Publication
Moffat R, Pirtea P, Gayet V, Wolf JP, Chapron C, de Ziegler D
• 12/2014
Ovarian stimulation improves assisted reproductive technology outcome by increasing the number of oocytes available for insemination and in-vitro handling. A recent Duplex protocol features a dual stimulation, with the second stimulation started immediately after the first oocyte retrieval. Remarkably, the Duplex protocol is unexpectadly well tolerated by women and provides twice as many oocytes and embryos as a regular antagonist protocol in less than 30 days.
Publication
Lambert S, Santulli P, Chouzenoux S, Marcellin L, Borghese B, de Ziegler D, Batteux F, Chapron C
• 11/2014
OBJECTIVES: To assess interleukin-1β (IL-1β) and its inhibitory soluble interleukin-1 receptor type II (IL-1sRII) levels into the serum of patients with various forms of endometriosis and normal women, and investigate the correlation with disease activity. PATIENTS AND METHODS: In this prospective laboratory study (2005-2010), 510 women with histologically proven endometriosis and 93 endometriosis-free controls have been enrolled. Laparoscopic complete exploration of the abdominopelvic cavity and blood samples have been performed in each patient. For each serum, IL-1β and IL-1sRII have been evaluated using Elisa. RESULTS: IL-1β and IL-1sRII have been respectively detectable in 64% and 54.6% of serum samples from all 603 women studied. IL-1β was higher in women with deep infiltrating endometriosis (DIE) (mean 10.0pg/mL [0.005-416.2]) than in endometriosis-free women (mean 0.5pg/mL [0.01-1.7], P<0.01) or in women with superficial endometriosis (SUP) (mean 0.6pg/mL [0.1-2.9], P<0.01). Also, IL-1sRII was higher in DIE (mean 236.7pg/mL [0.9-6975]) than in the witness group (mean 85.0pg/mL [1-235.2], P<0.05) or in SUP (mean 85.1pg/mL [0.6-302], P<0.01). CONCLUSION: This study highlights both a marked significant increase in serum IL-1β and IL-1sRII levels in DIE compared to SUP and normal women and suggests that a defect in the control of IL-1 can impact the pathophysiology of endometriosis.
Publication
Streuli I, Dubuisson J, Santulli P, de Ziegler D, Batteux F, Chapron C
• 11/2014
INTRODUCTION: Adenomyosis, characterized by the infiltration of the myometrium by ectopic endometrial islets, is a common condition that causes dysmenorrhea, abnormal uterine bleeding and infertility. Different treatment options exist, including medical and surgical treatments. The most commonly used medications are NSAIDs, progestogens and GnRH agonists (GnRHas). AREAS COVERED: We conducted a literature search for in vitro and animal studies, randomized and non-randomized studies, systematic reviews and ongoing trials registered on ClinicalTrials.gov. There are almost no well-conducted randomized controlled trials on the pharmacological treatment of adenomyosis and the information collected from published studies is insufficient. Several therapeutic targets have been identified through animal and in vitro studies, and it is hoped that they will lead to further clinical studies on new compounds and treatment targets in this heterogeneous disease. EXPERT OPINION: Hysterectomy is very effective at treating women with symptomatic adenomyosis who have completed their wish of pregnancy. For women with a future desire of pregnancy medical treatments remain the best options. Progestogens and GnRHas are the most frequently used long-term treatments for abnormal uterine bleeding and pain symptoms. In assisted reproductive techniques long agonist stimulation protocols and pretreatment with GnRHas for differed embryo transfer seem to improve pregnancy rates.
