferring frozen-thawed blastocysts originating from GQE and PQE. METHODS: This is a retrospective cohort follow-up study performed between November 2012 and February 2015 at the IVF Laboratory Unit of Cochin University Hospital (Paris, France) including 3108 day-2 supernumerary embryos resulting from 1237 IVF/ICSI cycles. RESULTS: Total blastulation rate was 67.2% from GQE and 48.7% from PQE. Percentage of good-quality blastocysts was 60.7 and 47.9% respectively including 14.7 and 7.3% top-quality blastocysts. A total of 150 blastocysts originating from GQE and 729 from PQE were frozen, and then, 37 and 164 were thawed and transferred respectively resulting in 19 (51.4%) and 61 (37.9%) clinical pregnancies with 13 (35.1%) deliveries from GQE and 32 (19.9%) from PQE (p = 0.046) without any difference in neonatal outcomes. Quality of blastocysts that resulted in live birth was similar in the two groups. Women < 35 years old and day-5 blastocyst expansion were predictive of pregnancy and live birth. CONCLUSIONS: (i) PQE are able to reach the blastocyst stage, to implant, and to give healthy babies and (ii) women age and day of blastocyst expansion are predictive of pregnancy and live birth.
Publication
Vannuccini S, Tosti C, Carmona F, Huang SJ, Chapron C, Guo SW, Petraglia F
• 11/2017
Adenomyosis is a uterine disorder becoming more commonly diagnosed in women of reproductive age because of diagnostic imaging advancements. The new epidemiological scenario and the clinical evidence of pelvic pain, abnormal uterine bleeding and infertility are changing the classic perspective of adenomyosis as a premenopausal disease. In the last decade, the evaluation of multiple molecular mediators has improved our knowledge of pathogenic mechanisms of adenomyosis, supporting that this is an independent disease from endometriosis. Although they share common genetic mutations and epigenetic changes in sex steroid hormone receptors and similar inflammatory mediators, an increasing number of recent studies have shown pathogenic pathways specific for adenomyosis. A PubMed search up to October 2016 summarizes the key mediators of pain, abnormal uterine bleeding and infertility in adenomyosis, including sex steroid hormone receptors, inflammatory molecules, extracellular matrix enzymes, growth factors and neuroangiogenic factors.
Publication
Alexandre FR, Badaroux E, Bilello JP, Bot S, Bouisset T, Brandt G, Cappelle S, Chapron C, Chaves D, Convard T, Counor C, Da Costa D, Dukhan D, Gay M, Gosselin G, Griffon JF, Gupta K, HernandezSantiago B, La Colla M, Lioure MP, Milhau J, Paparin JL, Peyronnet J, Parsy C, Pierra Rouvière C, Rahali H, Rahali R, Salanson A, Seifer M, Serra I, Standring D, Surleraux D, Dousson CB
• 09/2017
Herein we describe the discovery of IDX21437 35b, a novel RPd-aminoacid-based phosphoramidate prodrug of 2'-α-chloro-2'-β-C-methyluridine monophosphate. Its corresponding triphosphate 6 is a potent inhibitor of the HCV NS5B RNA-dependent RNA polymerase (RdRp). Despite showing very weak activity in the in vitro Huh-7 cell based HCV replicon assay, 35b demonstrated high levels of active triphosphate 6 in mouse liver and human hepatocytes. A biochemical study revealed that the metabolism of 35b was mainly attributed to carboxyesterase 1 (CES1), an enzyme which is underexpressed in HCV Huh-7-derived replicon cells. Furthermore, due to its metabolic activation, 35b was efficiently processed in liver cells compared to other cell types, including human cardiomyocytes. The selected RP diastereoisomeric configuration of 35b was assigned by X-ray structural determination. 35b is currently in Phase II clinical trials for the treatment of HCV infection.
Publication
Bourdon M, Santulli P, de Ziegler D, Gayet V, Maignien C, Marcellin L, Chapron C
• 09/2017
OBJECTIVE: The aim of this study was to assess the progression of pain symptoms during assisted reproductive technology (ART) cycles following administration of GnRH agonist (GnRHa) versus human chorionic gonadotrophin (hCG) triggering. DESIGN: Observational cohort study. SETTING: A tertiary care university hospital in France. POPULATION: Patients who underwent ART programs. METHODS: Between January 01, 2014, and June 31, 2014, 122 cycles were allocated to 2 groups: GnRHa triggering with a scheduled differed embryo transfer (n = 57) or hCG triggering with a fresh embryo transfer (n = 70). Pelvic pain scores were evaluated using a visual analog scale (VAS) with regard to dysmenorrhea, dyspareunia, noncyclic pelvic pain, gastrointestinal, and lower urinary tract pain. The total VAS score was defined as the sum of the scores for the various symptoms. Evaluations were carried out twice: during the synchronization treatment prior to ovarian stimulation and during a final evaluation 3 weeks postretrieval. The data were processed using univariate and multivariate logistic regression models. MAIN OUTCOME MEASURES: Trends for total VAS change (ie, final VAS score - synchronization VAS score). RESULTS: For both groups, pain increased during the ART procedure. Trends for the total VAS change revealed that the increase in pain was significantly less in the -'GnRHa triggering-' group compared to the -'hCG triggering-' group (3.77 ± 7.73 and 6.50 ± 6.57, P < .05, respectively). Multivariate logistic regression indicated that GnRHa triggering was associated with less of an increase in pain compared to hCG triggering (odds ratio = 0.31, 95% confidence interval 0.13-0.71, P < .05). CONCLUSION: Compared to hCG, GnRHa triggering limits pain symptom progression in the period immediately after ART.
Publication
Riccio LGC, Baracat EC, Chapron C, Batteux F, Abrão MS
• 09/2017
The physiopathology of endometriosis is not completely understood and its progression is associated with a local and systemic inflammatory reaction. It is important to clarify the potential role of the immune system to better understand its implication in the pathogenesis of endometriosis, which includes the study of the role of B cells and antibodies. The aim of this study was to review the literature about the role of B lymphocytes in endometriosis. A search for -'endometriosis-', -'B cells-' and -'B lymphocytes-' in databases resulted in 140 citations; after applying inclusion and exclusion criteria, a total of 22 studies were assessed. The analyzed samples in the studies varied and different markers and techniques were used by the authors to evaluate the direct or indirect role of B lymphocytes in endometriosis. Most studies demonstrated increased number and/or activation of B cells while seven studies found no difference and two studies showed decreased number of B cells. Increased B lymphocytes and excessive production of autoantibodies in endometriosis have been described in the literature, but their role in the development of the disease is not well understood. Moreover, the association of these factors with clinical symptoms, location and severity of the disease has not been investigated. Further studies are necessary to clarify the role of B cells in the development of endometriosis and propose new therapeutic strategies such as the use of drugs that target these cells.