Publication
Sibiude J, Santulli P, Marcellin L, Borghese B, Dousset B, Chapron C
• 10/2014
OBJECTIVE: To assess whether a history of surgery for endometriosis could be considered as a marker for disease severity. METHODS: This cross-sectional study included 780 women with histologically proven endometriosis who underwent surgery. We compared 309 patients with a history of surgery for endometriosis (study group) with 471 patients who did not receive prior surgical intervention (control group). Multivariate logistic regression was performed to assess the risk of deeply infiltrating endometriosis (defined by invasion of the muscularis by endometriotic tissue). RESULTS: Patients with a history of surgery displayed an increased prevalence of deeply infiltrating endometriosis (242 patients [78.3%] compared with 210 patients [44.6%], respectively; P<.001). Moreover, the study group showed significantly higher stage, mean total (P<.001), and mean adhesions (P<.001) scores based on the American Society for Reproductive Medicine classification system. Furthermore, history of previous surgery remained independently associated with the presence of deeply infiltrating endometriosis (compared with superficial endometriosis and ovarian endometrioma grouped together) in multivariate regression analysis, which adjusted for preoperative pain scores, age, body mass index, smoking habits, oral contraceptive pill use, infertility, and parity (adjusted odds ratio 2.96, 95% confidence interval 1.99-4.39; P<.001). The number of previous surgeries for endometriosis correlated significantly with lesion severity. Among women presenting with deeply infiltrating endometriosis (n=452), surgical history was significantly associated with a higher mean number of deeply infiltrating endometriosis lesions (3.1 ± 1.9 compared with 2.6 ± 1.8; P=.001) and with increased severity of deeply infiltrating endometriosis lesions, especially in the case of intestinal lesions (159 patients [66.0%] compared with 77 patients [37%], P<.001). CONCLUSION: A history of surgery for endometriosis correlates with the presence and severity of deeply infiltrating endometriosis, which underlines the necessity of a thorough preoperative assessment and a complete information of these patients before undertaking subsequent surgeries. LEVEL OF EVIDENCE: : II.
Publication
Governini L, Carrarelli P, Rocha AL, Leo VD, Luddi A, Arcuri F, Piomboni P, Chapron C, Bilezikjian LM, Petraglia F
• 10/2014
The present study investigated expression and protein localization of FOXL2 messenger RNA (mRNA) in endometrium of healthy women and in patients with endometriosis during endometrial cycle. In endometriotic lesions, FOXL2 mRNA and protein were evaluated and a possible correlation with activin A mRNA expression changes was also studied. Endometrium was collected from healthy women (n = 52) and from women with endometriosis (n = 31) by hysteroscopy; endometriotic tissues were collected by laparoscopy (n = 38). FOXL2 gene expression analysis in endometrium of healthy women showed a significant expression and no significant changes in mRNA levels between proliferative and secretory phases; a similar pattern was observed in endometrium of patients with endometriosis. Immunohistochemical evaluation showed that FOXL2 protein localized in stromal and glandular cells and colocalized with SUMO-1. FOXL2 mRNA expression was 3-fold higher in endometriosis than in healthy endometrium (P < .01) and a positive correlation between FOXL2 and activin A mRNA was found (P < .05) in endometriosis. In conclusion, FOXL2 mRNA expression and its protein localization do not change during endometrial cycle in eutopic endometrium from healthy individuals or patients with endometriosis; the hyperexpression of FOXL2 in endometriotic lesions suggests an involvement of this transcriptional regulator, probably associated with activin A expression and related to the pathogenesis of endometriosis.
Publication
Borghese B, Chartier M, Souza C, Santulli P, LafayPillet MC, de Ziegler D, Chapron C
• 08/2014
OBJECTIVES: The identification of epidemiological factors increasing the risk of endometriosis could shorten the time to diagnosis. Specific blood groups may be more common in patients with endometriosis. STUDY DESIGN: We designed a cross-sectional study of 633 Caucasian women living in the same geographic area. Study group included 311 patients with histologically proven endometriosis. Control group included 322 patients without endometriosis as checked during surgery. Frequencies of ABO and Rhesus groups in the study and control groups were compared using univariate and multivariate analyses. RESULTS: We observed a higher proportion of Rh-negative women in the study group, as compared to healthy controls. Multivariate analysis showed that Rh-negative women are twice as likely to develop endometriosis (aOR = 1.90; 95% CI: 1.20-2.90). There was no significant difference in ABO group distribution between patients and controls. There was no difference when taking into account either the clinical forms (superficial endometriosis, endometrioma, and deep infiltration endometriosis) or the rAFS stages. CONCLUSION: Rh-negative women are twice as likely to develop endometriosis. Chromosome 1p, which contains the genes coding for the Rhesus, could also harbor endometriosis susceptibility genes.
Publication
Lafay Pillet MC, Huchon C, Santulli P, Borghese B, Chapron C, Fauconnier A
• 08/2014
STUDY QUESTION: Is it possible to detect associated deep infiltrating endometriosis (DIE) before surgery for patients operated on for endometriomas using a preoperative clinical symptoms questionnaire? SUMMARY ANSWER: A diagnostic score of DIE associated with endometriomas using four clinical symptoms defined a high-risk group where the probability of DIE was 88% and a low-risk group with a 10% probability of DIE. WHAT IS KNOWN ALREADY: Many clinical symptoms are already known to be associated with DIE but they have not yet been used to build a clinical prediction model. STUDY DESIGN, SIZE, DURATION: We built a diagnostic score of DIE based on a case control study of 326 consecutive patients operated on for an endometrioma between January 2005 and October 2011: 164 had associated DIE (DIE+) and 162 had no DIE (DIE-). We derived the score on a training sample obtained from a random selection of 2/3 of the population (211 patients, 101 DIE+, 110 DIE-), and validated the results on the remaining third (115 patients, 63 DIE+, 52 DIE-). The gold standard for the diagnosis of DIE was based on surgical exploration and histological diagnosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were consecutive patients aged 18-42 years who underwent surgery for an endometrioma with histological confirmation and complete treatment of their endometriotic lesions: data for these women were extracted from a prospective database including a standardized preoperative questionnaire. On the training dataset, variables associated with DIE in a univariate analysis were introduced in a multiple logistic regression and selected by a backward stepwise procedure and a Jackknife procedure. A diagnostic score of DIE was built with the scaled/rounded coefficients of the multiple regression. Two cut-off values delimitated a high and a low risk group, and their diagnostic accuracy was tested on the validation dataset. MAIN RESULTS AND THE ROLE OF CHANCE: Four variables were independently associated with DIE: visual analogue scale of gastro-intestinal symptoms ≥5 or of deep dyspareunia >5 (adjusted diagnostic odds ratio (aDOR) = 6.0, 95% confidence interval (CI) [2.9-12.1]), duration of pain greater than 24 months (aDOR = 3.8, 95% CI [1.9-7.7]), severe dysmenorrhoea (defined as the prescription of the oral contraceptive pill for the treatment of a primary dysmenorrhoea or the worsening of a secondary dysmenorrhoea) (aDOR = 3.8, 95% CI [1.9-7.6]) and primary or secondary infertility (aDOR = 2.5, 95% CI [1.2-4.9]). The sum of these variables weighted by their rounded/scaled coefficients constituted the score ranging from 0 to 53. A score <13 defined a low-risk group where the probability of DIE was 10% (95% CI [7-15] with a sensitivity of 95% (95% CI [89-98]) and a negative likelihood ratio of 0.1 (95% CI [0.0-0.3]). A score ≥35 defined a high-risk group where the probability of DIE was 88% (95% CI [83-92%]), with a specificity of 94% (95% CI [87-97]), and a positive likelihood ratio of 8.1 (95% CI [3.9-17.0]). The performance of the score was confirmed on the validation dataset with 11% of DIE+ patients having a score <13 (sensibility: 95%) and 90% of DIE+ patients having a score ≥35 (specificity: 94%). LIMITATION, REASONS FOR CAUTION: This study was performed in a department specialized in DIE management. Score accuracy could be different in less specialized centres. WIDER IMPLICATIONS OF THE FINDINGS: This score could have a major clinical impact on the time of diagnosis, the management of DIE and could reduce the cost of investigations by helping to identify high-risk patients, while preserving the quality of care. STUDY FUNDING/COMPETING INTERESTS: The authors have no competing interests to declare. No grant supported the study.
Publication
Bilello JP, Lallos LB, McCarville JF, La Colla M, Serra I, Chapron C, Gillum JM, Pierra C, Standring DN, Seifer M
• 08/2014
The hepatitis C virus (HCV) nonstructural 5A (NS5A) protein is a clinically validated target for drugs designed to treat chronic HCV infection. This study evaluated the in vitro activity, selectivity, and resistance profile of a novel anti-HCV compound, samatasvir (IDX719), alone and in combination with other antiviral agents. Samatasvir was effective and selective against infectious HCV and replicons, with 50% effective concentrations (EC50s) falling within a tight range of 2 to 24 pM in genotype 1 through 5 replicons and with a 10-fold EC50 shift in the presence of 40% human serum in the genotype 1b replicon. The EC90/EC50 ratio was low (2.6). A 50% cytotoxic concentration (CC50) of >100 μM provided a selectivity index of >5 × 10(7). Resistance selection experiments (with genotype 1a replicons) and testing against replicons bearing site-directed mutations (with genotype 1a and 1b replicons) identified NS5A amino acids 28, 30, 31, 32, and 93 as potential resistance loci, suggesting that samatasvir affects NS5A function. Samatasvir demonstrated an overall additive effect when combined with interferon alfa (IFN-α), ribavirin, representative HCV protease, and nonnucleoside polymerase inhibitors or the nucleotide prodrug IDX184. Samatasvir retained full activity in the presence of HIV and hepatitis B virus (HBV) antivirals and was not cross-resistant with HCV protease, nucleotide, and nonnucleoside polymerase inhibitor classes. Thus, samatasvir is a selective low-picomolar inhibitor of HCV replication in vitro and is a promising candidate for future combination therapies with other direct-acting antiviral drugs in HCV-infected patients.
Publication
Chapron C, Glen R, La Colla M, Mayes BA, McCarville JF, Moore S, Moussa A, Sarkar R, Seifer M, Serra I, Stewart A
• 06/2014
The synthesis of 2'-O,4'-C-methylene-bridged bicyclic guanine ribonucleosides bearing 2'-C-methyl or 5'-C-methyl modifications is described. Key to the successful installation of the methyl functionality in both cases was the use of a one-pot oxidation-Grignard procedure to avoid formation of the respective unreactive hydrates prior to alkylation. The 2'-C-methyl- and 5'-C-methyl-modified bicyclic guanosines were evaluated, along with the known uracil-, cytosine-, adenine-, guanine-LNA and guanine-ENA nucleosides, as potential antiviral agents and found to be inactive in the hepatitis C virus (HCV) cell-based replicon assay. Examination of the corresponding nucleoside triphosphates, however, against the purified HCV NS5B polymerase indicated that LNA-G and 2'-C-methyl-LNA-G are potent inhibitors of both 1b wild type and S282T mutant enzymes in vitro. Activity was further demonstrated for the LNA-G-triphosphate against HCV NS5B polymerase genotypes 1a, 2a, 3a and 4a. A phosphorylation by-pass prodrug strategy may be required to promote anti-HCV activity in the replicon assay.
Publication
Leconte M, Chouzenoux S, Nicco C, Chéreau C, Arkwright S, Santulli P, Weill B, Chapron C, Dousset B, Batteux F
• 06/2014
Immunological and angiogenetic factors enhance the implantation of endometrial cells in the peritoneal cavity. The aim of this work was to determine the role of the CXCL12-CXCR4 axis in the attraction and the peritoneal implantation of endometriotic stromal cells in deep infiltrating endometriosis (DIE). Biopsies of DIE nodules were obtained from 14 patients undergoing surgical treatment for DIE with low rectal involvement and from 12 patients without macroscopic endometriosis undergoing laparoscopy. CXCR4 expression was evaluated by Western blot analysis and flow cytometry in eutopic endometrial cells and DIE stromal cells in primary cultures derived from the biopsies. CXCL12-induced migration of DIE eutopic endometrial stromal cells was evaluated by transwell migration. CXCL12 was assayed in peritoneal fluids by ELISA. CXCR4 expression was higher in eutopic endometrial stromal cells than in control endometrial cells (p<0.05) and in DIE stromal cells (p<0.05). Eutopic endometrial stromal cells were more attracted by CXCL12 than control cells (p<0.01). CXCL12 was higher in DIE peritoneal fluids than in controls (p<0.05). CXCR4 was down-regulated in deep infiltrating endometriotic stromal cells. The CXCL12-CXCR4 axis plays a role in the attraction of eutopic endometrial cells into the peritoneal cavity, and the down-regulation of CXCR4 in resident endometriotic cells could cause their arrest in situ.
